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Sun X, Guo Y, Zheng X, Bai Y, Lu Y, Yang X, Cai Z, Xu E, He Y, Heng BC, Xu M, Deng X, Zhang X. Optimizing the Electrical Microenvironment Provided by 3D Micropillar Topography on a Piezoelectric BaTiO 3 Substrate to Enhance Osseointegration. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2414161. [PMID: 39564749 DOI: 10.1002/adma.202414161] [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: 09/19/2024] [Revised: 11/02/2024] [Indexed: 11/21/2024]
Abstract
The electrical properties of bone implant scaffolds are a pivotal factor in regulating cellular behavior and promoting osteogenesis. The previous study shows that built-in electric fields established between electropositive nanofilms and electronegative bone defect walls are beneficial for promoting bone defect healing. Considering that the physiological electrical microenvironment is spatially distributed in 3D, it is imperative to establish a 3D spatial charged microenvironment on bone scaffolds to optimize the efficacy of osseointegration. Nevertheless, this still poses a formidable challenge. Here, a bone repair strategy that utilizes micro-scale 3D topography is developed on a piezoelectric BaTiO3 (BTO) substrate to provide 3D spatial electrical stimulation. The BTO micropillar arrays, especially with a height of 50 µm and positive-charge distribution (50 µm positive), promote the spreading, cytoskeletal reorganization, focal adhesion maturation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). They enhanced the clustering of mechanosensing integrin α5 in BMSCs. The biomimetic 3D spatial electrical microenvironment accelerated bone repair and osseointegration in a rat femoral diaphysis defect repair model. The study thus reveals that implants with a 3D spatial electrical microenvironment can significantly enhance osseointegration, thereby providing a new strategy to optimize the performance of electroactive biomaterials for tissue regenerative therapies.
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Affiliation(s)
- Xiaowen Sun
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Yaru Guo
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Xiaona Zheng
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Yunyang Bai
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Yixuan Lu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Xue Yang
- First Clinical Division, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Ziming Cai
- School of Materials Science and Physics, China University of Mining and Technology, Xuzhou, 221116, P. R. China
| | - Erxiang Xu
- State Key Lab of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Ying He
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Boon Chin Heng
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Mingming Xu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Xuliang Deng
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
| | - Xuehui Zhang
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, NMPA Key Laboratory for Dental Materials, Beijing Laboratory of Biomedical Materials & Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China
- Oral Translational Medicine Research Center, Joint Training base for Shanxi Provincial Key Laboratory in Oral and Maxillofacial Repair, Reconstruction and Regeneration, The First People's Hospital of Jinzhong, Jinzhong, Shanxi, 030600, P. R. China
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Karakaya E, Gleichauf L, Schöbel L, Hassan A, Soufivand AA, Tessmar J, Budday S, Boccaccini AR, Detsch R. Engineering peptide-modified alginate-based bioinks with cell-adhesive properties for biofabrication. RSC Adv 2024; 14:13769-13786. [PMID: 38681843 PMCID: PMC11046382 DOI: 10.1039/d3ra08394b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 03/16/2024] [Indexed: 05/01/2024] Open
Abstract
Alginate (ALG) and its oxidised form alginate-dialdehyde (ADA) are highly attractive materials for hydrogels used in 3D bioprinting as well as drop-on-demand (DoD) approaches. However, both polymers need to be modified using cell-adhesive peptide sequences, to obtain bioinks exhibiting promising cell-material interactions. Our study explores the modification of ALG- and ADA-based bioinks with the adhesive peptides YIGSR (derived from laminin), RRETEWA (derived from fibronectin) and IKVAV (derived from laminin) for 3D bioprinting. Two coupling methods, carbodiimide and Schiff base reactions, were employed to modify the polymers with peptides. Analytical techniques, including FTIR and NMR were used to assess the chemical composition, revealing challenges in confirming the presence of peptides. The modified bioinks exhibited decreased stability, viscosity, and stiffness, particularly-ADA-based bioinks in contrast to ALG. Sterile hydrogel capsules or droplets were produced using a manual manufacturing process and DoD printing. NIH/3T3 cell spreading analysis showed enhanced cell spreading in carbodiimide-modified ADA, Schiff base-modified ADA, and PEG-Mal-modified ADA. The carbodiimide coupling of peptides worked for ADA, however the same was not observed for ALG. Finally, a novel mixture of all used peptides was evaluated regarding synergistic effects on cell spreading which was found to be effective, showing higher aspect ratios compared to the single peptide coupled hydrogels in all cases. The study suggests potential applications of these modified bioinks in 3D bioprinting approaches and highlights the importance of peptide selection as well as their combination for improved cell-material interactions.
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Affiliation(s)
- Emine Karakaya
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
| | - Luisa Gleichauf
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
| | - Lisa Schöbel
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
| | - Ahmed Hassan
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
| | - Anahita Ahmadi Soufivand
- Department of Mechanical Engineering, Institute of Continuum Mechanics and Biomechanics, Friedrich-Alexander-University Erlangen-Nuremberg Germany
| | - Joerg Tessmar
- Department for Functional Materials in Medicine and Dentistry, University of Würzburg Germany
| | - Silvia Budday
- Department of Mechanical Engineering, Institute of Continuum Mechanics and Biomechanics, Friedrich-Alexander-University Erlangen-Nuremberg Germany
| | - Aldo R Boccaccini
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
| | - Rainer Detsch
- Department of Material Science and Engineering, Institute for Biomaterials, Friedrich-Alexander University Erlangen-Nuremberg Germany
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3
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Du R, Li L, Ji J, Fan Y. Receptor-Ligand Binding: Effect of Mechanical Factors. Int J Mol Sci 2023; 24:ijms24109062. [PMID: 37240408 DOI: 10.3390/ijms24109062] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/20/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Gaining insight into the in situ receptor-ligand binding is pivotal for revealing the molecular mechanisms underlying the physiological and pathological processes and will contribute to drug discovery and biomedical application. An important issue involved is how the receptor-ligand binding responds to mechanical stimuli. This review aims to provide an overview of the current understanding of the effect of several representative mechanical factors, such as tension, shear stress, stretch, compression, and substrate stiffness on receptor-ligand binding, wherein the biomedical implications are focused. In addition, we highlight the importance of synergistic development of experimental and computational methods for fully understanding the in situ receptor-ligand binding, and further studies should focus on the coupling effects of these mechanical factors.
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Affiliation(s)
- Ruotian Du
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Long Li
- State Key Laboratory of Nonlinear Mechanics, Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China
| | - Jing Ji
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
| | - Yubo Fan
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China
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Ligorio C, Mata A. Synthetic extracellular matrices with function-encoding peptides. NATURE REVIEWS BIOENGINEERING 2023; 1:1-19. [PMID: 37359773 PMCID: PMC10127181 DOI: 10.1038/s44222-023-00055-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 03/16/2023] [Indexed: 06/28/2023]
Abstract
The communication of cells with their surroundings is mostly encoded in the epitopes of structural and signalling proteins present in the extracellular matrix (ECM). These peptide epitopes can be incorporated in biomaterials to serve as function-encoding molecules to modulate cell-cell and cell-ECM interactions. In this Review, we discuss natural and synthetic peptide epitopes as molecular tools to bioengineer bioactive hydrogel materials. We present a library of functional peptide sequences that selectively communicate with cells and the ECM to coordinate biological processes, including epitopes that directly signal to cells, that bind ECM components that subsequently signal to cells, and that regulate ECM turnover. We highlight how these epitopes can be incorporated in different biomaterials as individual or multiple signals, working synergistically or additively. This molecular toolbox can be applied in the design of biomaterials aimed at regulating or controlling cellular and tissue function, repair and regeneration.
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Affiliation(s)
- Cosimo Ligorio
- Biodiscovery Institute, University of Nottingham, Nottingham, UK
- Department of Chemical and Environmental Engineering, University of Nottingham, Nottingham, UK
| | - Alvaro Mata
- Biodiscovery Institute, University of Nottingham, Nottingham, UK
- Department of Chemical and Environmental Engineering, University of Nottingham, Nottingham, UK
- School of Pharmacy, University of Nottingham, Nottingham, UK
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Lim R, Banerjee A, Biswas R, Chari AN, Raghavan S. Mechanotransduction through adhesion molecules: Emerging roles in regulating the stem cell niche. Front Cell Dev Biol 2022; 10:966662. [PMID: 36172276 PMCID: PMC9511051 DOI: 10.3389/fcell.2022.966662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/18/2022] [Indexed: 11/23/2022] Open
Abstract
Stem cells have been shown to play an important role in regenerative medicine due to their proliferative and differentiation potential. The challenge, however, lies in regulating and controlling their potential for this purpose. Stem cells are regulated by growth factors as well as an array of biochemical and mechanical signals. While the role of biochemical signals and growth factors in regulating stem cell homeostasis is well explored, the role of mechanical signals has only just started to be investigated. Stem cells interact with their niche or to other stem cells via adhesion molecules that eventually transduce mechanical cues to maintain their homeostatic function. Here, we present a comprehensive review on our current understanding of the influence of the forces perceived by cell adhesion molecules on the regulation of stem cells. Additionally, we provide insights on how this deeper understanding of mechanobiology of stem cells has translated toward therapeutics.
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Affiliation(s)
- Ryan Lim
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Avinanda Banerjee
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Ritusree Biswas
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Campus, Bangalore, India
- Sastra University, Thanjavur, TN, India
| | - Anana Nandakumar Chari
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
| | - Srikala Raghavan
- A∗STAR Skin Research Lab (ASRL), Agency for Science, Technology and Research (A*STAR) 8A Biomedical Grove, Singapore, Singapore
- Institute for Stem Cell Science and Regenerative Medicine (inStem), GKVK Campus, Bangalore, India
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6
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Vermeulen S, Birgani ZT, Habibovic P. Biomaterial-induced pathway modulation for bone regeneration. Biomaterials 2022; 283:121431. [DOI: 10.1016/j.biomaterials.2022.121431] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/28/2022] [Accepted: 02/17/2022] [Indexed: 12/18/2022]
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7
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Sung TC, Lu MW, Tian Z, Lee HHC, Pan J, Ling QD, Higuchi A. Poly(vinyl alcohol- co-itaconic acid) hydrogels grafted with several designed peptides for human pluripotent stem cell culture and differentiation into cardiomyocytes. J Mater Chem B 2021; 9:7662-7673. [PMID: 34586153 DOI: 10.1039/d1tb01555a] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We developed poly(vinyl alcohol-co-itaconic acid) (PV) hydrogels grafted with laminin-derived peptides that had different joint segments and several specific designs, including dual chain motifs. PV hydrogels grafted with a peptide derived from laminin-β4 (PMQKMRGDVFSP) containing a joint segment, dual chain motif and cationic amino acid insertion could attach human pluripotent stem (hPS) cells and promoted high expansion folds in long-term culture (over 10 passages) with low differentiation rates, whereas hPS cells attached poorly on PV hydrogels grafted with laminin-α5 peptides that had joint segments with and without a cationic amino acid or on PV hydrogels grafted with laminin-β4 peptides containing the joint segment only. The inclusion of a cationic amino acid in the laminin-β4 peptide was critical for hPS cell attachment on PV hydrogels, which contributed to the zeta potential shifting to higher values (3-4 mV enhancement). The novel peptide segment-grafted PV hydrogels developed in this study supported hPS cell proliferation, which induced better hPS cell expansion than recombinant vitronectin-coated dishes (gold standard of hPS cell culture dishes) in xeno-free culture conditions. After long-term culture on peptide-grafted hydrogels, hPS cells could be induced to differentiate into specific lineages of cells, such as cardiomyocytes, with high efficiency.
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Affiliation(s)
- Tzu-Cheng Sung
- School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
| | - Ming-Wei Lu
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan.
| | - Zeyu Tian
- School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
| | - Henry Hsin-Chung Lee
- Department of Surgery, Hsinchu Cathay General Hospital, No. 678, Sec 2, Zhonghua Rd., Hsinchu, 30060, Taiwan.,Graduate Institute of Translational and Interdisciplinary Medicine, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan
| | - Jiandong Pan
- School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China.
| | - Qing-Dong Ling
- Cathay Medical Research Institute, Cathay General Hospital, No. 32, Ln 160, Jian-Cheng Road, Hsi-Chi City, Taipei 221, Taiwan
| | - Akon Higuchi
- School of Ophthalmology and Optometry, The Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China. .,Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan. .,R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan 320, Taiwan.,Nano Medical Engineering Laboratory, Riken Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.,Department of Reproduction, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
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8
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El-Rashidy AA, El Moshy S, Radwan IA, Rady D, Abbass MMS, Dörfer CE, Fawzy El-Sayed KM. Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review. Polymers (Basel) 2021; 13:2950. [PMID: 34502988 PMCID: PMC8434088 DOI: 10.3390/polym13172950] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 01/23/2023] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) have a multi-differentiation potential into specialized cell types, with remarkable regenerative and therapeutic results. Several factors could trigger the differentiation of MSCs into specific lineages, among them the biophysical and chemical characteristics of the extracellular matrix (ECM), including its stiffness, composition, topography, and mechanical properties. MSCs can sense and assess the stiffness of extracellular substrates through the process of mechanotransduction. Through this process, the extracellular matrix can govern and direct MSCs' lineage commitment through complex intracellular pathways. Hence, various biomimetic natural and synthetic polymeric matrices of tunable stiffness were developed and further investigated to mimic the MSCs' native tissues. Customizing scaffold materials to mimic cells' natural environment is of utmost importance during the process of tissue engineering. This review aims to highlight the regulatory role of matrix stiffness in directing the osteogenic differentiation of MSCs, addressing how MSCs sense and respond to their ECM, in addition to listing different polymeric biomaterials and methods used to alter their stiffness to dictate MSCs' differentiation towards the osteogenic lineage.
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Affiliation(s)
- Aiah A. El-Rashidy
- Biomaterials Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt;
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
| | - Sara El Moshy
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Israa Ahmed Radwan
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Dina Rady
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Marwa M. S. Abbass
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Christof E. Dörfer
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, 24105 Kiel, Germany;
| | - Karim M. Fawzy El-Sayed
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, 24105 Kiel, Germany;
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
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Macías I, Alcorta-Sevillano N, Infante A, Rodríguez CI. Cutting Edge Endogenous Promoting and Exogenous Driven Strategies for Bone Regeneration. Int J Mol Sci 2021; 22:7724. [PMID: 34299344 PMCID: PMC8306037 DOI: 10.3390/ijms22147724] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022] Open
Abstract
Bone damage leading to bone loss can arise from a wide range of causes, including those intrinsic to individuals such as infections or diseases with metabolic (diabetes), genetic (osteogenesis imperfecta), and/or age-related (osteoporosis) etiology, or extrinsic ones coming from external insults such as trauma or surgery. Although bone tissue has an intrinsic capacity of self-repair, large bone defects often require anabolic treatments targeting bone formation process and/or bone grafts, aiming to restore bone loss. The current bone surrogates used for clinical purposes are autologous, allogeneic, or xenogeneic bone grafts, which although effective imply a number of limitations: the need to remove bone from another location in the case of autologous transplants and the possibility of an immune rejection when using allogeneic or xenogeneic grafts. To overcome these limitations, cutting edge therapies for skeletal regeneration of bone defects are currently under extensive research with promising results; such as those boosting endogenous bone regeneration, by the stimulation of host cells, or the ones driven exogenously with scaffolds, biomolecules, and mesenchymal stem cells as key players of bone healing process.
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Affiliation(s)
- Iratxe Macías
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
| | - Natividad Alcorta-Sevillano
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
- University of Basque Country UPV/EHU, 48940 Leioa, Spain
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
| | - Clara I. Rodríguez
- Stem Cells and Cell Therapy Laboratory, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Spain; (I.M.); (N.A.-S.)
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10
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Najafi H, Jafari M, Farahavar G, Abolmaali SS, Azarpira N, Borandeh S, Ravanfar R. Recent advances in design and applications of biomimetic self-assembled peptide hydrogels for hard tissue regeneration. Biodes Manuf 2021; 4:735-756. [PMID: 34306798 PMCID: PMC8294290 DOI: 10.1007/s42242-021-00149-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/12/2021] [Indexed: 12/22/2022]
Abstract
Abstract The development of natural biomaterials applied for hard tissue repair and regeneration is of great importance, especially in societies with a large elderly population. Self-assembled peptide hydrogels are a new generation of biomaterials that provide excellent biocompatibility, tunable mechanical stability, injectability, trigger capability, lack of immunogenic reactions, and the ability to load cells and active pharmaceutical agents for tissue regeneration. Peptide-based hydrogels are ideal templates for the deposition of hydroxyapatite crystals, which can mimic the extracellular matrix. Thus, peptide-based hydrogels enhance hard tissue repair and regeneration compared to conventional methods. This review presents three major self-assembled peptide hydrogels with potential application for bone and dental tissue regeneration, including ionic self-complementary peptides, amphiphilic (surfactant-like) peptides, and triple-helix (collagen-like) peptides. Special attention is given to the main bioactive peptides, the role and importance of self-assembled peptide hydrogels, and a brief overview on molecular simulation of self-assembled peptide hydrogels applied for bone and dental tissue engineering and regeneration. Graphic abstract
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Affiliation(s)
- Haniyeh Najafi
- Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
| | - Mahboobeh Jafari
- Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
| | - Ghazal Farahavar
- Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
| | - Samira Sadat Abolmaali
- Pharmaceutical Nanotechnology Department, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Mohammad Rasoul-Allah Research Tower, 7193711351 Shiraz, Iran
| | - Sedigheh Borandeh
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, 71345-1583 Shiraz, Iran
- Polymer Technology Research Group, Department of Chemical and Metallurgical Engineering, Aalto University, 02152 Espoo, Finland
| | - Raheleh Ravanfar
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 USA
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11
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Nanofibrous Gelatin-Based Biomaterial with Improved Biomimicry Using D-Periodic Self-Assembled Atelocollagen. Biomimetics (Basel) 2021; 6:biomimetics6010020. [PMID: 33803778 PMCID: PMC8006151 DOI: 10.3390/biomimetics6010020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 01/14/2023] Open
Abstract
Design of bioinspired materials that mimic the extracellular matrix (ECM) at the nanoscale is a challenge in tissue engineering. While nanofibrillar gelatin materials mimic chemical composition and nano-architecture of natural ECM collagen components, it lacks the characteristic D-staggered array (D-periodicity) of 67 nm, which is an important cue in terms of cell recognition and adhesion properties. In this study, a nanofibrous gelatin matrix with improved biomimicry is achieved using a formulation including a minimal content of D-periodic self-assembled atelocollagen. We suggest a processing route approach consisting of the thermally induced phase separation of the gelatin based biopolymeric mixture precursor followed by chemical-free material cross-linking. The matrix nanostructure is characterized using field emission gun scanning electron microscopy (FEG-SEM), transmission electron microscopy (TEM), wide angle X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR). The cell culture assays indicate that incorporation of 2.6 wt.% content of D-periodic atelocollagen to the gelatin material, produces a significant increase of MC3T3-E1 mouse preosteoblast cells attachment and human mesenchymal stem cells (hMSCs) proliferation, in comparison with related bare gelatin matrices. The presented results demonstrate the achievement of an efficient route to produce a cost-effective, compositionally defined and low immunogenic “collagen-like” instructive biomaterial, based on gelatin.
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12
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Shrestha S, Li F, Truong VX, Forsythe JS, Frith JE. Interplay of Hydrogel Composition and Geometry on Human Mesenchymal Stem Cell Osteogenesis. Biomacromolecules 2020; 21:5323-5335. [PMID: 33237736 DOI: 10.1021/acs.biomac.0c01408] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Microgels are emerging as an outstanding platform for tissue regeneration because they overcome issues associated with conventional bulk/macroscopic hydrogels such as limited cell-cell contact and cell communication and low diffusion rates. Owing to the enhanced mass transfer and injectability via a minimally invasive procedure, these microgels are becoming a promising approach for bone regeneration applications. Nevertheless, there still remains a huge gap between the understanding of how the hydrogel matrix composition can influence cell response and overall tissue formation when switching from bulk formats to microgel format, which is often neglected or rarely studied. Here, we fabricated polyethylene glycol-based microgels and bulk hydrogels incorporating gelatin and hyaluronic acid (HA), either individually or together, and assessed the impact of both hydrogel composition and format upon the osteogenic differentiation of encapsulated human bone marrow-derived mesenchymal stem cells (hBMSCs). Osteogenesis was significantly greater in microgels than bulk hydrogels for both gelatin alone (Gel) and gelatin HA composite (Gel:HA) hydrogels, as determined by the expression of Runt-related transcription factor (Runx2) and alkaline phosphatase (ALP) genes and mineral deposition. Interestingly, Gel and Gel:HA hydrogels behaved differently between bulk and microgel format. In bulk format, overall osteogenic outcomes were better in Gel:HA hydrogels, but in microgel format, while the level of osteogenic gene expression was equivalent between both compositions, the degree of mineralization was reduced in Gel:HA microgels. Investigation into the affinity of hydroxyapatite for the different matrix compositions indicated that the decreased mineralization of Gel:HA microgels was likely due to a low affinity of hydroxyapatite to bind to HA and support mineral deposition, which has a greater impact on microgels than bulk hydrogels. Together, these findings suggest that both hydrogel composition and format can determine the success of tissue formation and that there is a complex interplay of these two factors on both cell behavior and matrix deposition. This has important implications for tissue engineering, showing that hydrogel composition and geometry must be evaluated together when optimizing conditions for cell differentiation and tissue formation.
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Affiliation(s)
- Surakshya Shrestha
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia
| | - Fanyi Li
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia
| | - Vinh X Truong
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia
| | - John S Forsythe
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia
| | - Jessica E Frith
- Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia
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Fraser D, Nguyen T, Benoit DSW. Matrix Control of Periodontal Ligament Cell Activity Via Synthetic Hydrogel Scaffolds. Tissue Eng Part A 2020; 27:733-747. [PMID: 33107404 DOI: 10.1089/ten.tea.2020.0278] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Rebuilding the tooth-supporting tissues (periodontium) destroyed by periodontitis remains a clinical challenge. Periodontal ligament cells (PDLCs), multipotent cells within the periodontal ligament (PDL), differentiate and form new PDL and mineralized tissues (cementum and bone) during native tissue repair in response to specific extracellular matrix (ECM) cues. Thus, harnessing ECM cues to control PDLC activity ex vivo, and ultimately, to design a PDLC delivery vehicle for tissue regeneration is an important goal. In this study, poly(ethylene glycol) hydrogels were used as a synthetic PDL ECM to interrogate the roles of cell-matrix interactions and cell-mediated matrix remodeling in controlling PDLC activity. Results showed that PDLCs within matrix metalloproteinase (MMP)-degradable hydrogels expressed key PDL matrix genes and showed a six to eightfold increase in alkaline phosphatase (ALP) activity compared with PDLCs in nondegradable hydrogel controls. The increase in ALP activity, commonly considered an early marker of cementogenic/osteogenic differentiation, occurred independent of the presentation of the cell-binding ligand RGD or soluble media cues and remained elevated when inhibiting PDLC-matrix binding and intracellular tension. ALP activity was further increased in softer hydrogels regardless of degradability and was accompanied by an increase in PDLC volume. However, scaffolds that fostered PDLC ALP activity did not necessarily promote hydrogel ECM mineralization. Rather, matrix mineralization was greatest in stiffer, MMP-degradable hydrogels and required the presence of soluble media cues. These divergent outcomes illustrate the complexity of the PDLC response to ECM cues and the limitations of current scaffold materials. Nevertheless, key biomaterial design principles for controlling PDLC activity were identified for incorporation into scaffolds for periodontal tissue regeneration. Impact statement Engineered scaffolds are an attractive approach for delivering periodontal ligament cells (PDLCs) to rebuild the tooth-supporting tissues. Replicating key extracellular matrix (ECM) cues within tissue engineered scaffolds may maximize PDLC potential. However, the identity of important ECM cues and how they can be harnessed to control PDLC activity is still unknown. In this study, matrix degradability, cell-matrix binding, and stiffness were varied using synthetic poly(ethylene glycol) hydrogels for three-dimensional PDLC culture. PDLCs exhibited dramatic and divergent responses to these cues, supporting further investigation of ECM-replicating scaffolds for control of PDLC behavior and periodontal tissue regeneration.
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Affiliation(s)
- David Fraser
- Translational Biomedical Science, University of Rochester, Rochester, New York, USA.,Eastman Institute for Oral Health, University of Rochester, Rochester, New York, USA
| | - Tram Nguyen
- Department of Biomedical Engineering, University of Rochester, Rochester, New York, USA
| | - Danielle S W Benoit
- Department of Biomedical Engineering, University of Rochester, Rochester, New York, USA.,Department of Chemical Engineering, University of Rochester, Rochester, New York, USA.,Materials Science Program, University of Rochester, Rochester, New York, USA.,Center for Oral Biology, University of Rochester, Rochester, New York, USA.,Center for Musculoskeletal Research, University of Rochester, Rochester, New York, USA
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Dhavalikar P, Robinson A, Lan Z, Jenkins D, Chwatko M, Salhadar K, Jose A, Kar R, Shoga E, Kannapiran A, Cosgriff-Hernandez E. Review of Integrin-Targeting Biomaterials in Tissue Engineering. Adv Healthc Mater 2020; 9:e2000795. [PMID: 32940020 PMCID: PMC7960574 DOI: 10.1002/adhm.202000795] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/27/2020] [Indexed: 12/12/2022]
Abstract
The ability to direct cell behavior has been central to the success of numerous therapeutics to regenerate tissue or facilitate device integration. Biomaterial scientists are challenged to understand and modulate the interactions of biomaterials with biological systems in order to achieve effective tissue repair. One key area of research investigates the use of extracellular matrix-derived ligands to target specific integrin interactions and induce cellular responses, such as increased cell migration, proliferation, and differentiation of mesenchymal stem cells. These integrin-targeting proteins and peptides have been implemented in a variety of different polymeric scaffolds and devices to enhance tissue regeneration and integration. This review first presents an overview of integrin-mediated cellular processes that have been identified in angiogenesis, wound healing, and bone regeneration. Then, research utilizing biomaterials are highlighted with integrin-targeting motifs as a means to direct these cellular processes to enhance tissue regeneration. In addition to providing improved materials for tissue repair and device integration, these innovative biomaterials provide new tools to probe the complex processes of tissue remodeling in order to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.
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Affiliation(s)
- Prachi Dhavalikar
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Andrew Robinson
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Ziyang Lan
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Dana Jenkins
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Malgorzata Chwatko
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Karim Salhadar
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Anupriya Jose
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Ronit Kar
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Erik Shoga
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Aparajith Kannapiran
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
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15
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Xin S, Gregory CA, Alge DL. Interplay between degradability and integrin signaling on mesenchymal stem cell function within poly(ethylene glycol) based microporous annealed particle hydrogels. Acta Biomater 2020; 101:227-236. [PMID: 31711899 PMCID: PMC6960331 DOI: 10.1016/j.actbio.2019.11.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/25/2022]
Abstract
Microporous annealed particle (MAP) hydrogels are promising materials for delivering therapeutic cells. It has previously been shown that spreading and mechanosensing activation of human mesenchymal stem cells (hMSCs) incorporated in these materials can be modulated by tuning the modulus of the microgel particle building blocks. However, the effects of degradability and functionalization with different integrin-binding peptides on cellular responses has not been explored. In this work, RGDS functionalized and enzymatically degradable poly(ethylene glycol) (PEG) microgels were annealed into MAP hydrogels via thiol-ene click chemistry and photopolymerization. During cell-mediated degradation, the microgel surfaces were remodeled to wrinkles or ridges, but the scaffold integrity was maintained. Moreover, cell spreading, proliferation, and secretion of extracellular matrix proteins were significantly enhanced in faster matrix metalloproteinase degrading (KCGPQGIWGQCK) MAP hydrogels compared to non-degradable controls after 8 days of culture. We subsequently evaluated paracrine activity by hMSCs seeded in the MAP hydrogels functionalized with either RGDS or c(RRETAWA), which is specific for α5β1 integrins, and evaluated the interplay between degradability and integrin-mediated signaling. Importantly, c(RRETAWA) functionalization upregulated secretion of bone morphogenetic protein-2 overall and on a per cell basis, but this effect was critically dependent on microgel degradability. In contrast, RGDS functionalization led to higher overall vascular endothelial growth factor secretion in degradable scaffolds due to the high cell number. These results demonstrate that integrin-binding peptides can modulate hMSC behavior in PEG-based MAP hydrogels, but the results strongly depend on the susceptibility of the microgel building blocks to cell-mediated matrix remodeling. This relationship should be considered in future studies aiming to further develop these materials for stem cell delivery and tissue engineering applications. STATEMENT OF SIGNIFICANCE: Microporous annealed particle (MAP) hydrogels are attracting increasing interest for tissue repair and regeneration and have shown superior results compared to conventional hydrogels in multiple applications. Here, we studied the impact of MAP hydrogel degradability and functionalization with different integrin-binding peptides on human mesenchymal stem cells (hMSCs) that were incorporated during particle annealing. Degradability was found to improve cell growth, spreading, and extracellular matrix production regardless of the integrin-binding peptide. Moreover, in degradable MAP hydrogels the integrin-binding peptide c(RRETAWA) was found to increase osteogenic protein expression by hMSCs compared to RGDS-functionalized MAP hydrogels. These results have important implications for the development of a MAP hydrogel-based hMSC delivery system for bone tissue engineering.
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Affiliation(s)
- Shangjing Xin
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843 USA
| | - Carl A Gregory
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine Texas A&M Health Science Center, College Station, TX, 77807 USA
| | - Daniel L Alge
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843 USA; Department of Materials Science and Engineering, Texas A&M University, College Station, TX, 77843 USA.
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16
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Sharma P, Kaur H, Roy S. Designing a Tenascin-C-Inspired Short Bioactive Peptide Scaffold to Direct and Control Cellular Behavior. ACS Biomater Sci Eng 2019; 5:6497-6510. [DOI: 10.1021/acsbiomaterials.9b01115] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Pooja Sharma
- Institute of Nanoscience and Technology, Habitat Centre, Sector 64, Phase 10, Mohali, Punjab 160062, India
| | - Harsimran Kaur
- Institute of Nanoscience and Technology, Habitat Centre, Sector 64, Phase 10, Mohali, Punjab 160062, India
| | - Sangita Roy
- Institute of Nanoscience and Technology, Habitat Centre, Sector 64, Phase 10, Mohali, Punjab 160062, India
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17
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Hunckler MD, Medina JD, Coronel MM, Weaver JD, Stabler CL, García AJ. Linkage Groups within Thiol-Ene Photoclickable PEG Hydrogels Control In Vivo Stability. Adv Healthc Mater 2019; 8:e1900371. [PMID: 31111689 DOI: 10.1002/adhm.201900371] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/06/2019] [Indexed: 11/11/2022]
Abstract
Thiol-norbornene (thiol-ene) photoclickable poly(ethylene glycol) (PEG) hydrogels are a versatile biomaterial for cell encapsulation, drug delivery, and regenerative medicine. Numerous in vitro studies with these 4-arm ester-linked PEG-norbornene (PEG-4eNB) hydrogels demonstrate robust cytocompatibility and ability to retain long-term integrity with nondegradable crosslinkers. However, when transplanted in vivo into the subcutaneous or intraperitoneal space, these PEG-4eNB hydrogels with nondegradable crosslinkers rapidly degrade within 24 h. This characteristic limits the usefulness of PEG-4eNB hydrogels in biomedical applications. Replacing the ester linkage with an amide linkage (PEG-4aNB) mitigates this rapid in vivo degradation, and the PEG-4aNB hydrogels maintain long-term in vivo stability for months. Furthermore, when compared to PEG-4eNB, the PEG-4aNB hydrogels demonstrate equivalent mechanical properties, crosslinking kinetics, and high cytocompatibility with rat islets and human mesenchymal stem cells. Thus, the PEG-4aNB hydrogels may be a suitable replacement platform without necessitating critical design changes or sacrificing key properties relevant to the well-established PEG-4eNB hydrogels.
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Affiliation(s)
- Michael D. Hunckler
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology 315 Ferst Dr. NW Atlanta GA 30332 USA
| | - Juan D. Medina
- Coulter Department of Biomedical Engineering Georgia Institute of Technology 313 Ferst Dr. NW Atlanta GA 30332 USA
| | - Maria M. Coronel
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology 315 Ferst Dr. NW Atlanta GA 30332 USA
| | - Jessica D. Weaver
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology 315 Ferst Dr. NW Atlanta GA 30332 USA
| | - Cherie L. Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering University of Florida 1275 Center Dr. Gainesville FL 32611 USA
| | - Andrés J. García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology 315 Ferst Dr. NW Atlanta GA 30332 USA
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18
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Xin S, Chimene D, Garza JE, Gaharwar AK, Alge DL. Clickable PEG hydrogel microspheres as building blocks for 3D bioprinting. Biomater Sci 2019; 7:1179-1187. [PMID: 30656307 PMCID: PMC9179007 DOI: 10.1039/c8bm01286e] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Three-dimensional (3D) bioprinting is important in the development of complex tissue structures for tissue engineering and regenerative medicine. However, the materials used for bioprinting, referred to as bioinks, must have a balance between a high viscosity for rapid solidification after extrusion and low shear force for cytocompatibility, which is difficult to achieve. Here, a novel bioink consisting of poly(ethylene glycol) (PEG) microgels prepared via off-stoichiometry thiol-ene click chemistry is introduced. Importantly, the microgel bioink is easily extruded, exhibits excellent stability after printing due to interparticle adhesion forces, and can be photochemically annealed with a second thiol-ene click reaction to confer long-term stability to printed constructs. The modularity of the bioink is also an advantage, as the PEG microgels have highly tunable physicochemical properties. The low force required for extrusion and cytocompatibility of the thiol-ene annealing reaction also permit cell incorporation during printing with high viability, and cells are able to spread and proliferate in the interstitial spaces between the microgels after the constructs have been annealed. Overall, these results indicate that our microgel bioink is a promising and versatile platform that could be leveraged for bioprinting and regenerative manufacturing.
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Affiliation(s)
- Shangjing Xin
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA.
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19
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Ghosal K, Sarkar K. Poly(ester amide) derived from municipal polyethylene terephthalate waste guided stem cells for osteogenesis. NEW J CHEM 2019. [DOI: 10.1039/c9nj02940k] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A novel poly(ester amide) was synthesized by using recycled poly(ethylene terephthalate) waste and soybean oil and other renewable resources for bone tissue engineering applications.
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Affiliation(s)
- Krishanu Ghosal
- Gene Therapy and Tissue Engineering Lab
- Department of Polymer Science and Technology
- University of Calcutta
- Kolkata-700009
- India
| | - Kishor Sarkar
- Gene Therapy and Tissue Engineering Lab
- Department of Polymer Science and Technology
- University of Calcutta
- Kolkata-700009
- India
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20
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Lopes D, Martins-Cruz C, Oliveira MB, Mano JF. Bone physiology as inspiration for tissue regenerative therapies. Biomaterials 2018; 185:240-275. [PMID: 30261426 PMCID: PMC6445367 DOI: 10.1016/j.biomaterials.2018.09.028] [Citation(s) in RCA: 239] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 09/15/2018] [Accepted: 09/17/2018] [Indexed: 12/14/2022]
Abstract
The development, maintenance of healthy bone and regeneration of injured tissue in the human body comprise a set of intricate and finely coordinated processes. However, an analysis of current bone regeneration strategies shows that only a small fraction of well-reported bone biology aspects has been used as inspiration and transposed into the development of therapeutic products. Specific topics that include inter-scale bone structural organization, developmental aspects of bone morphogenesis, bone repair mechanisms, role of specific cells and heterotypic cell contact in the bone niche (including vascularization networks and immune system cells), cell-cell direct and soluble-mediated contact, extracellular matrix composition (with particular focus on the non-soluble fraction of proteins), as well as mechanical aspects of native bone will be the main reviewed topics. In this Review we suggest a systematic parallelization of (i) fundamental well-established biology of bone, (ii) updated and recent advances on the understanding of biological phenomena occurring in native and injured tissue, and (iii) critical discussion of how those individual aspects have been translated into tissue regeneration strategies using biomaterials and other tissue engineering approaches. We aim at presenting a perspective on unexplored aspects of bone physiology and how they could be translated into innovative regeneration-driven concepts.
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Affiliation(s)
- Diana Lopes
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago,, 3810 193 Aveiro, Portugal
| | - Cláudia Martins-Cruz
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago,, 3810 193 Aveiro, Portugal
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago,, 3810 193 Aveiro, Portugal.
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago,, 3810 193 Aveiro, Portugal.
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21
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Ida T, Kaku M, Kitami M, Terajima M, Rosales Rocabado JM, Akiba Y, Nagasawa M, Yamauchi M, Uoshima K. Extracellular matrix with defective collagen cross-linking affects the differentiation of bone cells. PLoS One 2018; 13:e0204306. [PMID: 30252876 PMCID: PMC6155528 DOI: 10.1371/journal.pone.0204306] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 09/06/2018] [Indexed: 01/05/2023] Open
Abstract
Fibrillar type I collagen, the predominant organic component in bone, is stabilized by lysyl oxidase (LOX)-initiated covalent intermolecular cross-linking, an important determinant of bone quality. However, the impact of collagen cross-linking on the activity of bone cells and subsequent tissue remodeling is not well understood. In this study, we investigated the effect of collagen cross-linking on bone cellular activities employing a loss-of-function approach, using a potent LOX inhibitor, β-aminopropionitrile (BAPN). Osteoblastic cells (MC3T3-E1) were cultured for 2 weeks in the presence of 0–2 mM BAPN to obtain low cross-linked collagen matrices. The addition of BAPN to the cultures diminished collagen cross-links in a dose-dependent manner and, at 1 mM level, none of the major cross-links were detected without affecting collagen production. After the removal of cellular components from these cultures, MC3T3-E1, osteoclasts (RAW264.7), or mouse primary bone marrow-derived stromal cells (BMSCs) were seeded. MC3T3-E1 cells grown on low cross-link matrices showed increased alkaline phosphatase (ALP) activity. The number of multinucleate tartrate-resistant acid phosphatase (TRAP)-positive cells increased in RAW264.7 cells. Initial adhesion, proliferation, and ALP activity of BMSCs also increased. In the animal experiments, 4-week-old C57BL/6 mice were fed with BAPN-containing diet for 8 weeks. At this point, biochemical analysis of bone demonstrated that collagen cross-links decreased without affecting collagen content. Then, the diet was changed to a control diet to minimize the direct effect of BAPN. At 2 and 4 weeks after the change, histological samples were prepared. Histological examination of femur samples at 4 weeks showed a significant increase in the number of bone surface osteoblasts, while the bone volume and surface osteoclast numbers were not significantly affected. These results clearly demonstrated that the extent of collagen cross-linking of bone matrix affected the differentiation of bone cells, underscoring the importance of collagen cross-linking in the regulation of cell behaviors and tissue remodeling in bone. Characterization of collagen cross-linking in bone may be beneficial to obtain insight into not only bone mechanical property, but also bone cellular activities.
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Affiliation(s)
- Takako Ida
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaru Kaku
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Megumi Kitami
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masahiko Terajima
- North Carolina Oral Health Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | | | - Yosuke Akiba
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masako Nagasawa
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Mitsuo Yamauchi
- North Carolina Oral Health Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Katsumi Uoshima
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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22
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Carles-Carner M, Saleh LS, Bryant SJ. The effects of hydroxyapatite nanoparticles embedded in a MMP-sensitive photoclickable PEG hydrogel on encapsulated MC3T3-E1 pre-osteoblasts. Biomed Mater 2018; 13:045009. [PMID: 29611815 PMCID: PMC5988492 DOI: 10.1088/1748-605x/aabb31] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This study investigated the effects of introducing hydroxyapatite nanoparticles into a matrix metalloproteinase (MMP) sensitive poly(ethylene glycol) (PEG) hydrogel containing cell adhesion peptides of RGD for bone tissue engineering. MC3T3-E1 pre-osteoblasts were encapsulated in the biomimetic PEG hydrogel, which was formed from the photoclick thiol-norbornene reaction system, cultured for up to 28 d in growth medium or osteogenic differentiation medium, and evaluated by cellular morphology and differentiation by alkaline phosphatase (ALP) activity and bone-like extracellular matrix deposition for mineral and collagen. Hydroxyapatite nanoparticles were incorporated during hydrogel formation and cell encapsulation at 0%, 0.1% or 1% (w/w). Incorporation of hydroxyapatite nanoparticles did not affect the hydrogel properties as measured by compressive modulus and equilibrium swelling. In growth medium, encapsulated MC3T3-E1 cells remained largely round regardless of hydroxyapatite concentration. ALP activity increased by 25% at day 14 and total collagen content increased by 55% at day 28 with increasing hydroxyapatite concentration from 0% to 1%. In differentiation medium, cell spreading was evident regardless of hydroxyapatite indicating that the MC3T3-E1 cells were able to degrade the hydrogel. For the 1% hydroxyapatite condition, ALP activity was 27% higher at day 14 and total collagen content was 22% higher at day 28 in differentiation medium when compared to growth medium. Mineral deposits were more abundant and spatial elaboration of collagen type I was more evident in the 1% (w/w) hydroxyapatite condition with differentiation medium when compared to all other conditions. Overall, osteogenesis was observed in the hydrogels with hydroxyapatite nanoparticles in growth medium but was enhanced in differentiation medium. In summary, a biomimetic hydrogel comprised of MMP-sensitive crosslinks, RGD cell adhesion peptides, and 1% (w/w) hydroxyapatite nanoparticles is promising for bone tissue engineering.
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Affiliation(s)
- Maria Carles-Carner
- Department of Chemical and Biological Engineering, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80309, United States of America
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23
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Keremidarska-Markova M, Radeva E, Mitev D, Hristova-Panusheva K, Paull B, Nesterenko P, Šepitka J, Junkar I, Iglič A, Krasteva N. Increased elastic modulus of plasma polymer coatings reinforced with detonation nanodiamond particles improves osteogenic differentiation of mesenchymal stem cells. Turk J Biol 2018; 42:195-203. [PMID: 30814881 PMCID: PMC6353295 DOI: 10.3906/biy-1711-26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In the present study we demonstrated that composite PPHMDS/DND coatings with elastic moduli close to those of mature bone tissue (0.2-2.8 GPa) stimulated growth and osteogenic differentiation of human adipose-derived mesenchymal stem cells (hADMSCs). Composite coatings were prepared by a method of plasma polymerization (PP) where detonation nanodiamond (DND) particles in different amounts (0.1, 0.5, and 1 mg/mL) were added to hexamethyldisiloxane (HMDS) before plasma deposition. This method allows variation only in the reduced elastic modulus (Er´) with increase in the particle concentration, while the other surface properties, including surface wettability and topography, did not change. The response of hAD-MSCs to the increasing stifness showed an effect on adhesion and osteogenic differentiation but not on cell proliferation. Matrix mineralization and cell spreading were maximized on PPHMDS/DND coatings with the highest elastic modulus (2.826 GPa), while the differences in proliferation rates among the samples were negligible. In general, PPHMDS/DND coatings provide better conditions for growth and osteogenic differentiation of hAD-MSCs in comparison to glass coverslips, confirming their suitability for osteo-integration applications. Additionally, our findings support the hypothesis that biomaterials with elasticity similar to that of the native tissue can improve the differentiation potential of mesenchymal stem cells.
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Affiliation(s)
| | - Ekaterina Radeva
- Georgi Nadjakov Institute of Solid State Physics, Bulgarian Academy of Sciences , Sofia , Bulgaria
| | - Dimitar Mitev
- Georgi Nadjakov Institute of Solid State Physics, Bulgarian Academy of Sciences , Sofia , Bulgaria
| | | | | | | | - Joseph Šepitka
- Faculty of Mechanical Engineering, Czech Technical University in Prague , Prague , Czech Republic
| | - Ita Junkar
- Jozef Stefan Institute , Ljubljana , Slovenia
| | - Aleš Iglič
- Laboratory of Biophysics, Faculty of Electrical Engineering, University of Ljubljana , Ljubljana , Slovenia
| | - Natalia Krasteva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences , Sofia , Bulgaria
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He XT, Wu RX, Xu XY, Wang J, Yin Y, Chen FM. Macrophage involvement affects matrix stiffness-related influences on cell osteogenesis under three-dimensional culture conditions. Acta Biomater 2018; 71:132-147. [PMID: 29462712 DOI: 10.1016/j.actbio.2018.02.015] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/29/2018] [Accepted: 02/12/2018] [Indexed: 12/16/2022]
Abstract
Accumulating evidence indicates that the physicochemical properties of biomaterials exert profound influences on stem cell fate decisions. However, matrix-based regulation selected through in vitro analyses based on a given cell population do not genuinely reflect the in vivo conditions, in which multiple cell types are involved and interact dynamically. This study constitutes the first investigation of how macrophages (Mφs) in stiffness-tunable transglutaminase cross-linked gelatin (TG-gel) affect the osteogenesis of bone marrow-derived mesenchymal stem cells (BMMSCs). When a single cell type was cultured, low-stiffness TG-gels promoted BMMSC proliferation, whereas high-stiffness TG-gels supported cell osteogenic differentiation. However, Mφs in high-stiffness TG-gels were more likely to polarize toward the pro-inflammatory M1 phenotype. Using either conditioned medium (CM)-based incubation or Transwell-based co-culture, we found that Mφs encapsulated in the low-stiffness matrix exerted a positive effect on the osteogenesis of co-cultured BMMSCs. Conversely, Mφs in high-stiffness TG-gels negatively affected cell osteogenic differentiation. When both cell types were cultured in the same TG-gel type and placed into the Transwell system, the stiffness-related influences of Mφs on BMMSCs were significantly altered; both the low- and high-stiffness matrix induced similar levels of BMMSC osteogenesis. Although the best material parameter for synergistically affecting Mφs and BMMSCs remains unknown, our data suggest that Mφ involvement in the co-culture system alters previously identified material-related influences on BMMSCs, such as matrix stiffness-related effects, which were identified based on a culture system involving a single cell type. Such Mφ-stem cell interactions should be considered when establishing proper matrix parameter-associated cell regulation in the development of biomimetic biomaterials for regenerative applications. STATEMENT OF SIGNIFICANCE The substrate stiffness of a scaffold plays critical roles in modulating both reparative cells, such as mesenchymal stem cells (MSCs), and immune cells, such as macrophages (Mφs). Although the influences of material stiffness on either Mφs or MSCs, have been extensively described, how the two cell types respond to matrix cues to dynamically affect each other in a three-dimensional (3D) biosystem remains largely unknown. Here, we report our findings that, in a platform wherein Mφs and bone marrow-derived MSCs coexist, matrix stiffness can influence stem cell fate through both direct matrix-associated regulation and indirect Mφ-based modulation. Our data support future studies of the MSC-Mφ-matrix interplay in the 3D context to optimize matrix parameters for the development of the next biomaterial.
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Sun M, Chi G, Xu J, Tan Y, Xu J, Lv S, Xu Z, Xia Y, Li L, Li Y. Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5. Stem Cell Res Ther 2018; 9:52. [PMID: 29490668 PMCID: PMC5831741 DOI: 10.1186/s13287-018-0798-0] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 01/18/2018] [Accepted: 02/05/2018] [Indexed: 01/12/2023] Open
Abstract
Background Human mesenchymal stem cell (hMSC) differentiation into osteoblasts has important clinical significance in treating bone injury, and the stiffness of the extracellular matrix (ECM) has been shown to be an important regulatory factor for hMSC differentiation. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through integrin α5/β1, FAK, and Wnt signaling, subsequently regulating the osteogenic phenotype of hMSCs. Methods hMSCs were cultured on tunable polyacrylamide hydrogels coated with fibronectin with stiffness corresponding to a Young’s modulus of 13–16 kPa and 62–68 kPa. After hMSCs were cultured on gels for 1 week, gene expression of alpha-1typeIcollagen, BGLAP, and RUNX2 were evaluated by real-time PCR. After hMSCs were cultured on gels for 24 h, signaling molecules relating to integrin α5 (FAK, ERK, p-ERK, Akt, p-Akt, GSK-3β, p-GSK-3β, and β-catenin) were evaluated by western blot analysis. Results Osteogenic differentiation was increased on 62–68 kPa ECM, as evidenced by alpha-1 type I collagen, BGLAP, and RUNX2 gene expression, calcium deposition, and ALP staining. In the process of differentiation, gene and protein expression of integrin α5/β1 increased, together with protein expression of the downstream signaling molecules FAK, p-ERK, p-Akt, GSK-3β, p-GSK-3β, and β-catenin, indicating that these molecules can affect the osteogenic differentiation of hMSCs. An antibody blocking integrin α5 suppressed the stiffness-induced expression of all osteoblast markers examined. In particular, alpha-1 type I collagen, RUNX2, and BGLAP were significantly downregulated, indicating that integrin α5 regulates hMSC osteogenic differentiation. Downstream expression of FAK, ERK, p-ERK, and β-catenin protein was unchanged, whereas Akt, p-Akt, GSK-3β, and p-GSK-3β were upregulated. Moreover, expression of Akt and p-Akt was upregulated with anti-integrin α5 antibody, but no difference was observed for FAK, ERK, and p-ERK between the with or without anti-integrin α5 antibody groups. At the same time, expression of GSK-3β and p-GSK-3β was upregulated and β-catenin levels showed no difference between the groups with or without anti-integrin α5 antibody. Since Akt, p-Akt, GSK-3β, and p-GSK-3β displayed the same changes between the groups with or without anti-integrin α5 antibody, we then detected the links among them. Expression of p-Akt and p-GSK-3β was reduced effectively in the presence of the Akt inhibitor Triciribine. However, Akt, GSK-3β, and β-catenin were unchanged. These results suggested that expression of p-GSK-3β was regulated by p-Akt on 62–68 kPa ECM. Conclusions Taken together, our results provide evidence that matrix stiffness (62–68 kPa) affects the osteogenic outcome of hMSCs through mechanotransduction events that are mediated by integrin α5. Electronic supplementary material The online version of this article (10.1186/s13287-018-0798-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Meiyu Sun
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Guangfan Chi
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Juanjuan Xu
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Ye Tan
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Jiayi Xu
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Ziran Xu
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Yuhan Xia
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
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Barui A, Chowdhury F, Pandit A, Datta P. Rerouting mesenchymal stem cell trajectory towards epithelial lineage by engineering cellular niche. Biomaterials 2018; 156:28-44. [DOI: 10.1016/j.biomaterials.2017.11.036] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 10/22/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
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Abstract
In their native environment, cells are immersed in a complex milieu of biochemical and biophysical cues. These cues may include growth factors, the extracellular matrix, cell-cell contacts, stiffness, and topography, and they are responsible for regulating cellular behaviors such as adhesion, proliferation, migration, apoptosis, and differentiation. The decision-making process used to convert these extracellular inputs into actions is highly complex and sensitive to changes both in the type of individual cue (e.g., growth factor dose/level, timing) and in how these individual cues are combined (e.g., homotypic/heterotypic combinations). In this review, we highlight recent advances in the development of engineering-based approaches to study the cellular decision-making process. Specifically, we discuss the use of biomaterial platforms that enable controlled and tailored delivery of individual and combined cues, as well as the application of computational modeling to analyses of the complex cellular decision-making networks.
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Affiliation(s)
- Pamela K Kreeger
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA; , .,Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705, USA.,Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
| | - Laura E Strong
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA; ,
| | - Kristyn S Masters
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA; , .,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.,Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
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Kim GO, Lee H, Ma E, Kang C, Kwon YU. Viability Studies of Cells on Nanostructured Surfaces With Various Feature Sizes. B KOREAN CHEM SOC 2017. [DOI: 10.1002/bkcs.11325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Geun-Oh Kim
- Department of Chemistry; Sungkyunwan University; Suwon 16419 Republic of Korea
| | - Hoyeon Lee
- The Graduate School of East-West Medical Science; Kyung Hee University; Yongin 17104 Republic of Korea
| | - Eungyung Ma
- The Graduate School of East-West Medical Science; Kyung Hee University; Yongin 17104 Republic of Korea
| | - Chulhun Kang
- The Graduate School of East-West Medical Science; Kyung Hee University; Yongin 17104 Republic of Korea
| | - Young-Uk Kwon
- Department of Chemistry; Sungkyunwan University; Suwon 16419 Republic of Korea
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Dong Y, A S, Rodrigues M, Li X, Kwon SH, Kosaric N, Khong S, Gao Y, Wang W, Gurtner GC. Injectable and Tunable Gelatin Hydrogels Enhance Stem Cell Retention and Improve Cutaneous Wound Healing. ADVANCED FUNCTIONAL MATERIALS 2017; 27. [DOI: 10.1002/adfm.201606619] [Citation(s) in RCA: 224] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Stem cells have shown substantial promise for various diseases in preclinical and clinical trials. However, low cell engraftment rates significantly limit the clinical translation of stem cell therapeutics. Numerous injectable hydrogels have been developed to enhance cell retention. Yet, the design of an ideal material with tunable properties that can mimic different tissue niches and regulate stem cell behaviors remains an unfulfilled promise. Here, an injectable poly(ethylene glycol) (PEG)–gelatin hydrogel is designed with highly tunable properties, from a multifunctional PEG‐based hyperbranched polymer and a commercially available thiolated gelatin. Spontaneous gelation occurs within about 2 min under the physiological condition. Murine adipose‐derived stem cells (ASCs) can be easily encapsulated into the hydrogel, which supports ASC growth and maintains their stemness. The hydrogel mechanical properties, biodegradability, and cellular responses can be finely controlled by changing hydrogel formulation and cell seeding densities. An animal study shows that the in situ formed hydrogel significantly improves cell retention, enhances angiogenesis, and accelerates wound closure using a murine wound healing model. These data suggest that injectable PEG–gelatin hydrogel can be used for regulating stem cell behaviors in 3D culture, delivering cells for wound healing and other tissue regeneration applications.
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Affiliation(s)
- Yixiao Dong
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
- Charles Institute of Dermatology School of Medicine and Medical Science University College Dublin Dublin 4 Ireland
| | - Sigen A
- Charles Institute of Dermatology School of Medicine and Medical Science University College Dublin Dublin 4 Ireland
| | - Melanie Rodrigues
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
| | - Xiaolin Li
- Charles Institute of Dermatology School of Medicine and Medical Science University College Dublin Dublin 4 Ireland
| | - Sun H. Kwon
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
| | - Nina Kosaric
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
| | - Sacha Khong
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
| | - Yongsheng Gao
- Charles Institute of Dermatology School of Medicine and Medical Science University College Dublin Dublin 4 Ireland
| | - Wenxin Wang
- Charles Institute of Dermatology School of Medicine and Medical Science University College Dublin Dublin 4 Ireland
| | - Geoffrey C. Gurtner
- Department of Surgery Stanford University School of Medicine Stanford CA 94305 USA
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Singh BN, Pramanik K. Development of novel silk fibroin/polyvinyl alcohol/sol–gel bioactive glass composite matrix by modified layer by layer electrospinning method for bone tissue construct generation. Biofabrication 2017; 9:015028. [DOI: 10.1088/1758-5090/aa644f] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Wu Y, Grande-Allen KJ, West JL. Adhesive Peptide Sequences Regulate Valve Interstitial Cell Adhesion, Phenotype and Extracellular Matrix Deposition. Cell Mol Bioeng 2016; 9:479-495. [PMID: 28220141 PMCID: PMC5315271 DOI: 10.1007/s12195-016-0451-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 05/30/2016] [Indexed: 12/13/2022] Open
Abstract
Knowledge of how extracellular matrix (ECM) binding impacts valve interstitial cells (VICs) is critical not only to better understanding the etiology of valvular diseases but also to constructing living valve substitutes that can grow and remodel. Use of ECM-mimicking adhesive peptides with specific affinity to different receptors provides insights into adhesion-mediated cell signaling and downstream outcomes. Expression of adhesion receptors by VICs was assessed by flow cytometry and used to guide the choice of peptides studied. The peptide RGDS with affinity to multiple integrin receptors, and specific receptor-targeting peptides DGEA (integrin α2β1), YIGSR (67kDa laminin/elastin receptor; 67LR), and VAPG (67LR) were incorporated into hydrogels to investigate their effects on VICs. DGEA, YIGSR, and VAPG alone were insufficient to induce stable VIC adhesion. As a result, these peptides were studied in combination with 1 mM RGDS. For VICs cultured on two-dimensional hydrogel surfaces, YIGSR and VAPG down-regulated the expression of smooth muscle α-actin (myofibroblast activation marker); DGEA promoted VIC adhesion and VIC-mediated ECM deposition and inhibited the activity of alkaline phosphatase (osteogenic differentiation marker). Further, YIGSR and DGEA in combination promoted ECM deposition while inhibiting both myofibroblastic and osteogenic differentiation. However, VICs behaved differently to adhesive ligands when cultured within three-dimensional hydrogels, with most VICs assuming a healthy, quiescent phenotype under all peptide conditions tested. DGEA promoted ECM deposition by VICs within hydrogels. Overall, we demonstrate that the presentation of defined peptides targeting specific adhesion receptors can be used to regulate VIC adhesion, phenotype and ECM synthesis.
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Affiliation(s)
- Yan Wu
- Department of Biomedical Engineering, Duke University, Durham, NC
27708
| | | | - Jennifer L. West
- Department of Biomedical Engineering, Duke University, Durham, NC
27708
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32
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Visser R, Rico-Llanos GA, Pulkkinen H, Becerra J. Peptides for bone tissue engineering. J Control Release 2016; 244:122-135. [PMID: 27794492 DOI: 10.1016/j.jconrel.2016.10.024] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/21/2016] [Accepted: 10/23/2016] [Indexed: 01/07/2023]
Abstract
Molecular signals in the form of growth factors are the main modulators of cell behavior. However, the use of growth factors in tissue engineering has several drawbacks, including their costs, difficult production, immunogenicity and short half-life. Furthermore, many of them are pleiotropic and, since a single growth factor can have different active domains, their effect is not always fully controllable. A very interesting alternative that has recently emerged is the use of biomimetic peptides. Sequences derived from the active domains of soluble or extracellular matrix proteins can be used to functionalize the biomaterials used as scaffolds for new tissue growth to either direct the attachment of cells or to be released as soluble ligands. Since these short peptides can be easily designed and cost-effectively synthesized in vitro, their use has opened up a world of new opportunities to obtain cheaper and more effective implants for regenerative medicine strategies. In this extensive review we will go through many of the most important peptides with potential interest for bone tissue engineering, not limiting to those that only mediate cell adhesion or induce the osteogenic differentiation of progenitor cells, but also focusing on those that direct angiogenesis because of its close relation with bone formation.
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Affiliation(s)
- Rick Visser
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain.
| | - Gustavo A Rico-Llanos
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain
| | - Hertta Pulkkinen
- BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Jose Becerra
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), Malaga, Spain; Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Spain; BIONAND, Andalusian Center for Nanomedicine and Biotechnology, Junta de Andalucia, University of Malaga, Spain
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Subbiah R, Hwang MP, Du P, Suhaeri M, Hwang JH, Hong JH, Park K. Tunable Crosslinked Cell-Derived Extracellular Matrix Guides Cell Fate. Macromol Biosci 2016; 16:1723-1734. [DOI: 10.1002/mabi.201600280] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/02/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Ramesh Subbiah
- Center for Biomaterials; Korea Institute of Science and Technology (KIST); Seoul 02792 Republic of Korea
- Department of Biomedical Engineering; Korea University of Science and Technology (UST); Daejon 34113 Republic of Korea
| | - Mintai P. Hwang
- Department of Bioengineering; Swanson School of Engineering; University of Pittsburgh; Pittsburgh PA 15261 USA
| | - Ping Du
- Center for Biomaterials; Korea Institute of Science and Technology (KIST); Seoul 02792 Republic of Korea
- Department of Biomedical Engineering; Korea University of Science and Technology (UST); Daejon 34113 Republic of Korea
| | - Muhammad Suhaeri
- Center for Biomaterials; Korea Institute of Science and Technology (KIST); Seoul 02792 Republic of Korea
- Department of Biomedical Engineering; Korea University of Science and Technology (UST); Daejon 34113 Republic of Korea
| | - Jun-Ha Hwang
- School of Life Sciences and Biotechnology; Korea University; Seoul 02841 Republic of Korea
| | - Jeong-Ho Hong
- School of Life Sciences and Biotechnology; Korea University; Seoul 02841 Republic of Korea
| | - Kwideok Park
- Center for Biomaterials; Korea Institute of Science and Technology (KIST); Seoul 02792 Republic of Korea
- Department of Biomedical Engineering; Korea University of Science and Technology (UST); Daejon 34113 Republic of Korea
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Gurumurthy B, Bierdeman PC, Janorkar AV. Composition of elastin like polypeptide-collagen composite scaffold influences in vitro osteogenic activity of human adipose derived stem cells. Dent Mater 2016; 32:1270-1280. [PMID: 27524229 DOI: 10.1016/j.dental.2016.07.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/16/2016] [Accepted: 07/19/2016] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Collagen-based scaffolds for guided bone regeneration (GBR) are continuously improved to overcome the mechanical weaknesses of collagen. We have previously demonstrated superior mechanical characteristics of the elastin-like polypeptide (ELP) reinforced collagen composites. The objectives of this research were to evaluate the efficacy of ELP-collagen composites to culture human adipose-derived stem cells (hASCs) and allow them to undergo osteogenic differentiation. We hypothesized that hASCs would show a superior osteogenic differentiation in stiffer ELP-collagen composites compared to the neat collagen hydrogels. METHODS Composite specimens were made by varying ELP (0-18mg/mL) and collagen (2-6mg/mL) in a 3:1 ratio. Tensile strength, elastic modulus, and toughness were determined by uniaxial tensile testing. hASCs cultured within the composites were characterized by biochemical assays to measure cell viability, protein content, and osteogenic differentiation (alkaline phosphatase activity, osteocalcin, and Alizarin red staining). Scanning electron microscopy and energy dispersive spectroscopy were used for morphological characterization of composites. RESULTS All composites were suitable for hASCs culture with viable cells over the 22-day culture period. The ELP-collagen composite with 18mg/mL of ELP and 6mg/mL of collagen had greater tensile strength and elastic modulus combined with higher osteogenic activity in terms of differentiation and subsequent mineralization over a period of 3 weeks compared to other compositions. The extra-cellular matrix deposits composed of calcium and phosphorous were specifically seen in the 18:6mg/mL ELP-collagen composite. SIGNIFICANCE The success of the 18:6mg/mL ELP-collagen composite to achieve long-term, 3-dimensional culture and osteogenic differentiation indicates its potential as a GBR scaffold.
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Affiliation(s)
- Bhuvaneswari Gurumurthy
- Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Patrick C Bierdeman
- Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, Jackson, MS 39216, United States
| | - Amol V Janorkar
- Department of Biomedical Materials Science, School of Dentistry, University of Mississippi Medical Center, Jackson, MS 39216, United States.
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Castillo Diaz LA, Elsawy M, Saiani A, Gough JE, Miller AF. Osteogenic differentiation of human mesenchymal stem cells promotes mineralization within a biodegradable peptide hydrogel. J Tissue Eng 2016; 7:2041731416649789. [PMID: 27493714 PMCID: PMC4959308 DOI: 10.1177/2041731416649789] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/20/2016] [Indexed: 01/07/2023] Open
Abstract
An attractive strategy for the regeneration of tissues has been the use of extracellular matrix analogous biomaterials. Peptide-based fibrillar hydrogels have been shown to mimic the structure of extracellular matrix offering cells a niche to undertake their physiological functions. In this study, the capability of an ionic-complementary peptide FEFEFKFK (F, E, and K are phenylalanine, glutamic acid, and lysine, respectively) hydrogel to host human mesenchymal stem cells in three dimensions and induce their osteogenic differentiation is demonstrated. Assays showed sustained cell viability and proliferation throughout the hydrogel over 12 days of culture and these human mesenchymal stem cells differentiated into osteoblasts simply upon addition of osteogenic stimulation. Differentiated osteoblasts synthesized key bone proteins, including collagen-1 (Col-1), osteocalcin, and alkaline phosphatase. Moreover, mineralization occurred within the hydrogel. The peptide hydrogel is a naturally biodegradable material as shown by oscillatory rheology and reversed-phase high-performance liquid chromatography, where both viscoelastic properties and the degradation of the hydrogel were monitored over time, respectively. These findings demonstrate that a biodegradable octapeptide hydrogel can host and induce the differentiation of stem cells and has the potential for the regeneration of hard tissues such as alveolar bone.
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Affiliation(s)
- Luis A Castillo Diaz
- School of Chemical Engineering and Analytical Science, The University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Mohamed Elsawy
- Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Alberto Saiani
- Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK; The School of Materials, The University of Manchester, Manchester, UK
| | - Julie E Gough
- The School of Materials, The University of Manchester, Manchester, UK
| | - Aline F Miller
- School of Chemical Engineering and Analytical Science, The University of Manchester, Manchester, UK; Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
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Rehmann MS, Luna JI, Maverakis E, Kloxin AM. Tuning microenvironment modulus and biochemical composition promotes human mesenchymal stem cell tenogenic differentiation. J Biomed Mater Res A 2016; 104:1162-74. [PMID: 26748903 PMCID: PMC5510610 DOI: 10.1002/jbm.a.35650] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 12/19/2015] [Accepted: 01/08/2016] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) are promising for the regeneration of tendon and ligament tissues. Toward realizing this potential, microenvironment conditions are needed for promoting robust lineage-specific differentiation into tenocytes/ligament fibroblasts. Here, we utilized a statistical design of experiments approach to examine combinations of matrix modulus, composition, and soluble factors in human MSC tenogenic/ligamentogenic differentiation. Specifically, well-defined poly(ethylene glycol)-based hydrogels were synthesized using thiol-ene chemistry providing a bioinert base for probing cell response to extracellular matrix cues. Monomer concentrations were varied to achieve a range of matrix moduli (E ∼ 10-90 kPa), and different ratios of integrin-binding peptides were incorporated (GFOGER and RGDS for collagen and fibronectin, respectively), mimicking aspects of developing tendon/ligament tissue. A face-centered central composite response surface design was utilized to understand the contributions of these cues to human MSC differentiation in the presence of soluble factors identified to promote tenogenesis/ligamentogenesis (BMP-13 and ascorbic acid). Increasing modulus and collagen mimetic peptide content increased relevant gene expression and protein production or retention (scleraxis, collagen I, tenascin-C). These findings could inform the design of materials for tendon/ligament regeneration. More broadly, the design of experiments enabled efficient data acquisition and analysis, requiring fewer replicates than if each factor had been varied one at a time. This approach can be combined with other stimuli (for example, mechanical stimulation) toward a better mechanistic understanding of differentiation down these challenging lineages.
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Affiliation(s)
- Matthew S Rehmann
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, 19716
| | - Jesus I Luna
- Department of Dermatology, School of Medicine, University of California, Davis, California, 95816
| | - Emanual Maverakis
- Department of Dermatology, School of Medicine, University of California, Davis, California, 95816
| | - April M Kloxin
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, 19716
- Department of Materials Science and Engineering, University of Delaware, Newark, Delaware, 19716
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Le NNT, Zorn S, Schmitt SK, Gopalan P, Murphy WL. Hydrogel arrays formed via differential wettability patterning enable combinatorial screening of stem cell behavior. Acta Biomater 2016; 34:93-103. [PMID: 26386315 PMCID: PMC4794413 DOI: 10.1016/j.actbio.2015.09.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 09/03/2015] [Accepted: 09/15/2015] [Indexed: 01/12/2023]
Abstract
Here, we have developed a novel method for forming hydrogel arrays using surfaces patterned with differential wettability. Our method for benchtop array formation is suitable for enhanced-throughput, combinatorial screening of biochemical and biophysical cues from chemically defined cell culture substrates. We demonstrated the ability to generate these arrays without the need for liquid handling systems and screened the combinatorial effects of substrate stiffness and immobilized cell adhesion peptide concentration on human mesenchymal stem cell (hMSC) behavior during short-term 2-dimensional cell culture. Regardless of substrate stiffness, hMSC initial cell attachment, spreading, and proliferation were linearly correlated with immobilized CRGDS peptide concentration. Increasing substrate stiffness also resulted in increased hMSC initial cell attachment, spreading, and proliferation; however, examination of the combinatorial effects of CRGDS peptide concentration and substrate stiffness revealed potential interplay between these distinct substrate signals. Maximal hMSC proliferation seen on substrates with either high stiffness or high CRGDS peptide concentration suggests that some baseline level of cytoskeletal tension was required for hMSC proliferation on hydrogel substrates and that multiple substrate signals could be engineered to work in synergy to promote mechanosensing and regulate cell behavior. STATEMENT OF SIGNIFICANCE Our novel array formation method using surfaces patterned with differential wettability offers the advantages of benchtop array formation for 2-dimensional cell cultures and enhanced-throughput screening without the need for liquid handling systems. Hydrogel arrays formed via our method are suitable for screening the influence of chemical (e.g. cell adhesive ligands) and physical (stiffness, size, shape, and thickness) substrate properties on stem cell behavior. The arrays are also fully compatible with commercially available micro-array add-on systems, which allows for simultaneous control of the insoluble and soluble cell culture environment. This study used hydrogel arrays to demonstrate that synergy between cell adhesion and mechanosensing can be used to regulate hMSC behavior.
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Affiliation(s)
- Ngoc Nhi T Le
- Materials Science Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Stefan Zorn
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA
| | - Samantha K Schmitt
- Materials Science Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Padma Gopalan
- Materials Science Program, University of Wisconsin-Madison, Madison, WI, USA; Department of Material Science and Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - William L Murphy
- Materials Science Program, University of Wisconsin-Madison, Madison, WI, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Material Science and Engineering, University of Wisconsin-Madison, Madison, WI, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI, USA.
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38
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Amso Z, Cornish J, Brimble MA. Short Anabolic Peptides for Bone Growth. Med Res Rev 2016; 36:579-640. [DOI: 10.1002/med.21388] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/24/2016] [Accepted: 02/15/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Zaid Amso
- School of Chemical Sciences; The University of Auckland, 23 Symonds St; Auckland 1142 New Zealand
| | - Jillian Cornish
- Department of Medicine; The University of Auckland; Auckland 1010 New Zealand
| | - Margaret A. Brimble
- School of Chemical Sciences; The University of Auckland, 23 Symonds St; Auckland 1142 New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences; The University of Auckland; Auckland 1142 New Zealand
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Lampert FM, Simunovic F, Finkenzeller G, Pfeifer D, Stark GB, Winninger O, Steiner D. Transcriptomic Changes in Osteoblasts Following Endothelial Cell-Cocultivation Suggest a Role of Extracellular Matrix in Cellular Interaction. J Cell Biochem 2016; 117:1869-79. [PMID: 26754918 DOI: 10.1002/jcb.25486] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 01/06/2016] [Indexed: 12/22/2022]
Abstract
Vascularization is important for bone development, fracture healing and engineering of artificial bone tissue. In the context of bone tissue engineering, it was shown that coimplantation of human primary umbilical vein endothelial cells (HUVECs) and human osteoblasts (hOBs) results in the formation of functional blood vessels and enhanced bone regeneration. Implanted endothelial cells do not only contribute to blood vessel formation, but also support proliferation, cell survival and osteogenic differentiation of coimplanted hOBs. These effects are partially mediated by direct heterotypic cell contacts. In a previous report we could show that cocultivated hOBs strongly increase the expression of genes involved in extracellular matrix (ECM) formation in HUVECs, suggesting that ECM may be involved in the intercellular communication between hOBs and HUVECs. The present study aimed at investigating whether comparable changes occur in hOBs. We therefore performed a microarray analysis of hOBs cultivated in direct contact with HUVECs, revealing 1,004 differentially expressed genes. The differentially expressed genes could be assigned to the functional clusters ECM, proliferation, apoptosis and osteogenic differentiation. The microarray data could be confirmed by performing quantitative real time RT-PCR on selected genes. Furthermore, we could show that the ECM produced by HUVECs increased the expression of the osteogenic differentiation marker alkaline phosphatase (ALP) in hOBs. In summary, our data demonstrate that HUVECs provoke complex changes in gene expression patterns in cocultivated hOBs and that ECM plays and important role in this interaction. J. Cell. Biochem. 117: 1869-1879, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Florian M Lampert
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Filip Simunovic
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Günter Finkenzeller
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Dietmar Pfeifer
- Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany
| | - G Björn Stark
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Oscar Winninger
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Dominik Steiner
- Department of Plastic and Hand Surgery, University Hospital of Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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Zhu C, Li J, Liu C, Zhou P, Yang H, Li B. Modulation of the gene expression of annulus fibrosus-derived stem cells using poly(ether carbonate urethane)urea scaffolds of tunable elasticity. Acta Biomater 2016; 29:228-238. [PMID: 26432437 DOI: 10.1016/j.actbio.2015.09.039] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 08/18/2015] [Accepted: 09/29/2015] [Indexed: 01/07/2023]
Abstract
Annulus fibrosus (AF) injuries commonly lead to substantial deterioration of the intervertebral disc (IVD). While tissue engineering has recently evolved into a promising approach for AF regeneration, it remains challenging due to the cellular, biochemical, and mechanical heterogeneity of AF tissue. In this study, we explored the use of AF-derived stem cells (AFSCs) to achieve diversified differentiation of cells for AF tissue engineering. Since the differentiation of stem cells relies significantly on the elasticity of the substrate, we synthesized a series of biodegradable poly(ether carbonate urethane)urea (PECUU) materials whose elasticity approximated that of native AF tissue. When AFSCs were cultured on electrospun PECUU fibrous scaffolds, the gene expression of collagen-I in the cells increased with the elasticity of scaffold material, whereas the expression of collagen-II and aggrecan genes showed an opposite trend. At the protein level, the content of collagen-I gradually increased with substrate elasticity, while collagen-II and GAG contents decreased. In addition, the cell traction forces (CTFs) of AFSCs gradually decreased with scaffold elasticity. Such substrate elasticity-dependent changes of AFSCs were similar to the gradual transition in the genetic, biochemical, and biomechanical characteristics of cells from inner to outer regions of native AF tissue. Together, findings from this study indicate that AFSCs, depending on the substrate elasticity, have strong tendencies to differentiate into various types of AF-like cells, thereby providing a solid foundation for the tissue engineering applications of AFSCs. STATEMENT OF SIGNIFICANCE Repairing the annulus fibrosus (AF) of intervertebral disc (IVD) is critical for the treatment of disc degeneration disease, but remains challenging due to the significant heterogeneity of AF tissue. Previously, we have identified rabbit AF-derived stem cells (AFSCs), which are AF tissue-specific and hold promise for AF regeneration. In this study, we synthesized a series of poly(ether carbonate urethane)ureas of various elasticity (or stiffness) and explored the potential of induced differentiation of AFSCs using electrospun PECUU scaffolds. This work has, for the first time, found that AFSCs are able to present different gene expression patterns simply as a result of the elasticity of scaffold material. Therefore, our findings will help supplement current knowledge of AF tissue regeneration and may benefit a diversified readership from scientific, engineering, and clinical settings whose work involves the biology and tissue engineering of IVD.
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Affiliation(s)
- Caihong Zhu
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China
| | - Jun Li
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China
| | - Chen Liu
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China
| | - Pinghui Zhou
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China.
| | - Bin Li
- Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, China.
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Han F, Zhu C, Guo Q, Yang H, Li B. Cellular modulation by the elasticity of biomaterials. J Mater Chem B 2016; 4:9-26. [DOI: 10.1039/c5tb02077h] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The elasticity of the extracellular matrix has been increasingly recognized as a dominating factor of cell fate and activities. This review provides an overview of the general principles and recent advances in the field of matrix elasticity-dependent regulation of a variety of cellular activities and functions, the underlying biomechanical and molecular mechanisms, as well as the pathophysiological implications.
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Affiliation(s)
- Fengxuan Han
- Department of Orthopaedics
- The First Affiliated Hospital
- Orthopaedic Institute
- Soochow University
- Suzhou
| | - Caihong Zhu
- Department of Orthopaedics
- The First Affiliated Hospital
- Orthopaedic Institute
- Soochow University
- Suzhou
| | - Qianping Guo
- Department of Orthopaedics
- The First Affiliated Hospital
- Orthopaedic Institute
- Soochow University
- Suzhou
| | - Huilin Yang
- Department of Orthopaedics
- The First Affiliated Hospital
- Orthopaedic Institute
- Soochow University
- Suzhou
| | - Bin Li
- Department of Orthopaedics
- The First Affiliated Hospital
- Orthopaedic Institute
- Soochow University
- Suzhou
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Markovic M, Van Hoorick J, Hölzl K, Tromayer M, Gruber P, Nürnberger S, Dubruel P, Van Vlierberghe S, Liska R, Ovsianikov A. Hybrid Tissue Engineering Scaffolds by Combination of Three-Dimensional Printing and Cell Photoencapsulation. J Nanotechnol Eng Med 2015; 6:0210011-210017. [PMID: 26858826 DOI: 10.1115/1.4031466] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 08/25/2015] [Indexed: 11/08/2022]
Abstract
Three-dimensional (3D) printing offers versatile possibilities for adapting the structural parameters of tissue engineering scaffolds. However, it is also essential to develop procedures allowing efficient cell seeding independent of scaffold geometry and pore size. The aim of this study was to establish a method for seeding the scaffolds using photopolymerizable cell-laden hydrogels. The latter facilitates convenient preparation, and handling of cell suspension, while distributing the hydrogel precursor throughout the pores, before it is cross-linked with light. In addition, encapsulation of living cells within hydrogels can produce constructs with high initial cell loading and intimate cell-matrix contact, similar to that of the natural extra-cellular matrix (ECM). Three dimensional scaffolds were produced from poly(lactic) acid (PLA) by means of fused deposition modeling. A solution of methacrylamide-modified gelatin (Gel-MOD) in cell culture medium containing photoinitiator Li-TPO-L was used as a hydrogel precursor. Being an enzymatically degradable derivative of natural collagen, gelatin-based matrices are biomimetic and potentially support the process of cell-induced remodeling. Preosteoblast cells MC3T3-E1 at a density of 10 × 106 cells per 1 mL were used for testing the seeding procedure and cell proliferation studies. Obtained results indicate that produced constructs support cell survival and proliferation over extended duration of our experiment. The established two-step approach for scaffold seeding with the cells is simple, rapid, and is shown to be highly reproducible. Furthermore, it enables precise control of the initial cell density, while yielding their uniform distribution throughout the scaffold. Such hybrid tissue engineering constructs merge the advantages of rigid 3D printed constructs with the soft hydrogel matrix, potentially mimicking the process of ECM remodeling.
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Affiliation(s)
- Marica Markovic
- Austrian Cluster for Tissue Regeneration, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
| | - Jasper Van Hoorick
- Polymer Chemistry and Biomaterials Research Group, Ghent University, Krijgslaan 281 S4-bis, Ghent 9000, Belgium; Brussels Photonics Team, Department of Applied Physics and Photonics, Vrije Universiteit Brussel, Pleinlaan 2, Elsene 1050, Belgium e-mail:
| | - Katja Hölzl
- Austrian Cluster for Tissue Regeneration, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
| | - Maximilian Tromayer
- Austrian Cluster for Tissue Regeneration, Institute of Applied Synthetic Chemistry, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
| | - Peter Gruber
- Austrian Cluster for Tissue Regeneration, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
| | - Sylvia Nürnberger
- Austrian Cluster for Tissue Regeneration, Medical University of Vienna, Department of Trauma Surgery, Währinger Gürtel 18-20, Vienna 1090, Austria e-mail:
| | - Peter Dubruel
- Polymer Chemistry and Biomaterials Research Group, Ghent University, Krijgslaan 281 S4-bis, Ghent 9000, Belgium e-mail:
| | - Sandra Van Vlierberghe
- Polymer Chemistry and Biomaterials Research Group, Ghent University, Krijgslaan 281 S4-bis, 9000 Ghent, Brussels, Photonics Team, Department of Applied Physics and Photonics, Vrije Universiteit Brussel, Pleinlaan 2, Elsene 1050, Belgium e-mail:
| | - Robert Liska
- Austrian Cluster for Tissue Regeneration, Institute of Applied Synthetic Chemistry Division of Macromolecular Chemistry, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
| | - Aleksandr Ovsianikov
- Austrian Cluster for Tissue Regeneration, Institute of Materials Science and Technology, Technische Universität Wien (TU Wien), Getreidemarkt 9, Vienna 1060, Austria e-mail:
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Liu X, Shi S, Feng Q, Bachhuka A, He W, Huang Q, Zhang R, Yang X, Vasilev K. Surface Chemical Gradient Affects the Differentiation of Human Adipose-Derived Stem Cells via ERK1/2 Signaling Pathway. ACS APPLIED MATERIALS & INTERFACES 2015; 7:18473-18482. [PMID: 26237746 DOI: 10.1021/acsami.5b04635] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
To understand the role of surface chemistry on cell behavior and the associated molecular mechanisms, we developed and utilized a surface chemical gradient of amine functional groups by carefully adjusting the gas composition of 1,7-octadiene (OD) and allylamine (AA) of the plasma phase above a moving substrate. The chemical gradient surface used in the present work shows an increasing N/C ratio and wettability from the OD side toward the AA side with no change in surface topography. Under standard culture conditions (with serum), human adipose-derived stem cells (hASCs) adhesion and spreading area increased toward the AA side of the gradient. However, there were no differences in cell behavior in the absence of serum. These results, supported by the trends in proteins adsorption on the gradient surface, demonstrated that surface chemistry affects the response of hASCs through cell-adhesive serum proteins, rather than interacting directly with the cells. The expression of p-ERK and the osteogenic differentiation increased toward the AA side of the gradient, while adipogenic differentiation decreased in the same direction; however, when the activation of ERK1/2 was blocked by PD98059, the levels of osteogenic or adipogenic differentiation on different regions of the chemical gradient were the same. This indicates that ERK1/2 may be an important downstream signaling pathway of surface chemistry directed stem cell fate.
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Affiliation(s)
- Xujie Liu
- Graduate School at Shenzhen, Tsinghua University , Shenzhen 518055, China
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Shengjun Shi
- The Burns Department of Zhujiang Hospital, Southern Medical University , Guangzhou 510280, China
| | - Qingling Feng
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Akash Bachhuka
- Mawson Institute, University of South Australia , Mawson Lakes 5095, Australia
| | - Wei He
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Qianli Huang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Ranran Zhang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Xing Yang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University , Beijing 100084, China
| | - Krasimir Vasilev
- Mawson Institute, University of South Australia , Mawson Lakes 5095, Australia
- School of Advanced Manufacturing, University of South Australia , Mawson Lakes 5095, Australia
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44
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Effect of type I collagen derived from tilapia scale on odontoblast-like cells. Tissue Eng Regen Med 2015. [DOI: 10.1007/s13770-014-0114-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Lv H, Li L, Sun M, Zhang Y, Chen L, Rong Y, Li Y. Mechanism of regulation of stem cell differentiation by matrix stiffness. Stem Cell Res Ther 2015; 6:103. [PMID: 26012510 PMCID: PMC4445995 DOI: 10.1186/s13287-015-0083-4] [Citation(s) in RCA: 267] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Stem cell behaviors are regulated by multiple microenvironmental cues. As an external signal, mechanical stiffness of the extracellular matrix is capable of governing stem cell fate determination, but how this biophysical cue is translated into intracellular signaling remains elusive. Here, we elucidate mechanisms by which stem cells respond to microenvironmental stiffness through the dynamics of the cytoskeletal network, leading to changes in gene expression via biophysical transduction signaling pathways in two-dimensional culture. Furthermore, a putative rapid shift from original mechanosensing to de novo cell-derived matrix sensing in more physiologically relevant three-dimensional culture is pointed out. A comprehensive understanding of stem cell responses to this stimulus is essential for designing biomaterials that mimic the physiological environment and advancing stem cell-based clinical applications for tissue engineering.
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Affiliation(s)
- Hongwei Lv
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China. .,College of Public Health, Jilin University, Changchun, 130021, China.
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
| | - Meiyu Sun
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
| | - Yin Zhang
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China. .,College of Public Health, Jilin University, Changchun, 130021, China.
| | - Li Chen
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China. .,College of Public Health, Jilin University, Changchun, 130021, China.
| | - Yue Rong
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China. .,College of Clinical Medicine, Jilin University, Changchun, 130021, China.
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
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Ghasemi-Mobarakeh L, Prabhakaran MP, Tian L, Shamirzaei-Jeshvaghani E, Dehghani L, Ramakrishna S. Structural properties of scaffolds: Crucial parameters towards stem cells differentiation. World J Stem Cells 2015; 7:728-744. [PMID: 26029344 PMCID: PMC4444613 DOI: 10.4252/wjsc.v7.i4.728] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 12/18/2014] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Tissue engineering is a multidisciplinary field that applies the principles of engineering and life-sciences for regeneration of damaged tissues. Stem cells have attracted much interest in tissue engineering as a cell source due to their ability to proliferate in an undifferentiated state for prolonged time and capability of differentiating to different cell types after induction. Scaffolds play an important role in tissue engineering as a substrate that can mimic the native extracellular matrix and the properties of scaffolds have been shown to affect the cell behavior such as the cell attachment, proliferation and differentiation. Here, we focus on the recent reports that investigated the various aspects of scaffolds including the materials used for scaffold fabrication, surface modification of scaffolds, topography and mechanical properties of scaffolds towards stem cells differentiation effect. We will present a more detailed overview on the effect of mechanical properties of scaffolds on stem cells fate.
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47
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Lin CC, Ki CS, Shih H. Thiol-norbornene photo-click hydrogels for tissue engineering applications. J Appl Polym Sci 2015; 132:41563. [PMID: 25558088 PMCID: PMC4280501 DOI: 10.1002/app.41563] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Thiol-norbornene (thiol-ene) photo-click hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are cross-linked through light mediated orthogonal reactions between multi-functional norbornene-modified macromers (e.g., poly(ethylene glycol), hyaluronic acid, gelatin) and sulfhydryl-containing linkers (e.g., dithiothreitol, PEG-dithiol, bis-cysteine peptides) using low concentration of photoinitiator. The gelation of thiol-norbornene hydrogels can be initiated by long-wave UV light or visible light without additional co-initiator or co-monomer. The cross-linking and degradation behaviors of thiol-norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned owing to the orthogonal reactivity between norbornene and thiol moieties. Uniquely, the cross-linking of step-growth thiol-norbornene hydrogels is not oxygen-inhibited, therefore the gelation is much faster and highly cytocompatible compared with chain-growth polymerized hydrogels using similar gelation conditions. These hydrogels have been prepared as tunable substrates for 2D cell culture, as microgels or bulk gels for affinity-based or protease-sensitive drug delivery, and as scaffolds for 3D cell culture. Reports from different laboratories have demonstrated the broad utility of thiol-norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas-related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, as well as cancer cell biology. This article provides an up-to-date overview on thiol-norbornene hydrogel cross-linking and degradation mechanisms, tunable material properties, as well as the use of thiol-norbornene hydrogels in drug delivery and tissue engineering applications.
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Affiliation(s)
- Chien-Chi Lin
- Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indiana University-Purdue University Indianapolis, Indianapolis, IN. 46202, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN. 47907, USA
| | - Chang Seok Ki
- Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indiana University-Purdue University Indianapolis, Indianapolis, IN. 46202, USA
- Department of Biosystems and Biomaterials Science and Engineering, Seoul National University, Seoul. 151-742 Republic of Korea
| | - Han Shih
- Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indiana University-Purdue University Indianapolis, Indianapolis, IN. 46202, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN. 47907, USA
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Ho MH, Li CH, Hsiao SW, Thien DVH. Preparation of Chitosan/Hydroxyapatite Substrates with Controllable Osteoconductivity Tracked by AFM. Ann Biomed Eng 2014; 43:1024-35. [DOI: 10.1007/s10439-014-1162-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 10/10/2014] [Indexed: 12/01/2022]
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