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Singh RK, Verma K, Kumar GCM, Jalageri MB. Potential of Graphene-Functionalized Polymer Surfaces for Dental Applications: A Systematic review. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2025; 36:191-211. [PMID: 39190630 DOI: 10.1080/09205063.2024.2396224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024]
Abstract
Graphene, a two-dimensional carbon nanomaterial, has garnered widespread attention across various fields due to its outstanding properties. In dental implantology, researchers are exploring the use of graphene-functionalized polymer surfaces to enhance both the osseointegration process and the long-term success of dental implants. This review consolidates evidence from in-vivo and in-vitro studies, highlighting graphene's capacity to improve bone-to-implant contact, exhibit antibacterial properties, and enhance mechanical strength. This research investigates the effects of incorporating graphene derivatives into polymer materials on tissue response and compatibility. Among 123 search results, 14 articles meeting the predefined criteria were analyzed. The study primarily focuses on assessing the impact of GO and rGO on cellular function and stability in implants. Results indicate promising improvements in cellular function and stability with the use of GO-coated or composited implants. However, it is noted that interactions between Graphene derivatives and polymers may alter the inherent properties of the materials. Therefore, further rigorous research is deemed imperative to fully elucidate their potential in human applications. Such comprehensive understanding is essential for unlocking the extensive benefits associated with the utilization of Graphene derivatives in biomedical contexts.
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Affiliation(s)
- Rohit Kumar Singh
- Department of Mechanical Engineering, National Institute of Technology Karnataka, Surathkal, India
| | - Khyati Verma
- Department of Mechanical Engineering, National Institute of Technology Karnataka, Surathkal, India
| | - G C Mohan Kumar
- Department of Mechanical Engineering, National Institute of Technology Karnataka, Surathkal, India
| | - Mallikarjun B Jalageri
- Department of Mechanical Engineering, National Institute of Technology Karnataka, Surathkal, India
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2
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Morawski M, Krasnodębski M, Rochoń J, Kubiszewski H, Marzęcki M, Topyła D, Murat K, Staszewski M, Szczytko J, Maleszewski M, Grąt M. Decellularized Liver Matrices for Expanding the Donor Pool-An Evaluation of Existing Protocols and Future Trends. Biomolecules 2025; 15:98. [PMID: 39858491 PMCID: PMC11762870 DOI: 10.3390/biom15010098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Liver transplantation is the only curative option for end-stage liver disease and is necessary for an increasing number of patients with advanced primary or secondary liver cancer. Many patient groups can benefit from this treatment, however the shortage of liver grafts remains an unsolved problem. Liver bioengineering offers a promising method for expanding the donor pool through the production of acellular scaffolds that can be seeded with recipient cells. Decellularization protocols involve the removal of cells using various chemical, physical, and enzymatic steps to create a collagenous network that provides support for introduced cells and future vascular and biliary beds. However, the removal of the cells causes varying degrees of matrix damage, that can affect cell seeding and future organ performance. The main objective of this review is to present the existing techniques of producing decellularized livers, with an emphasis on the assessment and definition of acellularity. Decellularization agents are discussed, and the standard process of acellular matrix production is evaluated. We also introduce the concept of the stepwise assessment of the matrix during decellularization through decellularization cycles. This method may lead to shorter detergent exposure times and less scaffold damage. The introduction of apoptosis induction in the field of organ engineering may provide a valuable alternative to existing long perfusion protocols, which lead to significant matrix damage. A thorough understanding of the decellularization process and the action of the various factors influencing the final composition of the scaffold is essential to produce a biocompatible matrix, which can be the basis for further studies regarding recellularization and retransplantation.
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Affiliation(s)
- Marcin Morawski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Maciej Krasnodębski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Jakub Rochoń
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Hubert Kubiszewski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Michał Marzęcki
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Dominik Topyła
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Kacper Murat
- Institute of Telecommunications, Warsaw University of Technology, 00-665 Warsaw, Poland; (M.M.); (D.T.); (K.M.)
| | - Mikołaj Staszewski
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
| | - Jacek Szczytko
- Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland;
| | - Marek Maleszewski
- Department of Embryology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland;
| | - Michał Grąt
- Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (M.K.); (J.R.); (H.K.); (M.S.); (M.G.)
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3
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Zhang Y, Li L, Dong L, Cheng Y, Huang X, Xue B, Jiang C, Cao Y, Yang J. Hydrogel-Based Strategies for Liver Tissue Engineering. CHEM & BIO ENGINEERING 2024; 1:887-915. [PMID: 39975572 PMCID: PMC11835278 DOI: 10.1021/cbe.4c00079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/15/2024] [Accepted: 09/15/2024] [Indexed: 02/21/2025]
Abstract
The liver's role in metabolism, detoxification, and immune regulation underscores the urgency of addressing liver diseases, which claim millions of lives annually. Due to donor shortages in liver transplantation, liver tissue engineering (LTE) offers a promising alternative. Hydrogels, with their biocompatibility and ability to mimic the liver's extracellular matrix (ECM), support cell survival and function in LTE. This review analyzes recent advances in hydrogel-based strategies for LTE, including decellularized liver tissue hydrogels, natural polymer-based hydrogels, and synthetic polymer-based hydrogels. These materials are ideal for in vitro cell culture and obtaining functional hepatocytes. Hydrogels' tunable properties facilitate creating artificial liver models, such as organoids, 3D bioprinting, and liver-on-a-chip technologies. These developments demonstrate hydrogels' versatility in advancing LTE's applications, including hepatotoxicity testing, liver tissue regeneration, and treating acute liver failure. This review highlights the transformative potential of hydrogels in LTE and their implications for future research and clinical practice.
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Affiliation(s)
- Yu Zhang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Luofei Li
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Liang Dong
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Yuanqi Cheng
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Xiaoyu Huang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Bin Xue
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Chunping Jiang
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Yi Cao
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Jiapeng Yang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
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4
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Yadav CJ, Yadav U, Afrin S, Lee JY, Kamel J, Park KM. Heparin Immobilization Enhances Hemocompatibility, Re-Endothelization, and Angiogenesis of Decellularized Liver Scaffolds. Int J Mol Sci 2024; 25:12132. [PMID: 39596200 PMCID: PMC11595110 DOI: 10.3390/ijms252212132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/04/2024] [Accepted: 11/09/2024] [Indexed: 11/28/2024] Open
Abstract
Bioengineered livers are currently an acceptable alternative to orthotopic liver transplants to overcome the scarcity of donors. However, the challenge of using a bioengineered liver is the lack of an intact endothelial layer in the vascular network leading to thrombosis. Heparin-modified surfaces have been demonstrated to decrease thrombogenicity in earlier research. However, in our study, we aimed to apply heparin immobilization to enhance the hemocompatibility, endothelial cell (EC) adhesion, and angiogenesis of rat decellularized liver scaffolds (DLS). Heparin was immobilized on the DLS by the end-point attachment technique. The scaffold's hemocompatibility was assessed using ex vivo blood perfusion and platelet adhesion studies. The heparinized scaffold (HEP-DLS) showed a significantly reduced thrombogenicity and platelet aggregation. HEP-DLS was recellularized with EA.hy926 cells via the portal vein and maintained in the bioreactor for 7 days, showing increased EC adhesion and coverage within the blood vessels. The Resazurin reduction assay confirmed the presence of actively proliferating cells in the HEP-DLS. The scaffolds were implanted subcutaneously into the dorsum of mice for 21 days to evaluate cell migration and angiogenesis. The results showed significant increases in the number of blood vessels in the HEP-DLS group. Our results demonstrated that heparin immobilization reduces thrombosis, promotes re-endothelialization, and enhances angiogenesis in DLS. The research provides insight into the potential use of heparin in the formation of a functioning vasculature.
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Affiliation(s)
| | | | | | | | | | - Kyung-Mee Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea; (C.J.Y.); (U.Y.); (S.A.); (J.-Y.L.); (J.K.)
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5
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Wani SI, Mir TA, Nakamura M, Tsuchiya T, Alzhrani A, Iwanaga S, Arai K, Alshehri EA, Shamma T, Obeid DA, Chinnappan R, Assiri AM, Yaqinuddin A, Vashist YK, Broering DC. A review of current state-of-the-art materiobiology and technological approaches for liver tissue engineering. BIOPRINTING 2024; 42:e00355. [DOI: 10.1016/j.bprint.2024.e00355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
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6
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Hussein KH, Ahmadzada B, Correa JC, Sultan A, Wilken S, Amiot B, Nyberg SL. Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities. Bioact Mater 2024; 40:280-305. [PMID: 38973992 PMCID: PMC11226731 DOI: 10.1016/j.bioactmat.2024.06.001] [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: 04/03/2024] [Revised: 05/30/2024] [Accepted: 06/01/2024] [Indexed: 07/09/2024] Open
Abstract
Liver transplantation represents the only definitive treatment for patients with end-stage liver disease. However, the shortage of liver donors provokes a dramatic gap between available grafts and patients on the waiting list. Whole liver bioengineering, an emerging field of tissue engineering, holds great potential to overcome this gap. This approach involves two main steps; the first is liver decellularization and the second is recellularization. Liver decellularization aims to remove cellular and nuclear materials from the organ, leaving behind extracellular matrices containing different structural proteins and growth factors while retaining both the vascular and biliary networks. Recellularization involves repopulating the decellularized liver with appropriate cells, theoretically from the recipient patient, to reconstruct the parenchyma, vascular tree, and biliary network. The aim of this review is to identify the major advances in decellularization and recellularization strategies and investigate obstacles for the clinical application of bioengineered liver, including immunogenicity of the designed liver extracellular matrices, the need for standardization of scaffold fabrication techniques, selection of suitable cell sources for parenchymal repopulation, vascular, and biliary tree reconstruction. In vivo transplantation models are also summarized for evaluating the functionality of bioengineered livers. Finally, the regulatory measures and future directions for confirming the safety and efficacy of bioengineered liver are also discussed. Addressing these challenges in whole liver bioengineering may offer new solutions to meet the demand for liver transplantation and improve patient outcomes.
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Affiliation(s)
- Kamal H. Hussein
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
- Department of Surgery, Anesthesiology, and Radiology, College of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Boyukkhanim Ahmadzada
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Julio Cisneros Correa
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Ahmer Sultan
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Silvana Wilken
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Bruce Amiot
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
| | - Scott L. Nyberg
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
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7
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Horie H, Oshima Y, Fukumitsu K, Iwaki K, Munekage F, Makino K, Wakama S, Ito T, Tomofuji K, Ogiso S, Uebayashi EY, Ishii T, Ishihara K, Hatano E. Antithrombotic Revascularization Strategy of Bioengineered Liver Using a Biomimetic Polymer. Tissue Eng Part A 2024. [PMID: 39276095 DOI: 10.1089/ten.tea.2024.0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2024] Open
Abstract
A bioengineered liver has the potential to save patients with end-stage liver disease, and a three-dimensional decellularized scaffold is a promising approach for practical use. The main challenge in bioengineered liver transplantation is thrombogenicity during blood perfusion. We aimed to apply a novel antithrombotic polymer to revascularize liver scaffolds and evaluate the thrombogenicity and biosafety of the polymer-treated scaffolds. A biomimetic polymer, 2-metacryloyloxyethyl phosphorylcholine (MPC) was prepared for modification of the extracellular matrix in liver scaffolds. The polymer was injected into the rat liver scaffolds' portal vein and could extensively react to the vessel walls. In an ex vivo blood perfusion experiment, we demonstrated significantly less platelet deposition in the polymer-treated scaffolds than nontreated or re-endothelialized scaffolds with human umbilical vein endothelial cells. In the heterotopic transplantation model, liver volume was better maintained in the polymer-treated groups, and platelet deposition was suppressed in these groups. Additionally, the polymer-treated liver scaffolds maintained the metabolic function of the recellularized rat primary hepatocytes during perfusion culture. The MPC polymer treatment efficiently suppressed thrombus formation during blood perfusion in liver scaffolds and maintained the function of recellularized hepatocytes. Revascularizing liver scaffolds using this polymer is a promising approach for bioengineered liver transplantation.
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Affiliation(s)
- Hiroshi Horie
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yu Oshima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Surgery, Nagahama City Hospital, Shiga, Japan
| | - Ken Fukumitsu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Surgery, Kyoto Katsura Hospital, Kyoto, Japan
| | - Kentaro Iwaki
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fumiaki Munekage
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenta Makino
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Wakama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Katsuhiro Tomofuji
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Ogiso
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Takamichi Ishii
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuhiko Ishihara
- Department of Materials Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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8
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Gupta S, Sharma A, Petrovski G, Verma RS. Vascular reconstruction of the decellularized biomatrix for whole-organ engineering-a critical perspective and future strategies. Front Bioeng Biotechnol 2023; 11:1221159. [PMID: 38026872 PMCID: PMC10680456 DOI: 10.3389/fbioe.2023.1221159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Whole-organ re-engineering is the most challenging goal yet to be achieved in tissue engineering and regenerative medicine. One essential factor in any transplantable and functional tissue engineering is fabricating a perfusable vascular network with macro- and micro-sized blood vessels. Whole-organ development has become more practical with the use of the decellularized organ biomatrix (DOB) as it provides a native biochemical and structural framework for a particular organ. However, reconstructing vasculature and re-endothelialization in the DOB is a highly challenging task and has not been achieved for constructing a clinically transplantable vascularized organ with an efficient perfusable capability. Here, we critically and articulately emphasized factors that have been studied for the vascular reconstruction in the DOB. Furthermore, we highlighted the factors used for vasculature development studies in general and their application in whole-organ vascular reconstruction. We also analyzed in detail the strategies explored so far for vascular reconstruction and angiogenesis in the DOB for functional and perfusable vasculature development. Finally, we discussed some of the crucial factors that have been largely ignored in the vascular reconstruction of the DOB and the future directions that should be addressed systematically.
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Affiliation(s)
- Santosh Gupta
- Stem Cell and Molecular Biology, Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences. Indian Institute of Technology Madras, Chennai, India
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Akriti Sharma
- Stem Cell and Molecular Biology, Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences. Indian Institute of Technology Madras, Chennai, India
| | - Goran Petrovski
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, Split, Croatia
| | - Rama Shanker Verma
- Stem Cell and Molecular Biology, Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences. Indian Institute of Technology Madras, Chennai, India
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Mir TA, Alzhrani A, Nakamura M, Iwanaga S, Wani SI, Altuhami A, Kazmi S, Arai K, Shamma T, Obeid DA, Assiri AM, Broering DC. Whole Liver Derived Acellular Extracellular Matrix for Bioengineering of Liver Constructs: An Updated Review. Bioengineering (Basel) 2023; 10:1126. [PMID: 37892856 PMCID: PMC10604736 DOI: 10.3390/bioengineering10101126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 10/29/2023] Open
Abstract
Biomaterial templates play a critical role in establishing and bioinstructing three-dimensional cellular growth, proliferation and spatial morphogenetic processes that culminate in the development of physiologically relevant in vitro liver models. Various natural and synthetic polymeric biomaterials are currently available to construct biomimetic cell culture environments to investigate hepatic cell-matrix interactions, drug response assessment, toxicity, and disease mechanisms. One specific class of natural biomaterials consists of the decellularized liver extracellular matrix (dECM) derived from xenogeneic or allogeneic sources, which is rich in bioconstituents essential for the ultrastructural stability, function, repair, and regeneration of tissues/organs. Considering the significance of the key design blueprints of organ-specific acellular substrates for physiologically active graft reconstruction, herein we showcased the latest updates in the field of liver decellularization-recellularization technologies. Overall, this review highlights the potential of acellular matrix as a promising biomaterial in light of recent advances in the preparation of liver-specific whole organ scaffolds. The review concludes with a discussion of the challenges and future prospects of liver-specific decellularized materials in the direction of translational research.
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Affiliation(s)
- Tanveer Ahmed Mir
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
| | - Alaa Alzhrani
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21423, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia
| | - Makoto Nakamura
- Division of Biomedical System Engineering, Graduate School of Science and Engineering for Education, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan; (M.N.); (S.I.)
| | - Shintaroh Iwanaga
- Division of Biomedical System Engineering, Graduate School of Science and Engineering for Education, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan; (M.N.); (S.I.)
| | - Shadil Ibrahim Wani
- Division of Biomedical System Engineering, Graduate School of Science and Engineering for Education, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan; (M.N.); (S.I.)
| | - Abdullah Altuhami
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
| | - Shadab Kazmi
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
- Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Kenchi Arai
- Department of Clinical Biomaterial Applied Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Talal Shamma
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
| | - Dalia A. Obeid
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
| | - Abdullah M. Assiri
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
- College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia
| | - Dieter C. Broering
- Laboratory of Tissue/Organ Bioengineering & BioMEMS, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia (T.S.)
- College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia
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10
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Gao Y, Xiao J, Chen Z, Ma Y, Liu X, Yang D, Leo HL, Yu H, Kong J, Guo Q. Engineering orthotopic tumor spheroids with organ-specific vasculatures for local chemoembolization evaluation. Biomater Sci 2023; 11:2115-2128. [PMID: 36723179 DOI: 10.1039/d2bm01632j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Developing a three-dimensional (3D) in vitro tumor model with vasculature systems suitable for testing endovascular interventional therapies remains a challenge. Here we develop an orthotopic liver tumor spheroid model that captures the organ-level complexity of vasculature systems and the extracellular matrix to evaluate transcatheter arterial chemoembolization (TACE) treatment. The orthotopic tumor spheroids are derived by seeding HepG2 cell colonies with controlled size and location surrounding the portal triads in a decellularized rat liver matrix and are treated by clinically relevant drug-eluting beads embolized in a portal vein vasculature while maintaining dynamic physiological conditions with nutrient and oxygen supplies through the hepatic vein vasculature. The orthotopic tumor model exhibits strong drug retention inside the spheroids and embolization location-dependent cellular apoptosis responses in an analogous manner to in vivo conditions. Such a tumor spheroid model built in a decellularized scaffold containing organ-specific vasculatures, which closely resembles the unique tumor microenvironment, holds the promise to efficiently assess various diagnostic and therapeutic strategies for endovascular therapies.
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Affiliation(s)
- Yanan Gao
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Jingyu Xiao
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Zijian Chen
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. .,Department of Biomedical Engineering, National University of Singapore, Singapore, 117583, Singapore
| | - Yutao Ma
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Xiaoya Liu
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Dishuang Yang
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Hwa Liang Leo
- Department of Biomedical Engineering, National University of Singapore, Singapore, 117583, Singapore
| | - Hanry Yu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.,Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore.,Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research, Singapore 138669, Singapore.,Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore
| | - Jian Kong
- Department of Interventional Radiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
| | - Qiongyu Guo
- Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
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11
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Afzal Z, Huguet EL. Bioengineering liver tissue by repopulation of decellularised scaffolds. World J Hepatol 2023; 15:151-179. [PMID: 36926238 PMCID: PMC10011915 DOI: 10.4254/wjh.v15.i2.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/22/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Liver transplantation is the only curative therapy for end stage liver disease, but is limited by the organ shortage, and is associated with the adverse consequences of immunosuppression. Repopulation of decellularised whole organ scaffolds with appropriate cells of recipient origin offers a theoretically attractive solution, allowing reliable and timely organ sourcing without the need for immunosuppression. Decellularisation methodologies vary widely but seek to address the conflicting objectives of removing the cellular component of tissues whilst keeping the 3D structure of the extra-cellular matrix intact, as well as retaining the instructive cell fate determining biochemicals contained therein. Liver scaffold recellularisation has progressed from small rodent in vitro studies to large animal in vivo perfusion models, using a wide range of cell types including primary cells, cell lines, foetal stem cells, and induced pluripotent stem cells. Within these models, a limited but measurable degree of physiologically significant hepatocyte function has been reported with demonstrable ammonia metabolism in vivo. Biliary repopulation and function have been restricted by challenges relating to the culture and propagations of cholangiocytes, though advances in organoid culture may help address this. Hepatic vasculature repopulation has enabled sustainable blood perfusion in vivo, but with cell types that would limit clinical applications, and which have not been shown to have the specific functions of liver sinusoidal endothelial cells. Minority cell groups such as Kupffer cells and stellate cells have not been repopulated. Bioengineering by repopulation of decellularised scaffolds has significantly progressed, but there remain significant experimental challenges to be addressed before therapeutic applications may be envisaged.
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Affiliation(s)
- Zeeshan Afzal
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Laurent Huguet
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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12
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Mazloomnejad R, Babajani A, Kasravi M, Ahmadi A, Shariatzadeh S, Bahrami S, Niknejad H. Angiogenesis and Re-endothelialization in decellularized scaffolds: Recent advances and current challenges in tissue engineering. Front Bioeng Biotechnol 2023; 11:1103727. [PMID: 36873356 PMCID: PMC9978201 DOI: 10.3389/fbioe.2023.1103727] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/09/2023] [Indexed: 02/18/2023] Open
Abstract
Decellularization of tissues and organs has recently become a promising approach in tissue engineering and regenerative medicine to circumvent the challenges of organ donation and complications of transplantations. However, one main obstacle to reaching this goal is acellular vasculature angiogenesis and endothelialization. Achieving an intact and functional vascular structure as a vital pathway for supplying oxygen and nutrients remains the decisive challenge in the decellularization/re-endothelialization procedure. In order to better understand and overcome this issue, complete and appropriate knowledge of endothelialization and its determining variables is required. Decellularization methods and their effectiveness, biological and mechanical characteristics of acellular scaffolds, artificial and biological bioreactors, and their possible applications, extracellular matrix surface modification, and different types of utilized cells are factors affecting endothelialization consequences. This review focuses on the characteristics of endothelialization and how to optimize them, as well as discussing recent developments in the process of re-endothelialization.
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Affiliation(s)
- Radman Mazloomnejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Kasravi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Ahmadi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, United States
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Zhang CY, Fu CP, Li XY, Lu XC, Hu LG, Kankala RK, Wang SB, Chen AZ. Three-Dimensional Bioprinting of Decellularized Extracellular Matrix-Based Bioinks for Tissue Engineering. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113442. [PMID: 35684380 PMCID: PMC9182049 DOI: 10.3390/molecules27113442] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 01/01/2023]
Abstract
Three-dimensional (3D) bioprinting is one of the most promising additive manufacturing technologies for fabricating various biomimetic architectures of tissues and organs. In this context, the bioink, a critical element for biofabrication, is a mixture of biomaterials and living cells used in 3D printing to create cell-laden structures. Recently, decellularized extracellular matrix (dECM)-based bioinks derived from natural tissues have garnered enormous attention from researchers due to their unique and complex biochemical properties. This review initially presents the details of the natural ECM and its role in cell growth and metabolism. Further, we briefly emphasize the commonly used decellularization treatment procedures and subsequent evaluations for the quality control of the dECM. In addition, we summarize some of the common bioink preparation strategies, the 3D bioprinting approaches, and the applicability of 3D-printed dECM bioinks to tissue engineering. Finally, we present some of the challenges in this field and the prospects for future development.
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Affiliation(s)
- Chun-Yang Zhang
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Chao-Ping Fu
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
- Correspondence: (C.-P.F.); (A.-Z.C.)
| | - Xiong-Ya Li
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Xiao-Chang Lu
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Long-Ge Hu
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Ranjith Kumar Kankala
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Shi-Bin Wang
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
| | - Ai-Zheng Chen
- Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, China; (C.-Y.Z.); (X.-Y.L.); (X.-C.L.); (L.-G.H.); (R.K.K.); (S.-B.W.)
- Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen 361021, China
- Correspondence: (C.-P.F.); (A.-Z.C.)
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14
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Li K, Tharwat M, Larson EL, Felgendreff P, Hosseiniasl SM, Rmilah AA, Safwat K, Ross JJ, Nyberg SL. Re-Endothelialization of Decellularized Liver Scaffolds: A Step for Bioengineered Liver Transplantation. Front Bioeng Biotechnol 2022; 10:833163. [PMID: 35360393 PMCID: PMC8960611 DOI: 10.3389/fbioe.2022.833163] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/11/2022] [Indexed: 12/12/2022] Open
Abstract
Bioengineered livers (BELs) are an attractive therapeutic alternative to address the donor organ shortage for liver transplantation. The goal of BELs technology aims at replacement or regeneration of the native human liver. A variety of approaches have been proposed for tissue engineering of transplantable livers; the current review will highlight the decellularization-recellularization approach to BELs. For example, vascular patency and appropriate cell distribution and expansion are critical components in the production of successful BELs. Proper solutions to these components of BELs have challenged its development. Several strategies, such as heparin immobilization, heparin-gelatin, REDV peptide, and anti-CD31 aptamer have been developed to extend the vascular patency of revascularized bioengineered livers (rBELs). Other novel methods have been developed to enhance cell seeding of parenchymal cells and to increase graft functionality during both bench and in vivo perfusion. These enhanced methods have been associated with up to 15 days of survival in large animal (porcine) models of heterotopic transplantation but have not yet permitted extended survival after implantation of BELs in the orthotopic position. This review will highlight both the remaining challenges and the potential for clinical application of functional bioengineered grafts.
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Affiliation(s)
- Kewei Li
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department of Pediatric Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Mohammad Tharwat
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- General Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ellen L. Larson
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Philipp Felgendreff
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- Department for General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
| | | | - Anan Abu Rmilah
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | - Khaled Safwat
- General Surgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Scott L. Nyberg
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Scott L. Nyberg,
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15
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Dias ML, Paranhos BA, Goldenberg RCDS. Liver scaffolds obtained by decellularization: A transplant perspective in liver bioengineering. J Tissue Eng 2022; 13:20417314221105305. [PMID: 35756167 PMCID: PMC9218891 DOI: 10.1177/20417314221105305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/19/2022] [Indexed: 11/15/2022] Open
Abstract
Liver transplantation is the only definitive treatment for many diseases that affect this organ, however, its quantity and viability are reduced. The study of liver scaffolds based on an extracellular matrix is a tissue bioengineering strategy with great application in regenerative medicine. Collectively, recent studies suggest that liver scaffold transplantation may assist in reestablishing hepatic function in preclinical diseased animals, which represents a great potential for application as a treatment for patients with liver disease in the future. This review focuses on useful strategies to promote liver scaffold transplantation and the main open questions about this context. We outline the current knowledge about ex vivo bioengineered liver transplantation, including the surgical techniques, recipient survival time, scaffold preparation before transplantation, and liver disease models. We also highlight the current limitations and future directions regarding in vivo bioengineering techniques.
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Affiliation(s)
- Marlon Lemos Dias
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa - INCT - REGENERA, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Bruno Andrade Paranhos
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa - INCT - REGENERA, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
| | - Regina Coeli Dos Santos Goldenberg
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa - INCT - REGENERA, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil
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16
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Functional characterization of a bioengineered liver after heterotopic implantation in pigs. Commun Biol 2021; 4:1157. [PMID: 34620986 PMCID: PMC8497596 DOI: 10.1038/s42003-021-02665-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 09/08/2021] [Indexed: 01/03/2023] Open
Abstract
Organ bioengineering offers a promising solution to the persistent shortage of donor organs. However, the progression of this technology toward clinical use has been hindered by the challenges of reconstituting a functional vascular network, directing the engraftment of specific functional cell types, and defining appropriate culture conditions to concurrently support the health and phenotypic stability of diverse cell lineages. We previously demonstrated the ability to functionally reendothelialize the vasculature of a clinically scaled decellularized liver scaffold with human umbilical vein endothelial cells (HUVECs) and to sustain continuous perfusion in a large animal recovery model. We now report a method for seeding and engrafting primary porcine hepatocytes into a bioengineered liver (BEL) scaffold previously reendothelialized with HUVECs. The resulting BELs were competent for albumin production, ammonia detoxification and urea synthesis, indicating the presence of a functional hepatocyte compartment. BELs additionally slowed ammonia accumulation during in vivo perfusion in a porcine model of surgically induced acute liver failure. Following explant of the graft, BEL parenchyma showed maintenance of canonical endothelial and hepatocyte markers. Taken together, these results support the feasibility of engineering a clinically scaled functional BEL and establish a platform for optimizing the seeding and engraftment of additional liver specific cells.
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17
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Zhu X, Wang Z, Teng F. A review of regulated self-organizing approaches for tissue regeneration. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 167:63-78. [PMID: 34293337 DOI: 10.1016/j.pbiomolbio.2021.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 07/06/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022]
Abstract
Tissue and organ regeneration is the dynamic process by which a population of cells rearranges into a specific form with specific functions. Traditional tissue regeneration utilizes tissue grafting, cell implantation, and structured scaffolds to achieve clinical efficacy. However, tissue grafting methods face a shortage of donor tissue, while cell implantation may involve leakage of the implanted cells without a supportive 3D matrix. Cell migration, proliferation, and differentiation in structured scaffolds may disorganize and frustrate the artificially pre-designed structures, and sometimes involve immunogenic reactions. To overcome this limitation, the self-organizing properties and innate regenerative capability of tissue/organism formation in the absence of guidance by structured scaffolds has been investigated. This review emphasizes the growing subfield of the regulated self-organizing approach for neotissue formation and describes advances in the subfield using diverse, cutting-edge, inter-disciplinarity technologies. We cohesively summarize the directed self-organization of cells in the micro-engineered cell-ECM system and 3D/4D cell printing. Mathematical modeling of cellular self-organization is also discussed for providing rational guidance to intractable problems in tissue regeneration. It is envisioned that future self-organization approaches integrating biomathematics, micro-nano engineering, and gene circuits developed from synthetic biology will continue to work in concert with self-organizing morphogenesis to enhance rational control during self-organizing in tissue and organ regeneration.
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Affiliation(s)
- Xiaolu Zhu
- College of Mechanical & Electrical Engineering, Hohai University, Changzhou, Jiangsu, 213022, China; Changzhou Key Laboratory of Digital Manufacture Technology, Hohai University, Changzhou, Jiangsu, 213022, China; Jiangsu Key Laboratory of Special Robot Technology, Hohai University, Changzhou, Jiangsu, 213022, China.
| | - Zheng Wang
- College of Mechanical & Electrical Engineering, Hohai University, Changzhou, Jiangsu, 213022, China
| | - Fang Teng
- Department of Gynaecology and Obstetrics, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210004, China.
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18
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Khajavi M, Hashemi M, Kalalinia F. Recent advances in optimization of liver decellularization procedures used for liver regeneration. Life Sci 2021; 281:119801. [PMID: 34229008 DOI: 10.1016/j.lfs.2021.119801] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/19/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Abstract
Severe liver diseases have been considered the most common causes of adult deaths worldwide. Until now, liver transplantation is known as the only effective treatment for end stage liver disease. However, it is associated with several problems, most importantly, the side effects of immunosuppressive drugs that should be used after transplantation, and the shortage of tissue donors compared to the increasing number of patients requiring liver transplantation. Currently, tissue/organ decellularization as a new approach in tissue engineering is becoming a valid substitute for managing these kinds of problems. Decellularization of a whole liver is an attractive procedure to create three-dimensional (3D) scaffolds that micro-architecturally and structurally are similar to the native one and could support the repair or replacement of damaged or injured tissue. In this review, the different methods used for decellularization of liver tissue have been reviewed. In addition, the current approaches to overcome the challenges in these techniques are discussed.
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Affiliation(s)
- Mohaddeseh Khajavi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Hashemi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Kalalinia
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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19
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Cell Therapy and Bioengineering in Experimental Liver Regenerative Medicine: In Vivo Injury Models and Grafting Strategies. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00325-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Abstract
Purpose of Review
To describe experimental liver injury models used in regenerative medicine, cell therapy strategies to repopulate damaged livers and the efficacy of liver bioengineering.
Recent Findings
Several animal models have been developed to study different liver conditions. Multiple strategies and modified protocols of cell delivery have been also reported. Furthermore, using bioengineered liver scaffolds has shown promising results that could help in generating a highly functional cell delivery system and/or a whole transplantable liver.
Summary
To optimize the most effective strategies for liver cell therapy, further studies are required to compare among the performed strategies in the literature and/or innovate a novel modifying technique to overcome the potential limitations. Coating of cells with polymers, decellularized scaffolds, or microbeads could be the most appropriate solution to improve cellular efficacy. Besides, overcoming the problems of liver bioengineering may offer a radical treatment for end-stage liver diseases.
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20
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Asadi M, Khalili M, Lotfi H, Vaghefi Moghaddam S, Zarghami N, André H, Alizadeh E. Liver bioengineering: Recent trends/advances in decellularization and cell sheet technologies towards translation into the clinic. Life Sci 2021; 276:119373. [PMID: 33744324 DOI: 10.1016/j.lfs.2021.119373] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 02/07/2023]
Abstract
Development of novel technologies provides the best tissue constructs engineering and maximizes their therapeutic effects in regenerative therapy, especially for liver dysfunctions. Among the currently investigated approaches of tissue engineering, scaffold-based and scaffold-free tissues are widely suggested for liver regeneration. Analogs of liver acellular extracellular matrix (ECM) are utilized in native scaffolds to increase the self-repair and healing ability of organs. Native ECM analog could improve liver repairing through providing the supportive framework for cells and signaling molecules, exerting normal biomechanical, biochemical, and physiological signal complexes. Recently, innovative cell sheet technology is introduced as an alternative for conventional tissue engineering with the advantage of fewer scaffold restrictions and cell culture on a Thermo-Responsive Polymer Surface. These sheets release the layered cells through a temperature-controlled procedure without enzymatic digestion, while preserving the cell-ECM contacts and adhesive molecules on cell-cell junctions. In addition, several novelties have been introduced into the cell sheet and decellularization technologies to aid cell growth, instruct differentiation/angiogenesis, and promote cell migration. In this review, recent trends, advancements, and issues linked to translation into clinical practice are dissected and compared regarding the decellularization and cell sheet technologies for liver tissue engineering.
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Affiliation(s)
- Maryam Asadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Khalili
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajie Lotfi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nosratollah Zarghami
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Helder André
- Department of Clinical Neuroscience, St. Erik Eye Hospital, Karolinska Institute, 11282 Stockholm, Sweden
| | - Effat Alizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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21
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Dias ML, Batista CMP, Secomandi VJK, Silva AC, Monteiro VRS, Faccioli LA, Goldenberg RCS. Surgical Models to Explore Acellular Liver Scaffold Transplantation: Step-by-Step. Organogenesis 2020; 16:95-112. [PMID: 32799604 DOI: 10.1080/15476278.2020.1801273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Acellular liver scaffolds (ALS) have arisen as potential candidates for transplantation. Until now, all reports involving ALS transplantation failed in surgical method descriptions and do not offer support to scientists to reproduce the procedures used in experimental microsurgery to make the results comparable to literature. To overcome the lack of detail information, we described surgical steps details to perform heterotopic and partial orthotopic surgical models to promote ALS transplantation. After preservation and vessel cannulation steps, the liver grafts were decellularized. In addition, ex vivo blood perfusion tests were performed to obtain a successful anticoagulation treatment prior in vivo transplantation. Then, methods of partial liver resection, combination of hand-suture and cuff techniques to complete end-to-end anastomosis between the scaffold and the recipient animal were performed. These procedures which take 30-60 min and were efficient to allow acellular liver scaffold viability and recellularization of different types of cell post-surgery. In conclusion, our methods are practical and simple promising approach that provides the opportunity to investigate ways to achieve sufficient liver function post-transplantation in vivo.
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Affiliation(s)
- Marlon L Dias
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Cíntia M P Batista
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Victor J K Secomandi
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Alexandre C Silva
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil.,Department of Surgery, Clementino Fraga Filho Universitary Hospital, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Victoria R S Monteiro
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Lanuza A Faccioli
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
| | - Regina C S Goldenberg
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil.,National Institute of Science and Technology in Regenerative Medicine- REGENERA, Federal University of Rio De Janeiro , Rio De Janeiro, Brazil
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22
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Saleh T, Ahmed E, Yu L, Song SH, Park KM, Kwak HH, Woo HM. Conjugating homogenized liver-extracellular matrix into decellularized hepatic scaffold for liver tissue engineering. J Biomed Mater Res A 2020; 108:1991-2004. [PMID: 32180336 DOI: 10.1002/jbm.a.36920] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/29/2020] [Accepted: 03/09/2020] [Indexed: 12/13/2022]
Abstract
The generation of a transplantable liver scaffold is crucial for the treatment of end-stage liver failure. Unfortunately, decellularized liver scaffolds suffer from lack of bioactive molecules and functionality. In this study, we conjugated homogenized liver-extracellular matrix (ECM) into a decellularized liver in a rat model to improve its structural and functional properties. The homogenized ECM was prepared, characterized, and subsequently perfused into ethyl carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) activated liver scaffolds. Various techniques were performed to confirm the improvements that were accomplished through the conjugation process; these included micro/ultra-structural analyses, biochemical analysis of ECM components, DNA quantification, swelling ratio, structural stability, calcification properties, platelet activation study, static and dynamic seeding with EAhy926 endothelial cells and HepG2 hepatocarcinoma cells, subcutaneous implantation and intrahepatic transplantation. The results showed that the conjugated scaffolds have superior micro- and ultrastructural and biochemical characteristics. In addition, DNA contents, swelling ratios, calcification properties, platelet reactions, and host inflammatory reactions were not altered with the conjugation process. The conjugated scaffolds revealed better cellular spreading and popularity compared to the non-conjugated scaffolds. Intrahepatic transplantation showed that the conjugated scaffold had higher popularity of hepatic regenerative cells with better angiogenesis. The conjugation of the decellularized liver scaffold with homogenized liver-ECM is a promising tool to improve the quality of the generated scaffold for further transplantation.
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Affiliation(s)
- Tarek Saleh
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Ebtehal Ahmed
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Lina Yu
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Su-Hyeon Song
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Kyung-Mee Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Ho-Hyun Kwak
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Heung-Myong Woo
- Department of Veterinary Science, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea
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Hussein KH, Park KM, Yu L, Song SH, Woo HM, Kwak HH. Vascular reconstruction: A major challenge in developing a functional whole solid organ graft from decellularized organs. Acta Biomater 2020; 103:68-80. [PMID: 31887454 DOI: 10.1016/j.actbio.2019.12.029] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023]
Abstract
Bioengineering a functional organ holds great potential to overcome the current gap between the organ need and shortage of available organs. Whole organ decellularization allows the removal of cells from large-scale organs, leaving behind extracellular matrices containing different growth factors, structural proteins, and a vascular network with a bare surface. Successful application of decellularized tissues as transplantable organs is hampered by the inability to completely reline the vasculature by endothelial cells (ECs), leading to blood coagulation, loss of vascular patency, and subsequent death of reseeded cells. Therefore, an intact, continuous layer of endothelium is essential to maintain proper functioning of the vascular system, which includes the transfer of nutrients to surrounding tissues and protecting other types of cells from shear stress. Here, we aimed to summarize the available cell sources that can be used for reendothelialization in addition to different trials performed by researchers to reconstruct vascularization of decellularized solid organs. Additionally, different techniques for enhancing reendothelialization and the methods used for evaluating reendothelialization efficiency along with the future prospective applications of this field are discussed. STATEMENT OF SIGNIFICANCE: Despite the great progress in whole organ decellularization, reconstruction of vasculature within the engineered constructs is still a major roadblock. Reconstructed endothelium acts as a multifunctional barrier of vessels, which can reduce thrombosis and help delivering of oxygen and nutrients throughout the whole organ. Successful reendothelialization can be achieved through reseeding of appropriate cell types on the naked vasculature with or without modification of its surface. Here, we present the current research milestones that so far established to reconstruct the vascular network in addition to the methods used for evaluating the efficiency of reendotheilization. Thus, this review is quite significant and will aid the researchers to know where we stand toward biofabricating a transplantable organ from decellularizd extracellular matrix.
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Advances in Hepatic Tissue Bioengineering with Decellularized Liver Bioscaffold. Stem Cells Int 2019; 2019:2693189. [PMID: 31198426 PMCID: PMC6526559 DOI: 10.1155/2019/2693189] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 02/08/2019] [Accepted: 03/17/2019] [Indexed: 12/28/2022] Open
Abstract
The burden of liver diseases continues to grow worldwide, and liver transplantation is the only option for patients with end-stage liver disease. This procedure is limited by critical issues, including the low availability of donor organs; thus, novel therapeutic strategies are greatly needed. Recently, bioengineering approaches using decellularized liver scaffolds have been proposed as a novel strategy to overcome these challenges. The aim of this systematic literature review was to identify the major advances in the field of bioengineering using decellularized liver scaffolds and to identify obstacles and challenges for clinical application. The main findings of the articles and each contribution for technique optimization were highlighted, including the protocols of perfusion and decellularization, duration, demonstration of quality control—scaffold acellularity, matrix composition, and preservation of growth factors—and tissue functionality after recellularization. In previous years, many advances have been made as this technique has evolved from studies in animal models to human livers. As the field develops and this promising technique has become much more feasible, many challenges remain, including the selection of appropriate cell types for recellularization, route of cell administration, cell-seeding protocol, and scalability that must be standardized prior to clinical application.
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