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Tavares DF, Mano JF, Oliveira MB. Advances in abiotic tissue-based biomaterials: A focus on decellularization and devitalization techniques. Mater Today Bio 2025; 32:101735. [PMID: 40275948 PMCID: PMC12020859 DOI: 10.1016/j.mtbio.2025.101735] [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: 01/03/2025] [Revised: 03/14/2025] [Accepted: 04/05/2025] [Indexed: 04/26/2025] Open
Abstract
This Review explores the growing and diversifying field of tissue-derived abiotic constructs for tissue engineering applications, with main focus on decellularization and devitalization techniques and principles. Acellular fractions derived from biological tissues, such as the extracellular matrix (ECM), have long been considered a valuable approach for the generation of numerous scaffolds and more complex constructs. The removal of the cellular content has been considered essential to prevent the development of adverse immunological reactions. Nevertheless, the discovery of promising features of certain cellular components has sparked interest in the use of inactivated or devitalized cellular fractions for several applications, particularly in regenerative medicine and inflammation control. Devitalization has been described for several clinical applications, but remains poorly explored in terms of in vitro constructs compared to decellularization methods currently available. In this review, we present and critically evaluate a spectrum of approaches for the decellularization of whole-organs and in vitro constructs, and the most prevalent devitalization techniques, with a discussion on their implications on scaffolds composition, structure, and potentially therapeutic properties. Processing methodologies to achieve optimal cell-based abiotic materials and approaches for their effective characterization are described and discussed. The application of these materials in healthcare, with most focus on regenerative approaches and including examples of commercially available products, is also addressed.
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Affiliation(s)
- Diana F. Tavares
- 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
| | - Mariana B. Oliveira
- Department of Chemistry, CICECO – Aveiro Institute of Materials. University of Aveiro., Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
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Li M, Zhu W, Hu M, Mao X, Weng B, Peng J, Yin S, Mao H, Zhao J. Dynamic profiling of BMSC-dECM reveals accumulation of core matrisome proteins suppresses osteogenic differentiation and bone regeneration. J Adv Res 2025:S2090-1232(25)00315-7. [PMID: 40349957 DOI: 10.1016/j.jare.2025.05.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 03/25/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
INTRODUCTION The extracellular matrix (ECM) of bone mesenchymal stem cells (BMSCs) plays a critical role in tissue development and regeneration. Rather than being inert, the ECM exhibits a dynamic structure that determines cell fate. OBJECTIVES The aim of this study is to investigate the dynamic composition, functional properties, and underlying mechanisms of BMSC-ECM during osteogenic differentiation. We propose that dynamic alterations in BMSC-ECM, particularly in critical matrix proteins, are essential to regulate osteogenic differentiation and bone regeneration. METHODS Dynamic ECM from BMSCs was collected at different time points during culture with or without osteogenic induction, followed by decellularization. A mouse tibial defect model was introduced to assess bone regeneration in vivo. Proteomics was used to analyze the dynamic protein composition pattern, while a comparative transcriptomic analysis further determined the impact of dynamic BMSC-dECM on cellular mRNA profile. RESULTS Decellularized ECMs (dECMs) from late noninduced BMSCs exhibited distinct functional properties compared to the other groups. While early noninduced, early osteogenic (Os)-induced and late Os-induced dECMs promoted bone regeneration, late noninduced dECM dramatically inhibited this process. The protein composition of dECMs, rather than the structure or total ECM content, was the key factor determining their dynamic function. Accumulation of core matrisome during noninduced culture resulted in the inhibition of its function. Consistently, the gene expression profiles of replanted BMSCs on early noninduced/Os-induced dECM and late Os-induced dECM were similar, leaving the late noninduced dECM separate. Moreover, the core matrisome of the external dECM negatively regulated intracellular gene expression. Versican (VCAN) and Asporin (ASPN) might be the key ECM proteins influencing bone regeneration. CONCLUSIONS Accumulation of the core matrisome during noninduction led to solidification and the inactivation of bone regeneration. Targeting the core matrisome might effectively avoid the drawbacks of noninduced dECM, providing novel strategies for developing highly bioactive stem cell-derived dECM.
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Affiliation(s)
- Mei Li
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, the First Affiliated Hospital of Ningbo University, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Weilai Zhu
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Mingyu Hu
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Xufeng Mao
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Bowen Weng
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Jing Peng
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Shuishui Yin
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Haijiao Mao
- Department of Orthopaedic Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China.
| | - Jiyuan Zhao
- Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
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Qiu W, Zhou B, Luo Y, Chen Y, Chen Z, Wu K, Wu H, Wu B, Guo J, Fang F. An Optimized Decellularized Extracellular Matrix from Dental Pulp Stem Cell Sheets Promotes Axonal Regeneration by Multiple Modes in Spinal Cord Injury Rats. Adv Healthc Mater 2025; 14:e2402312. [PMID: 39148180 DOI: 10.1002/adhm.202402312] [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: 06/24/2024] [Revised: 08/07/2024] [Indexed: 08/17/2024]
Abstract
In the field of tissue engineering, the extracellular matrix (ECM) is considered an important element for promoting neural regeneration after spinal cord injury (SCI). Dental pulp stem cells (DPSCs), mesenchymal stem cells that originate from the neural crest, are easy to harvest and culture in vitro, express a variety of neurotrophic factors (NTFs) and deposit a large amount of ECM, making them a good choice for stem cell- or ECM-based treatment of SCI. In the present study, decellularized extracellular matrix (dECM) derived from DPSC sheets is used for the treatment of SCI. Optimization experiments reveal that incubating DPSC sheets with 1% Triton X-100 for 5 min is the best procedure for preparing DPSC dECM. It is found that DPSC dECM promotes nerve repair and regeneration after SCI and restores hindlimb motor function in rats. Mechanistically, DPSC dECM facilitates the migration and neural differentiation of neural stem cells, as well as M2 polarization of microglia, and inhibits the formation of glial scars. This study suggests that the use of DPSC dECM is a potential strategy for the treatment of SCI.
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Affiliation(s)
- Wei Qiu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Bangyi Zhou
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Yifei Luo
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, P. R. China
| | - Yuanting Chen
- Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, 518118, P. R. China
| | - Zehao Chen
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Keke Wu
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511495, P. R. China
| | - Hongle Wu
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, P. R. China
| | - Buling Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
- Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, 518118, P. R. China
| | - Jinshan Guo
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Fuchun Fang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. China
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Cui M, Sun Y, Zhang X, Yang P, Jiang W. Osteochondral tissue engineering in translational practice: histological assessments and scoring systems. Front Bioeng Biotechnol 2024; 12:1434323. [PMID: 39157444 PMCID: PMC11327087 DOI: 10.3389/fbioe.2024.1434323] [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: 05/17/2024] [Accepted: 07/15/2024] [Indexed: 08/20/2024] Open
Abstract
Osteochondral lesions are common pathological alterations in synovial joints. Different techniques have been designed to achieve osteochondral repair, and tissue-engineered osteochondral grafts have shown the most promise. Histological assessments and related scoring systems are crucial for evaluating the quality of regenerated tissue, and the interpretation and comparison of various repair techniques require the establishment of a reliable and widely accepted histological method. To date, there is still no consensus on the type of histological assessment and scoring system that should be used for osteochondral repair. In this review, we summarize common osteochondral staining methods, discuss the criteria regarding high-quality histological images, and assess the current histological scoring systems for osteochondral regeneration. Safranin O/Fast green is the most widely used staining method for the cartilage layer, whereas Gomori and Van Gieson staining detect new bone formation. We suggest including the graft-host interface and more sections together with the basic histological information for images. An ideal scoring system should analyze both the cartilage and bone regions, especially for the subchondral bone plate. Furthermore, histological assessments should be performed over a longer period of time to minimize discrepancies caused by defect size and animal species.
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Affiliation(s)
- Mengying Cui
- The Second Hospital of Jilin University, Jilin, China
| | - Yang Sun
- Orthopedic Medical Center, The Second Hospital of Jilin University, Jilin, China
| | | | - Pengju Yang
- Orthopedic Medical Center, The Second Hospital of Jilin University, Jilin, China
| | - Weibo Jiang
- Orthopedic Medical Center, The Second Hospital of Jilin University, Jilin, China
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Chocarro-Wrona C, López de Andrés J, Rioboó-Legaspi P, Pleguezuelos-Beltrán P, Antich C, De Vicente J, Gálvez-Martín P, López-Ruiz E, Marchal JA. Design and evaluation of a bilayered dermal/hypodermal 3D model using a biomimetic hydrogel formulation. Biomed Pharmacother 2024; 177:117051. [PMID: 38959608 DOI: 10.1016/j.biopha.2024.117051] [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: 04/29/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/05/2024] Open
Abstract
Due to the limitations of the current skin wound treatments, it is highly valuable to have a wound healing formulation that mimics the extracellular matrix (ECM) and mechanical properties of natural skin tissue. Here, a novel biomimetic hydrogel formulation has been developed based on a mixture of Agarose-Collagen Type I (AC) combined with skin ECM-related components: Dermatan sulfate (DS), Hyaluronic acid (HA), and Elastin (EL) for its application in skin tissue engineering (TE). Different formulations were designed by combining AC hydrogels with DS, HA, and EL. Cell viability, hemocompatibility, physicochemical, mechanical, and wound healing properties were investigated. Finally, a bilayered hydrogel loaded with fibroblasts and mesenchymal stromal cells was developed using the Ag-Col I-DS-HA-EL (ACDHE) formulation. The ACDHE hydrogel displayed the best in vitro results and acceptable physicochemical properties. Also, it behaved mechanically close to human native skin and exhibited good cytocompatibility. Environmental scanning electron microscopy (ESEM) analysis revealed a porous microstructure that allows the maintenance of cell growth and ECM-like structure production. These findings demonstrate the potential of the ACDHE hydrogel formulation for applications such as an injectable hydrogel or a bioink to create cell-laden structures for skin TE.
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Affiliation(s)
- Carlos Chocarro-Wrona
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain
| | - Julia López de Andrés
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain
| | - Pablo Rioboó-Legaspi
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain
| | - Paula Pleguezuelos-Beltrán
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain
| | - Cristina Antich
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain; National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 28050, United States
| | - Juan De Vicente
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; F2N2Lab, Magnetic Soft Matter Group, Department of Applied Physics, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | | | - Elena López-Ruiz
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain; Department of Health Sciences, University of Jaén, Jaén 23071, Spain.
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, Granada 18016, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, University Hospitals of Granada, University of Granada, Granada 18012, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada 18016, Spain; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada 18016, Spain; BioFab i3D, Biofabrication and 3D (bio)printing laboratory, Granada 18016, Spain.
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Xu Y, Liu X, Ahmad MA, Ao Q, Yu Y, Shao D, Yu T. Engineering cell-derived extracellular matrix for peripheral nerve regeneration. Mater Today Bio 2024; 27:101125. [PMID: 38979129 PMCID: PMC11228803 DOI: 10.1016/j.mtbio.2024.101125] [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: 03/05/2024] [Revised: 05/28/2024] [Accepted: 06/12/2024] [Indexed: 07/10/2024] Open
Abstract
Extracellular matrices (ECMs) play a key role in nerve repair and are recognized as the natural source of biomaterials. In parallel to extensively studied tissue-derived ECMs (ts-ECMs), cell-derived ECMs (cd-ECMs) also have the capability to partially recapitulate the complicated regenerative microenvironment of native nerve tissues. Notably, cd-ECMs can avoid the shortcomings of ts-ECMs. Cd-ECMs can be prepared by culturing various cells or even autologous cells in vitro under pathogen-free conditions. And mild decellularization can achieve efficient removal of immunogenic components in cd-ECMs. Moreover, cd-ECMs are more readily customizable to achieve the desired functional properties. These advantages have garnered significant attention for the potential of cd-ECMs in neuroregenerative medicine. As promising biomaterials, cd-ECMs bring new hope for the effective treatment of peripheral nerve injuries. Herein, this review comprehensively examines current knowledge about the functional characteristics of cd-ECMs and their mechanisms of interaction with cells in nerve regeneration, with a particular focus on the preparation, engineering optimization, and scalability of cd-ECMs. The applications of cd-ECMs from distinct cell sources reported in peripheral nerve tissue engineering are highlighted and summarized. Furthermore, current limitations that should be addressed and outlooks related to clinical translation are put forward as well.
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Affiliation(s)
- Yingxi Xu
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xianbo Liu
- Department of Orthodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | | | - Qiang Ao
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial, Institute of Regulatory Science for Medical Device, National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, China
| | - Yang Yu
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Dan Shao
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangdong, Guangzhou, China
| | - Tianhao Yu
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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Sheppard AJ, Delgado K, Barfield AM, Xu Q, Massey PA, Dong Y, Barton RS. Rapamycin Inhibits Senescence and Improves Immunomodulatory Function of Mesenchymal Stem Cells Through IL-8 and TGF-β Signaling. Stem Cell Rev Rep 2024; 20:816-826. [PMID: 38340274 PMCID: PMC10984889 DOI: 10.1007/s12015-024-10682-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stromal cells (MSCs) grown in high-density monolayers (sheets) are promising vehicles for numerous bioengineering applications. When MSC sheets are maintained in prolonged cultures, they undergo rapid senescence, limiting their downstream efficacy. Although rapamycin is a potential agent that can inhibit senescence in cell cultures, no study has investigated rapamycin's effect on MSCs grown in high-density culture and its effect on downstream target gene expression. In this study, placental-derived MSCs (PMSCs) were seeded at high density to generate PMSC sheets in 24 hours and were then treated with rapamycin or vehicle for up to 7 days. Autophagy activity, cell senescence and apoptosis, cell size and granularity, and senescence-associated cytokines (IL-6 and IL-8) were analyzed. Differential response in gene expression were assessed via microarray analysis. Rapamycin significantly increased PMSC sheet autophagy activity, inhibited cellular senescence, decreased cell size and granularity at all timepoints. Rapamycin also significantly decreased the number of cells in late apoptosis at day 7 of sheet culture, as well as caspase 3/7 activity at all timepoints. Notably, while rapamycin decreased IL-6 secretion, increased IL-8 levels were observed at all timepoints. Microarray analysis further confirmed the upregulation of IL-8 transcription, as well as provided a list of 396 genes with 2-fold differential expression, where transforming growth factor-β (TGF-β) signaling were identified as important upregulated pathways. Rapamycin both decreased senescence and has an immunomodulatory action of PMSCs grown in sheet culture, which will likely improve the chemotaxis of pro-healing cells to sites of tissue repair in future bioengineering applications.
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Affiliation(s)
- Aaron J Sheppard
- School of Medicine, LSU Health Shreveport, Shreveport, LA, USA
- Department of Orthopedic Surgery, LSU Health Shreveport, Shreveport, LA, USA
| | - Kristin Delgado
- School of Medicine, LSU Health Shreveport, Shreveport, LA, USA
| | | | - Qinqin Xu
- Department of Orthopedic Surgery, LSU Health Shreveport, Shreveport, LA, USA
| | - Patrick A Massey
- Department of Orthopedic Surgery, LSU Health Shreveport, Shreveport, LA, USA
| | - Yufeng Dong
- Department of Orthopedic Surgery, LSU Health Shreveport, Shreveport, LA, USA.
| | - Richard S Barton
- Department of Orthopedic Surgery, LSU Health Shreveport, Shreveport, LA, USA
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Wang YS, Chu WH, Zhai JJ, Wang WY, He ZM, Zhao QM, Li CY. High quality repair of osteochondral defects in rats using the extracellular matrix of antler stem cells. World J Stem Cells 2024; 16:176-190. [PMID: 38455106 PMCID: PMC10915955 DOI: 10.4252/wjsc.v16.i2.176] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/15/2023] [Accepted: 01/19/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Cartilage defects are some of the most common causes of arthritis. Cartilage lesions caused by inflammation, trauma or degenerative disease normally result in osteochondral defects. Previous studies have shown that decellularized extracellular matrix (ECM) derived from autologous, allogenic, or xenogeneic mesenchymal stromal cells (MSCs) can effectively restore osteochondral integrity. AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells (RMCs), a xenogeneic material from antler stem cells, is superior to the currently available treatments for osteochondral defects. METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70% confluence; 50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition. Decellularized sheets of adipocyte-derived MSCs (aMSCs) and antlerogenic periosteal cells (another type of antler stem cells) were used as the controls. Three weeks after ascorbic acid stimulation, the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints. RESULTS The defects were successfully repaired by applying the ECM-sheets. The highest quality of repair was achieved in the RMC-ECM group both in vitro (including cell attachment and proliferation), and in vivo (including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues). Notably, the antler-stem-cell-derived ECM (xenogeneic) performed better than the aMSC-ECM (allogenic), while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells. CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell, particularly the active form (RMC-ECM), can achieve high quality repair/reconstruction of osteochondral defects, suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.
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Affiliation(s)
- Yu-Su Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130000, Jilin Province, China
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, Jilin Province, China
| | - Wen-Hui Chu
- School of Life Science, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jing-Jie Zhai
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun 130000, Jilin Province, China
| | - Wen-Ying Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130000, Jilin Province, China
| | - Zhong-Mei He
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, Jilin Province, China
| | - Quan-Min Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, Jilin Province, China
| | - Chun-Yi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130000, Jilin Province, China.
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Golebiowska AA, Intravaia JT, Sathe VM, Kumbar SG, Nukavarapu SP. Decellularized extracellular matrix biomaterials for regenerative therapies: Advances, challenges and clinical prospects. Bioact Mater 2024; 32:98-123. [PMID: 37927899 PMCID: PMC10622743 DOI: 10.1016/j.bioactmat.2023.09.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 11/07/2023] Open
Abstract
Tissue engineering and regenerative medicine have shown potential in the repair and regeneration of tissues and organs via the use of engineered biomaterials and scaffolds. However, current constructs face limitations in replicating the intricate native microenvironment and achieving optimal regenerative capacity and functional recovery. To address these challenges, the utilization of decellularized tissues and cell-derived extracellular matrix (ECM) has emerged as a promising approach. These biocompatible and bioactive biomaterials can be engineered into porous scaffolds and grafts that mimic the structural and compositional aspects of the native tissue or organ microenvironment, both in vitro and in vivo. Bioactive dECM materials provide a unique tissue-specific microenvironment that can regulate and guide cellular processes, thereby enhancing regenerative therapies. In this review, we explore the emerging frontiers of decellularized tissue-derived and cell-derived biomaterials and bio-inks in the field of tissue engineering and regenerative medicine. We discuss the need for further improvements in decellularization methods and techniques to retain structural, biological, and physicochemical characteristics of the dECM products in a way to mimic native tissues and organs. This article underscores the potential of dECM biomaterials to stimulate in situ tissue repair through chemotactic effects for the development of growth factor and cell-free tissue engineering strategies. The article also identifies the challenges and opportunities in developing sterilization and preservation methods applicable for decellularized biomaterials and grafts and their translation into clinical products.
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Affiliation(s)
| | - Jonathon T. Intravaia
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
| | - Vinayak M. Sathe
- Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT, 06032, USA
| | - Sangamesh G. Kumbar
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Materials Science & Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT, 06032, USA
| | - Syam P. Nukavarapu
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Materials Science & Engineering, University of Connecticut, Storrs, CT, 06269, USA
- Department of Orthopaedic Surgery, University of Connecticut Health, Farmington, CT, 06032, USA
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10
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Taghiyar L, Asadi H, Baghaban Eslaminejad M. A bioscaffold of decellularized whole osteochondral sheet improves proliferation and differentiation of loaded mesenchymal stem cells in a rabbit model. Cell Tissue Bank 2023; 24:711-724. [PMID: 36939962 DOI: 10.1007/s10561-023-10084-2] [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: 12/03/2022] [Accepted: 02/27/2023] [Indexed: 03/21/2023]
Abstract
As a Natural decellularized extracellular matrix, osteochondral tissue is the best scaffold for the restoration of osteoarthritis defects. Bioscaffolds have the most similarly innate properties like biomechanical properties and the preserved connection of the bone-to-cartilage border. Although, their compacity and low porosity particularly, are proven to be difficulties of decellularization and cell penetration. This study aims to develop a new bioscaffold of decellularized osteochondral tissue (DOT) that is recellularized by bone marrow-derived mesenchymal stem cells (BM-MSCs), as a biphasic allograft, which preserved the interface between the cartilage section and subchondral bone of the joint. Whole osteochondral tissues of rabbit knee joints were sheeted in cartilaginous parts in 200-250 µm sections while connected to the subchondral bone and then fully decellularized. The BM-MSCs were seeded on the scaffolds in vitro; some constructs were subcutaneously implanted into the back of the rabbit. The cell penetration, differentiation to bone and cartilage, viability, and cell proliferation in vitro and in vivo were evaluated by qPCR, histological staining, MTT assay, and immunohistochemistry. DNA content analysis and SEM assessments confirmed the decellularization of the bioscaffold. Then, histological and SEM evaluations indicated that the cells could successfully penetrate the bone and cartilage lacunas in implanted grafts. MTT assay confirmed cell proliferation. Prominently, gene expression analysis showed that seeded cells differentiated into osteoblasts and chondrocytes in both bone and cartilage sections. More importantly, seeded cells on the bioscaffold started ECM secretion. Our results indicate that cartilage-to-bone border integrity was largely preserved. Additionally, ECM-sheeted DOT could be employed as a useful scaffold for promoting the regeneration of osteochondral defects.
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Affiliation(s)
- Leila Taghiyar
- Department of Stem Cells and Developmental Biology, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hamideh Asadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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11
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Sun J, Han L, Liu C, Ma J, Li X, Sun S, Wang Z. Effect of autologous lyophilized platelet‑rich fibrin on the reconstruction of osteochondral defects in rabbits. Exp Ther Med 2023; 26:569. [PMID: 37954116 PMCID: PMC10632968 DOI: 10.3892/etm.2023.12268] [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: 10/27/2022] [Accepted: 07/26/2023] [Indexed: 11/14/2023] Open
Abstract
Osteochondral defects caused by degenerative diseases of joints, traumas and inflammation are important issues in clinical practice. Different types of autologous platelet concentrate (PCs) are used in bone and cartilage regeneration. The present study aimed to investigate the effect of lyophilized platelet-rich fibrin (L-PRF) on the repair of osteochondral defects in rabbits. L-PRF was first prepared from fresh PRF (F-PRF) through freeze-drying, and histological and microstructural observations were performed to compare the characteristics of L-PRF and F-PRF. Thereafter, these bioactive scaffolds were implanted into osteochondral defects surgically created in rabbits to assess their effects on tissue repair using micro-CT scanning, histological observations and the evaluation scoring method for cartilage repair established by the International Cartilage Repair Society (ICRS). L-PRF had a histological structure similar to F-PRF. At 16 weeks after implantation surgery, full-thickness osteochondral defects with a diameter of 5 mm and a depth of 4 mm were well-filled with newly regenerated tissues, exhibiting the simultaneous regeneration of avascular articular cartilage and well-vascularized subchondral bone, as proven through macroscopic and microscopic observations in PRF-treated groups compared with that in the untreated group. The application of L-PRF and F-PRF for osteochondral defects in rabbits contributed to massive host remodeling and reconstruction of osteochondral tissues, thus offering a prospective bioactive scaffold for the simultaneous reconstruction of articular cartilage and subchondral bone tissue.
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Affiliation(s)
- Jianwei Sun
- The Fourth Recuperate Area, Guangzhou Special Service Recuperation Center of People's Liberation Army (PLA) of China Rocket Force, Guangzhou, Guangdong 510515, P.R. China
| | - Leng Han
- Department of Pathology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Chundong Liu
- Department of Stomatology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Junli Ma
- Department of Stomatology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Xiao Li
- Department of Stomatology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Shuohui Sun
- Department of Stomatology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong 510010, P.R. China
| | - Zhifa Wang
- Department of Stomatology, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong 510010, P.R. China
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12
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Chen YW, Lin YH, Lin TL, Lee KXA, Yu MH, Shie MY. 3D-biofabricated chondrocyte-laden decellularized extracellular matrix-contained gelatin methacrylate auxetic scaffolds under cyclic tensile stimulation for cartilage regeneration. Biofabrication 2023; 15:045007. [PMID: 37429300 DOI: 10.1088/1758-5090/ace5e1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 07/10/2023] [Indexed: 07/12/2023]
Abstract
Three-dimensional (3D) hydrogel constructs can mimic features of the extracellular matrix (ECM) and have tailorable physicochemical properties to support and maintain the regeneration of articular cartilage. Various studies have shown that mechanical cues affect the cellular microenvironment and thereby influence cellular behavior. In this study, we fabricated an auxetic scaffold to investigate the effect of 3D tensile stimulation on chondrocyte behavior. Different concentrations of decellularized extracellular matrix (dECM) were mixed with fish gelatin methacrylate (FGelMa) and employed for the preparation of dECM/FGelMa auxetic bio-scaffolds using 3D biofabrication technology. We show that when human chondrocytes (HCs) were incorporated into these scaffolds, their proliferation and the expression of chondrogenesis-related markers increased with dECM content. The function of HC was influenced by cyclic tensile stimulation, as shown by increased production of the chondrogenesis-related markers, collagen II and glycosaminoglycans, with the involvement of the yes-associated protein 1 signaling pathway. The biofabricated auxetic scaffold represents an excellent platform for exploring interactions between cells and their mechanical microenvironment.
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Affiliation(s)
- Yi-Wen Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan
- x-Dimension Center for Medical Research and Translation, China Medical University Hospital, Taichung 404332, Taiwan
- High Performance Materials Institute for x-Dimensional Printing, Asia University, Taichung City 41354, Taiwan
| | - Yen-Hong Lin
- x-Dimension Center for Medical Research and Translation, China Medical University Hospital, Taichung 404332, Taiwan
| | - Tsung-Li Lin
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan
- Department of Orthopedics, China Medical University Hospital, Taichung 404332, Taiwan
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung 406040, Taiwan
| | - Kai-Xing Alvin Lee
- Department of Orthopedics, China Medical University Hospital, Taichung 404332, Taiwan
| | - Min-Hua Yu
- x-Dimension Center for Medical Research and Translation, China Medical University Hospital, Taichung 404332, Taiwan
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung 406040, Taiwan
| | - Ming-You Shie
- x-Dimension Center for Medical Research and Translation, China Medical University Hospital, Taichung 404332, Taiwan
- Department of Biomedical Engineering, China Medical University, Taichung 406040, Taiwan
- School of Dentistry, China Medical University, Taichung 406040, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 41354, Taiwan
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13
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Yao S, Liang Z, Lee YW, Yung PSH, Lui PPY. Bioactive Decellularized Tendon-Derived Stem Cell Sheet for Promoting Graft Healing After Anterior Cruciate Ligament Reconstruction. Am J Sports Med 2023; 51:66-80. [PMID: 36592017 DOI: 10.1177/03635465221135770] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Stem cell sheets provide a scaffold-free option for the promotion of graft healing after anterior cruciate ligament reconstruction (ACLR). However, cell viability, stability, and potential uncontrolled actions create challenges for clinical translation. The decellularization of cell sheets may overcome these problems as studies have shown that the natural extracellular matrix of stem cells is bioactive and can promote tissue repair. HYPOTHESIS The decellularized tendon-derived stem cell (dTDSC) sheet can promote graft healing after ACLR. STUDY DESIGN Controlled laboratory study. METHODS An optimized decellularization protocol was developed to decellularize the TDSC sheets. A total of 64 Sprague-Dawley rats underwent ACLR with or without the dTDSC sheet wrapping the tendon graft (n = 32/group). At 2 and 6 weeks after surgery, graft healing was assessed by micro-computed tomography, histology, and biomechanical testing. The accumulation of iNOS+ and CD206+ cells and the expression of metalloproteinase 1 (MMP-1), MMP-13, and tissue inhibitor of metalloprotease 1 (TIMP-1) were assessed by immunohistochemistry. RESULTS The decellularization was successful, with the removal of 98.4% nucleic acid while preserving the collagenous proteins and bioactive factors. The expression of bone morphogenetic protein 2 (BMP-2) and VEGF in the dTDSC sheet was comparable with the TDSC sheet (P > .05). Micro-computed tomography showed significantly more tunnel bone formation in the dTDSC sheet group. The dTDSC sheet group demonstrated better graft osteointegration and higher integrity of graft midsubstance with significantly higher ultimate failure load (16.58 ± 7.24 vs 8.93 ± 2.45 N; P = .002) and stiffness (11.97 ± 5.21 vs 6.73 ± 2.20 N/mm; P = .027). Significantly fewer iNOS+ cells but more CD206+ cells, as well as lower MMP-1 and MMP-13 but higher TIMP-1 expression, were detected at the tendon-bone interface and graft midsubstance in the dTDSC sheet group. CONCLUSION An optimized decellularization protocol for producing bioactive dTDSC sheets was developed. Wrapping tendon graft with a dTDSC sheet promoted graft healing after ACLR, likely via enhancing bone formation and angiogenesis by BMP-2 and VEGF, modulating macrophage polarization and MMP/TIMP expression, and physically protecting the tendon graft. CLINICAL RELEVANCE dTDSC sheets alleviate the quality control and safety concerns of cell transplantation and can be used as a cell-free alternative for the promotion of graft healing in ACLR.
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Affiliation(s)
- Shiyi Yao
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zuru Liang
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yuk Wa Lee
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Patrick Shu Hang Yung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Pauline Po Yee Lui
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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14
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Guo X, Xi L, Yu M, Fan Z, Wang W, Ju A, Liang Z, Zhou G, Ren W. Regeneration of articular cartilage defects: Therapeutic strategies and perspectives. J Tissue Eng 2023; 14:20417314231164765. [PMID: 37025158 PMCID: PMC10071204 DOI: 10.1177/20417314231164765] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/03/2023] [Indexed: 04/03/2023] Open
Abstract
Articular cartilage (AC), a bone-to-bone protective device made of up to 80% water and populated by only one cell type (i.e. chondrocyte), has limited capacity for regeneration and self-repair after being damaged because of its low cell density, alymphatic and avascular nature. Resulting repair of cartilage defects, such as osteoarthritis (OA), is highly challenging in clinical treatment. Fortunately, the development of tissue engineering provides a promising method for growing cells in cartilage regeneration and repair by using hydrogels or the porous scaffolds. In this paper, we review the therapeutic strategies for AC defects, including current treatment methods, engineering/regenerative strategies, recent advances in biomaterials, and present emphasize on the perspectives of gene regulation and therapy of noncoding RNAs (ncRNAs), such as circular RNA (circRNA) and microRNA (miRNA).
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Affiliation(s)
- Xueqiang Guo
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Lingling Xi
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Mengyuan Yu
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Zhenlin Fan
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Weiyun Wang
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Andong Ju
- Abdominal Surgical Oncology, Xinxiang
Central Hospital, Institute of the Fourth Affiliated Hospital of Xinxiang Medical
University, Xinxiang, China
| | - Zhuo Liang
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
| | - Guangdong Zhou
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
- Department of Plastic and
Reconstructive Surgery, Shanghai Key Lab of Tissue Engineering, Shanghai 9th
People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,
China
- Guangdong Zhou, Department of Plastic and
Reconstructive Surgery, Shanghai Key Lab of Tissue Engineering, Shanghai 9th
People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639
Shanghai Manufacturing Bureau Road, Shanghai 200011, China.
| | - Wenjie Ren
- Institutes of Health Central Plain, The
Third Affiliated Hospital of Xinxiang Medical University, Clinical Medical Center of
Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang,
China
- Wenjie Ren, Institute of Regenerative
Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical
University, 601 Jinsui Avenue, Hongqi District, Xinxiang 453003, Henan, China.
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15
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Kamaraj M, Giri PS, Mahapatra S, Pati F, Rath SN. Bioengineering strategies for 3D bioprinting of tubular construct using tissue-specific decellularized extracellular matrix. Int J Biol Macromol 2022; 223:1405-1419. [PMID: 36375675 DOI: 10.1016/j.ijbiomac.2022.11.064] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/02/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022]
Abstract
The goal of the current study is to develop an extracellular matrix bioink that could mimic the biochemical components present in natural blood vessels. Here, we have used an innovative approach to recycle the discarded varicose vein for isolation of endothelial cells and decellularization of the same sample to formulate the decellularized extracellular matrix (dECM) bioink. The shift towards dECM bioink observed as varicose vein dECM provides the tissue-specific biochemical factors that will enhance the regeneration capability. Interestingly, the encapsulated umbilical cord mesenchymal stem cells expressed the markers of vascular smooth muscle cells because of the cues present in the vein dECM. Further, in vitro immunological investigation of dECM revealed a predominant M2 polarization which could further aid in tissue remodeling. A novel approach was used to fabricate vascular construct using 3D bioprinting without secondary support. The outcomes suggest that this could be a potential approach for patient- and tissue-specific blood vessel regeneration.
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Affiliation(s)
- Meenakshi Kamaraj
- Regenerative Medicine and Stem cell (RMS) Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Telangana, India
| | - Pravin Shankar Giri
- Regenerative Medicine and Stem cell (RMS) Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Telangana, India
| | - Sandeep Mahapatra
- Vascular & Endovascular Surgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Falguni Pati
- BioFabTE Lab, Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Telangana, India
| | - Subha Narayan Rath
- Regenerative Medicine and Stem cell (RMS) Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Telangana, India.
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16
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Wang Z, Han L, Zhou Y, Cai J, Sun S, Ma J, Wang W, Li X, Ma L. The combination of a 3D-Printed porous Ti-6Al-4V alloy scaffold and stem cell sheet technology for the construction of biomimetic engineered bone at an ectopic site. Mater Today Bio 2022; 16:100433. [PMID: 36157052 PMCID: PMC9493059 DOI: 10.1016/j.mtbio.2022.100433] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/29/2022] Open
Abstract
Cell sheet technology has been widely used in bone tissue engineering and regenerative medicine. However, controlling the shape and volume of large pieces of engineered bone tissue remains impossible without additional suitable scaffolds. Three-dimensional (3D) printed titanium (Ti) alloy scaffolds are mostly used as implant materials for repairing bone defects, but the unsatisfactory bioactivities of traditional Ti-based scaffolds severely limit their clinical applications. Herein, we hypothesize that the combination of bone marrow mesenchymal stem cell (BMSC) sheet technology and 3D porous Ti–6Al–4V (PT) alloy scaffolds could be used to fabricate biomimetic engineered bone. First, various concentrations of BMSCs were directly cocultured with PT scaffolds to obtain complexes of osteoblastic cell sheets and scaffolds. Then, as an experimental control, an osteoblastic BMSC sheet was prepared by continuous culturing under osteogenic conditions for 2 weeks without passaging and used to wrap the scaffolds. The BMSC sheet was composed of several layers of extracellular matrix (ECM) and a mass of BMSCs. The BMSCs exhibited excellent adherent, proliferative and osteogenic potential when cocultured with PT scaffolds, which may be attributed to the ability of the 3D microstructure of scaffolds to facilitate the biological behaviors of cells, as confirmed by the in vitro results. Moreover, the presence of BMSCs and ECM increased the angiogenic potential of PT scaffolds by the secretion of VEGF. Micro-CT and histological analysis confirmed the in vivo formation of biomimetic engineered bone when the complex of cocultured BMSCs and PT scaffolds and the scaffolds wrapped by prepared BMSC sheets were implanted subcutaneously into nude mice. Therefore, the combination of BMSC sheet technology and 3D-printed PT scaffolds could be used to construct customized biomimetic engineered bone, offering a novel and promising strategy for the precise repair of bone defects.
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Affiliation(s)
- Zhifa Wang
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Leng Han
- Department of Pathology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Ye Zhou
- Laboratory of Basic Medicine, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Jiacheng Cai
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Shuohui Sun
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Junli Ma
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Weijian Wang
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Xiao Li
- Department of Stomatology, General Hospital of Southern Theater of PLA, Guangzhou, 510010, China
| | - Limin Ma
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
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17
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McInnes AD, Moser MAJ, Chen X. Preparation and Use of Decellularized Extracellular Matrix for Tissue Engineering. J Funct Biomater 2022; 13:jfb13040240. [PMID: 36412881 PMCID: PMC9680265 DOI: 10.3390/jfb13040240] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/22/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022] Open
Abstract
The multidisciplinary fields of tissue engineering and regenerative medicine have the potential to revolutionize the practise of medicine through the abilities to repair, regenerate, or replace tissues and organs with functional engineered constructs. To this end, tissue engineering combines scaffolding materials with cells and biologically active molecules into constructs with the appropriate structures and properties for tissue/organ regeneration, where scaffolding materials and biomolecules are the keys to mimic the native extracellular matrix (ECM). For this, one emerging way is to decellularize the native ECM into the materials suitable for, directly or in combination with other materials, creating functional constructs. Over the past decade, decellularized ECM (or dECM) has greatly facilitated the advance of tissue engineering and regenerative medicine, while being challenged in many ways. This article reviews the recent development of dECM for tissue engineering and regenerative medicine, with a focus on the preparation of dECM along with its influence on cell culture, the modification of dECM for use as a scaffolding material, and the novel techniques and emerging trends in processing dECM into functional constructs. We highlight the success of dECM and constructs in the in vitro, in vivo, and clinical applications and further identify the key issues and challenges involved, along with a discussion of future research directions.
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Affiliation(s)
- Adam D. McInnes
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
- Correspondence: ; Tel.: +1-306-966-5435
| | - Michael A. J. Moser
- Department of Surgery, Health Sciences Building, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada
| | - Xiongbiao Chen
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
- Department of Mechanical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A9, Canada
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18
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Gao C, Fu L, Yu Y, Zhang X, Yang X, Cai Q. Strategy of a cell-derived extracellular matrix for the construction of an osteochondral interlayer. Biomater Sci 2022; 10:6472-6485. [PMID: 36173310 DOI: 10.1039/d2bm01230h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Osteochondral defects pose an enormous challenge due to the lack of an effective repair strategy. To tackle this issue, the importance of a calcified cartilage interlayer (CCL) in modulating osteochondral regeneration should be valued. Herein, we proposed that an extracellular matrix (ECM) derived from a suitable cell source might efficiently promote the formation of calcified cartilage. To the end, cell sheets from four kinds of cells, including bone marrow mesenchymal stem cells (BMSCs), pre-osteoblasts (MC3T3), chondrocytes (Cho), and artificially induced hypertrophic chondrocytes (HCho), were obtained by seeding the cells on electrospun fibrous meshes, followed by decellularization to prepare decellularized ECMs (D-ECMs) for BMSC re-seeding and differentiation studies. For cell proliferation, the BMSC-derived D-ECM exhibited the strongest promotion effect. For inducing the hypertrophic phenotype of re-seeded BMSCs, both the BMSC-derived and HCho-derived D-ECMs demonstrated stronger capacity in up-regulating the depositions of related proteins and the expressions of marker genes, as compared to the MC3T3-derived and Cho-derived D-ECMs. Accordingly, from the histological results of their subcutaneous implantation in rats, both the BMSC-derived and HCho-derived D-ECMs displayed obvious Masson's trichrome and Safranin-O/Fast-Green staining colors simultaneously, representing the characteristics related to osteogenesis and chondrogenesis. Differently, MC3T3-derived and Cho-derived D-ECMs were mainly detected during the osteogenic or chondrogenic expression, respectively. These findings confirmed that the BMSC-derived D-ECM could induce hypertrophic chondrocytes, though being a little inferior to the HCho-derived D-ECM. Overall, the BMSC-derived D-ECM could be a potential material in constructing the interlayer for osteochondral tissue engineering scaffolds to improve the regeneration efficiency.
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Affiliation(s)
- Chenyuan Gao
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Lei Fu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Yingjie Yu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
| | - Xin Zhang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing 100191, People's Republic of China.
| | - Xiaoping Yang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China. .,Foshan (Southern China) Institute for New Materials, Foshan 528200, Guangdong, China
| | - Qing Cai
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.
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19
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Ma B, Wang T, Li J, Wang Q. Extracellular matrix derived from Wharton's Jelly-derived mesenchymal stem cells promotes angiogenesis via integrin αVβ3/c-Myc/P300/VEGF. Stem Cell Res Ther 2022; 13:327. [PMID: 35851415 PMCID: PMC9290299 DOI: 10.1186/s13287-022-03009-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/17/2022] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Angiogenesis is required in many physiological conditions, including bone regeneration, wound healing, and tissue regeneration. Mesenchymal stem cells-derived extracellular matrix (MSCs-ECM) could guide intricate cellular and tissue processes such as homeostasis, healing and regeneration. METHODS The purpose of this study is to explore the effect and mechanism of ECM derived from decellularized Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) on endothelial cell viability and angiogenesis. The human umbilical vein endothelial cells (HUVECs) were pretreated with WJ-MSCs ECM for 2d/7d/14d, respectively. After pretreatment, the angiogenesis ability of HUVECs was detected. RESULTS In this study, we found for the first time that WJ-MSCs ECM could improve the angiogenesis ability of HUVECs with a time-dependent manner in vitro. Mechanically, WJ-MSCs ECM activated the focal adhesion kinase (FAK)/P38 signaling pathway via integrin αVβ3, which further promoted the expression of the cellular (c)-Myc. Further, c-Myc increased histone acetylation levels of the vascular endothelial growth factor (VEGF) promoter by recruiting P300, which ultimately promoting VEGF expression. CONCLUSIONS ECM derived from Wharton's Jelly-derived mesenchymal stem cells promotes angiogenesis via integrin αVβ3/c-Myc/P300/VEGF. This study is expected to provide a new approach to promote angiogenesis in bone and tissue regeneration.
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Affiliation(s)
- Beilei Ma
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Tengkai Wang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Qian Wang
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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20
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Liu T, Huang T, Shang M, Han G. CircRNA ITCH: Insight Into Its Role and Clinical Application Prospect in Tumor and Non-Tumor Diseases. Front Genet 2022; 13:927541. [PMID: 35910224 PMCID: PMC9335290 DOI: 10.3389/fgene.2022.927541] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
CircRNA E3 ubiquitin protein ligase (ITCH) (circRNA ITCH, circ-ITCH), a stable closed-loop RNA derived from the 20q11.22 region of chromosome 20, is a new circRNA discovered in the cytoplasm in recent decades. Studies have shown that it does not encode proteins, but regulates proteins expression at different levels. It is down-regulated in tumor diseases and is involved in a number of biological activities, including inhibiting cell proliferation, migration, invasion, and promoting apoptosis. It can also alter disease progression in non-tumor disease by affecting the cell cycle, inflammatory response, and critical proteins. Circ-ITCH also holds a lot of promise in terms of tumor and non-tumor clinical diagnosis, prognosis, and targeted therapy. As a result, in order to aid clinical research in the hunt for a new strategy for diagnosing and treating human diseases, this study describes the mechanism of circ-ITCH as well as its clinical implications.
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Affiliation(s)
- Tong Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tao Huang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Mei Shang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Gang Han
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, China
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21
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Zhang Q, Hu Y, Long X, Hu L, Wu Y, Wu J, Shi X, Xie R, Bi Y, Yu F, Li P, Yang Y. Preparation and Application of Decellularized ECM-Based Biological Scaffolds for Articular Cartilage Repair: A Review. Front Bioeng Biotechnol 2022; 10:908082. [PMID: 35845417 PMCID: PMC9280718 DOI: 10.3389/fbioe.2022.908082] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/09/2022] [Indexed: 11/16/2022] Open
Abstract
Cartilage regeneration is dependent on cellular-extracellular matrix (ECM) interactions. Natural ECM plays a role in mechanical and chemical cell signaling and promotes stem cell recruitment, differentiation and tissue regeneration in the absence of biological additives, including growth factors and peptides. To date, traditional tissue engineering methods by using natural and synthetic materials have not been able to replicate the physiological structure (biochemical composition and biomechanical properties) of natural cartilage. Techniques facilitating the repair and/or regeneration of articular cartilage pose a significant challenge for orthopedic surgeons. Whereas, little progress has been made in this field. In recent years, with advances in medicine, biochemistry and materials science, to meet the regenerative requirements of the heterogeneous and layered structure of native articular cartilage (AC) tissue, a series of tissue engineering scaffolds based on ECM materials have been developed. These scaffolds mimic the versatility of the native ECM in function, composition and dynamic properties and some of which are designed to improve cartilage regeneration. This review systematically investigates the following: the characteristics of cartilage ECM, repair mechanisms, decellularization method, source of ECM, and various ECM-based cartilage repair methods. In addition, the future development of ECM-based biomaterials is hypothesized.
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Affiliation(s)
- Qian Zhang
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Yixin Hu
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Xuan Long
- Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lingling Hu
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Yu Wu
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Ji Wu
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Xiaobing Shi
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Runqi Xie
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Yu Bi
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
| | - Fangyuan Yu
- Senior Department of Orthopedics, Forth Medical Center of Chinese PLA General Hospital, Beijing, China
- *Correspondence: Fangyuan Yu, ; Pinxue Li, ; Yu Yang,
| | - Pinxue Li
- School of Medicine, Nankai University, Tianjin, China
- *Correspondence: Fangyuan Yu, ; Pinxue Li, ; Yu Yang,
| | - Yu Yang
- Department of Orthopedics, The Second People’s Hospital of Guiyang, Guiyang, China
- *Correspondence: Fangyuan Yu, ; Pinxue Li, ; Yu Yang,
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22
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Zhao D, Wang X, Cheng B, Yin M, Hou Z, Li X, Liu K, Tie C, Yin M. Degradation-Kinetics-Controllable and Tissue-Regeneration-Matchable Photocross-linked Alginate Hydrogels for Bone Repair. ACS APPLIED MATERIALS & INTERFACES 2022; 14:21886-21905. [PMID: 35507922 DOI: 10.1021/acsami.2c01739] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Photocross-linked alginate hydrogels, due to their biodegradability, biocompatibility, strong control for gelling kinetics in space and time, and admirable adaptability for in situ polymerization with a minimally invasive approach in surgical procedures, have created great expectations in bone regeneration. However, hydrogels with suitable degradation kinetics that can match the tissue regeneration process have not been designed, which limits their further application in bone tissue engineering. Herein, we finely developed an oxidation strategy for alginate to obtain hydrogels with more suitable degradation rates and comprehensively explored their physical and biological performances in vitro and in vivo to further advance the clinical application for the hydrogels in bone repair. The physical properties of the gels can be tuned via tailoring the degree of alginate oxidation. In particular, in vivo degradation studies showed that the degradation rates of the gels were significantly increased by oxidizing alginate. The activity, proliferation, initial adhesion, and osteogenic differentiation of rat and rabbit bone marrow stromal cells (BMSCs) cultured with/in the hydrogels were explored, and the results demonstrated that the gels possessed excellent biocompatibility and that the encapsulated BMSCs were capable of osteogenic differentiation. Furthermore, in vivo implantation of rabbit BMSC-loaded gels into tibial plateau defects of rabbits demonstrated the feasibility of hydrogels with appropriate degradation rates for bone repair. This study indicated that hydrogels with increasingly controllable and matchable degradation kinetics and satisfactory bioproperties demonstrate great clinical potential in bone tissue engineering and regenerative medicine and could also provide references for drug/growth-factor delivery therapeutic strategies for diseases requiring specific drug/growth-factor durations of action.
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Affiliation(s)
- Delu Zhao
- Center of Stomatology, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
- Hefei Stomatological Clinic Hospital, Anhui Medical University & Hefei Stomatological Hospital, Hefei 230001, Anhui, China
| | - Xin Wang
- Center of Stomatology, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Bo Cheng
- Center of Stomatology, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Miaomiao Yin
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), Sauvage Center for Molecular Sciences, College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, Hubei, China
| | - Zhiqiang Hou
- Department of Spine and Spinal Cord Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China
| | - Xiaobao Li
- Department of Stomatology, Affiliated Wuhan Children's Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, Hubei, China
| | - Kun Liu
- Hefei Stomatological Clinic Hospital, Anhui Medical University & Hefei Stomatological Hospital, Hefei 230001, Anhui, China
| | - Chaorong Tie
- Center of Stomatology, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Miao Yin
- Center of Stomatology, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
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23
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Wang L, Jiang J, Lin H, Zhu T, Cai J, Su W, Chen J, Xu J, Li Y, Wang J, Zhang K, Zhao J. Advances in Regenerative Sports Medicine Research. Front Bioeng Biotechnol 2022; 10:908751. [PMID: 35646865 PMCID: PMC9136559 DOI: 10.3389/fbioe.2022.908751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/21/2022] [Indexed: 01/08/2023] Open
Abstract
Regenerative sports medicine aims to address sports and aging-related conditions in the locomotor system using techniques that induce tissue regeneration. It also involves the treatment of meniscus and ligament injuries in the knee, Achilles’ tendon ruptures, rotator cuff tears, and cartilage and bone defects in various joints, as well as the regeneration of tendon–bone and cartilage–bone interfaces. There has been considerable progress in this field in recent years, resulting in promising steps toward the development of improved treatments as well as the identification of conundrums that require further targeted research. In this review the regeneration techniques currently considered optimal for each area of regenerative sports medicine have been reviewed and the time required for feasible clinical translation has been assessed. This review also provides insights into the direction of future efforts to minimize the gap between basic research and clinical applications.
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Affiliation(s)
- Liren Wang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Regenerative Sports Medicine and Translational Youth Science and Technology Innovation Workroom, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Jiang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Regenerative Sports Medicine and Translational Youth Science and Technology Innovation Workroom, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Regenerative Sports Medicine Lab of the Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’ Hospital, Shanghai, China
| | - Hai Lin
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Tonghe Zhu
- School of Chemistry and Chemical Engineering, Shanghai Engineering Research Center of Pharmaceutical Intelligent Equipment, Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Non-Coding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai, China
| | - Jiangyu Cai
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Wei Su
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jiebo Chen
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Junjie Xu
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Yamin Li
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jing Wang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Kai Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- *Correspondence: Kai Zhang, ; Jinzhong Zhao,
| | - Jinzhong Zhao
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Regenerative Sports Medicine and Translational Youth Science and Technology Innovation Workroom, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Regenerative Sports Medicine Lab of the Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’ Hospital, Shanghai, China
- *Correspondence: Kai Zhang, ; Jinzhong Zhao,
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Neishabouri A, Soltani Khaboushan A, Daghigh F, Kajbafzadeh AM, Majidi Zolbin M. Decellularization in Tissue Engineering and Regenerative Medicine: Evaluation, Modification, and Application Methods. Front Bioeng Biotechnol 2022; 10:805299. [PMID: 35547166 PMCID: PMC9081537 DOI: 10.3389/fbioe.2022.805299] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 04/04/2022] [Indexed: 12/14/2022] Open
Abstract
Reproduction of different tissues using scaffolds and materials is a major element in regenerative medicine. The regeneration of whole organs with decellularized extracellular matrix (dECM) has remained a goal despite the use of these materials for different purposes. Recently, decellularization techniques have been widely used in producing scaffolds that are appropriate for regenerating damaged organs and may be able to overcome the shortage of donor organs. Decellularized ECM offers several advantages over synthetic compounds, including the preserved natural microenvironment features. Different decellularization methods have been developed, each of which is appropriate for removing cells from specific tissues under certain conditions. A variety of methods have been advanced for evaluating the decellularization process in terms of cell removal efficiency, tissue ultrastructure preservation, toxicity, biocompatibility, biodegradability, and mechanical resistance in order to enhance the efficacy of decellularization methods. Modification techniques improve the characteristics of decellularized scaffolds, making them available for the regeneration of damaged tissues. Moreover, modification of scaffolds makes them appropriate options for drug delivery, disease modeling, and improving stem cells growth and proliferation. However, considering different challenges in the way of decellularization methods and application of decellularized scaffolds, this field is constantly developing and progressively moving forward. This review has outlined recent decellularization and sterilization strategies, evaluation tests for efficient decellularization, materials processing, application, and challenges and future outlooks of decellularization in regenerative medicine and tissue engineering.
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Affiliation(s)
- Afarin Neishabouri
- Pediatric Urology and Regenerative Medicine Research Center, Children’s Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran
| | - Alireza Soltani Khaboushan
- Pediatric Urology and Regenerative Medicine Research Center, Children’s Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Daghigh
- Department of Physiology, Faculty of Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran
| | - Abdol-Mohammad Kajbafzadeh
- Pediatric Urology and Regenerative Medicine Research Center, Children’s Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran
- *Correspondence: Masoumeh Majidi Zolbin, ; Abdol-Mohammad Kajbafzadeh,
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Children’s Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran
- *Correspondence: Masoumeh Majidi Zolbin, ; Abdol-Mohammad Kajbafzadeh,
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25
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Recent Biomimetic Approaches for Articular Cartilage Tissue Engineering and Their Clinical Applications: Narrative Review of the Literature. Adv Orthop 2022; 2022:8670174. [PMID: 35497390 PMCID: PMC9054483 DOI: 10.1155/2022/8670174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
Since articular cartilage is lacking blood vessels and nerves, its capacity to heal is extremely limited. This means that ruptured cartilage affects the joint as a whole. A health issue known as osteoarthritis can develop as a result of injury and deterioration. Osteoarthritis development can be speeded up by the widespread deterioration of articular cartilage, which ranks third on the list of musculoskeletal disorders requiring rehabilitation, behind only low back pain and broken bones. The current treatments for cartilage repair are ineffective and rarely restore full function or tissue normalcy. A promising new technology in tissue engineering may help create functional cartilage tissue substitutes. Ensuring that the cell source is loaded with bioactive molecules that promote cellular differentiation and/or maturation is the general approach. This review summarizes recent advances in cartilage tissue engineering, and recent clinical trials have been conducted to provide a comprehensive overview of the most recent research developments and clinical applications in the framework of degenerated articular cartilage and osteoarthritis.
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26
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Zhou M, Guo M, Shi X, Ma J, Wang S, Wu S, Yan W, Wu F, Zhang P. Synergistically Promoting Bone Regeneration by Icariin-Incorporated Porous Microcarriers and Decellularized Extracellular Matrix Derived From Bone Marrow Mesenchymal Stem Cells. Front Bioeng Biotechnol 2022; 10:824025. [PMID: 35464719 PMCID: PMC9021399 DOI: 10.3389/fbioe.2022.824025] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 01/27/2022] [Indexed: 11/13/2022] Open
Abstract
Multifunctionality has becoming essential for bone tissue engineering materials, such as drug release. In this study, icariin (ICA)-incorporated poly(glycolide-co-caprolactone) (PGCL) porous microcarriers were fabricated and then coated with decellularized extracellular matrix (dECM) which was derived from bone marrow mesenchymal stem cells (BMSC). The porous structure was generated due to the soluble gelatin within the microcarriers. The initial released ICA in microcarriers regulated osteogenic ECM production by BMSCs during ECM formation. The dECM could further synergistically enhance the migration and osteogenic differentiation of BMSCs together with ICA as indicated by the transwell migration assay, ALP and ARS staining, as well as gene and protein expression. Furthermore, in vivo results also showed that dECM and ICA exhibited excellent synergistic effects in repairing rat calvarial defects. These findings suggest that the porous microcarriers loaded with ICA and dECM coatings have great potential in the field of bone tissue engineering.
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Affiliation(s)
- Mengyang Zhou
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Min Guo
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Xincui Shi
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Jie Ma
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Shutao Wang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Shuo Wu
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Weiqun Yan
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
- *Correspondence: Weiqun Yan, ; Feng Wu, ; Peibiao Zhang,
| | - Feng Wu
- Foshan Hospital of Traditional Chinese Medicine/Foshan Hospital of TCM, Foshan, China
- *Correspondence: Weiqun Yan, ; Feng Wu, ; Peibiao Zhang,
| | - Peibiao Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
- *Correspondence: Weiqun Yan, ; Feng Wu, ; Peibiao Zhang,
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27
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Begines B, Arevalo C, Romero C, Hadzhieva Z, Boccaccini AR, Torres Y. Fabrication and Characterization of Bioactive Gelatin-Alginate-Bioactive Glass Composite Coatings on Porous Titanium Substrates. ACS APPLIED MATERIALS & INTERFACES 2022; 14:15008-15020. [PMID: 35316017 PMCID: PMC8990524 DOI: 10.1021/acsami.2c01241] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/10/2022] [Indexed: 05/10/2023]
Abstract
In this research work, the fabrication of biphasic composite implants has been investigated. Porous, commercially available pure Ti (50 vol % porosity and pore distributions of 100-200, 250-355, and 355-500 μm) has been used as a cortical bone replacement, while different composites based on a polymer blend (gelatin and alginate) and bioactive glass (BG) 45S5 have been applied as a soft layer for cartilage tissues. The microstructure, degradation rates, biofunctionality, and wear behavior of the different composites were analyzed to find the best possible coating. Experiments demonstrated the best micromechanical balance for the substrate containing 200-355 μm size range distribution. In addition, although the coating prepared from alginate presented a lower mass loss, the composite containing 50% alginate and 50% gelatin showed a higher elastic recovery, which entails that this type of coating could replicate the functions of the soft tissue in areas of the joints. Therefore, results revealed that the combinations of porous commercially pure Ti and composites prepared from alginate/gelatin/45S5 BG are candidates for the fabrication of biphasic implants not only for the treatment of osteochondral defects but also potentially for any other diseases affecting simultaneously hard and soft tissues.
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Affiliation(s)
- Belen Begines
- Departamento
de Química Orgánica y Farmacéutica, Facultad
de Farmacia, Universidad de Sevilla, c/ Profesor García González
2, Seville 41012, Spain
| | - Cristina Arevalo
- Departamento
de Ingeniería y Ciencia de los Materiales y del Transporte, Escuela Politécnica Superior, c/ Virgen de África 7, Seville 41011, Spain
| | - Carlos Romero
- Departamento
de Ingeniería y Ciencia de los Materiales y del Transporte, Escuela Politécnica Superior, c/ Virgen de África 7, Seville 41011, Spain
- Department
of Materials Science and Engineering and Chemical Engineering, Universidad Carlos III de Madrid, Av. de la Universidad 30, Leganés, Madrid 28911, Spain
| | - Zoya Hadzhieva
- Institute
of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Cauerstraße 6, Erlangen 91058, Germany
| | - Aldo R. Boccaccini
- Institute
of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Cauerstraße 6, Erlangen 91058, Germany
| | - Yadir Torres
- Departamento
de Ingeniería y Ciencia de los Materiales y del Transporte, Escuela Politécnica Superior, c/ Virgen de África 7, Seville 41011, Spain
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28
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Chen YC, Liao HJ, Hsu YM, Shen YS, Chang CH. Delivery of Mesenchymal Stem Cell in Dialdehyde Methylcellulose-Succinyl-Chitosan Hydrogel Promotes Chondrogenesis in a Porcine Model. Polymers (Basel) 2022; 14:polym14071474. [PMID: 35406348 PMCID: PMC9002496 DOI: 10.3390/polym14071474] [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: 02/22/2022] [Revised: 03/22/2022] [Accepted: 03/27/2022] [Indexed: 02/04/2023] Open
Abstract
Due to the limitation in the current treatment modalities, such as secondary surgery in ACI and fibrocartilage formation in microfracture surgery, various scaffolds or hydrogels have been developed for cartilage regeneration. In the present study, we used sodium periodate to oxidize methylcellulose and formed dialdehyde methylcellulose (DAC) after dialysis and freeze-drying process, DAC was further mixed with succinyl-chitosan (SUC) to form an DAC-SUC in situ forming hydrogel. The hydrogel is a stiffness, elastic-like and porous hydrogel according to the observation of SEM and rheological analysis. DAC-SUC13 hydrogel possess well cell-compatibility as well as biodegradability. Most bone marrow mesenchymal stem cells (BM-pMSCs) were alive in the hydrogel and possess chondrogenesis potential. According to the results of animal study, we found DAC-SUC13 hydrogel can function as a stem cell carrier to promote glycosaminoglycans and type II collagen synthesis in the osteochondral defects of porcine knee. These findings suggested that DAC-SUC13 hydrogel combined with stem cell is a potential treatment for cartilage defects repair in the future.
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Affiliation(s)
- Yu-Chun Chen
- Department of Chemical Engineering, National United University, Miaoli 360302, Taiwan;
| | - Hsiu-Jung Liao
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; (H.-J.L.); (Y.-M.H.); (Y.-S.S.)
| | - Yuan-Ming Hsu
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; (H.-J.L.); (Y.-M.H.); (Y.-S.S.)
| | - Yi-Shan Shen
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; (H.-J.L.); (Y.-M.H.); (Y.-S.S.)
- Department of Biomedical Engineering, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; (H.-J.L.); (Y.-M.H.); (Y.-S.S.)
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan City 320315, Taiwan
- Correspondence:
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29
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Zhou S, Bei Z, Wei J, Yan X, Wen H, Cao Y, Li H. Mussel-inspired injectable chitosan hydrogel modified with catechol for cell adhesion and cartilage defect repair. J Mater Chem B 2022; 10:1019-1030. [PMID: 34994756 DOI: 10.1039/d1tb02241e] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Repairing articular cartilage defects is a great challenge due to the poor self-regenerative capability of cartilage. Hydrogel-based tissue engineering has been considered an effective strategy. In this study, inspired by mussel chemistry, catechol-modified chitosan (CS-C) hydrogel was prepared under the catalysis of horseradish peroxidase/hydrogen peroxide (HRP/H2O2) for cartilage defect repair in a rat model. The rheological and swelling properties and biodegradation behavior of the CS-C hydrogel were investigated. Besides, the chondrogenic effect of bone mesenchymal stem cells (BMSCs) within the CS-C hydrogel was also assessed in vitro. Moreover, after injecting in rat cartilage defects, the capability of cartilage repair of the BMSC-laden CS-C hydrogel was evaluated in vivo. The results showed that the rheological property, swelling property and biodegradation behavior of the CS-C hydrogel changed with the concentration of CS-C macromolecules. Besides, the CS-C hydrogel had good biocompatibility with BMSCs and could promote the proliferation and chondrogenic differentiation of BMSCs in vitro. As for cartilage defect repair in vivo, through the evaluation of gross observation and histology, the BMSC-laden CS-C hydrogel showed better reconstruction of hyaline cartilage than the untreated group and CS-C hydrogel only. Therefore, CS-C hydrogel laden with BMSC might be a promising strategy for repairing cartilage defects.
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Affiliation(s)
- Siqi Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Zhongwu Bei
- Key Laboratory of Optoelectronic Chemical Materials and Devices of Ministry of Education, Jianghan University, Wuhan 430056, China
| | - Jian Wei
- Department of Joint Orthopedics, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, 545007, China
| | - Xinxin Yan
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Haiyan Wen
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yiping Cao
- Key Laboratory of Optoelectronic Chemical Materials and Devices of Ministry of Education, Jianghan University, Wuhan 430056, China
| | - Haohuan Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
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Jiang D, Xie X, Wang C, Li W, He J. Exosomal MicroRNA-204 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) Inhibits Cell Proliferation and Induces Apoptosis Through NF- κB Signaling Pathway in Breast Cancer. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Our study intends to assess the relationship between exosomes derived from bone marrow mesenchymal stem cells (BMSC-exo) and breast cancer. BMSC-exo were isolated and characterized by transmission electron microscopy. After transfection of BMSCs with miR-204 inhibitor, breast cancer
cells were incubated with BMSC-exo followed by analysis of cell proliferation by CCK-8 assay, cell apoptosis by flow cytometry, and expression of apoptosis-related protein and NF-κB signaling by western blot. The co-culture of BMSC-exo with breast cancer cells enhanced miR-204
transcription, inhibited cell proliferation and induced apoptosis. Further, BMSC-exo accelerated apoptosis as demonstrated by the increased level of Bax and casepase-3 and decreased Bcl-2 expression, as well as reduced NF-κB signaling activity. But knockdown of miR-204 abolished
the effect of BMSC-exo on apoptosis and proliferation with NF-κB signaling activation. In conclusion, miR-204 from BMSC-exo restrains growth of breast cancer cell and might be a novel target for treating breast cancer.
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Affiliation(s)
- Daqing Jiang
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine of Xi’an Jiaotong University, Xi’an, Shannxi, 710061, China
| | - Xianxin Xie
- Department of Breast Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning, 110042, China
| | - Cong Wang
- Department of Breast Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning, 110042, China
| | - Weijie Li
- Department of Breast Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning, 110042, China
| | - Jianjun He
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine of Xi’an Jiaotong University, Xi’an, Shannxi, 710061, China
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31
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Wen C, Lin L, Zou R, Lin F, Liu Y. Mesenchymal stem cell-derived exosome mediated long non-coding RNA KLF3-AS1 represses autophagy and apoptosis of chondrocytes in osteoarthritis. Cell Cycle 2022; 21:289-303. [PMID: 34964696 PMCID: PMC8855872 DOI: 10.1080/15384101.2021.2019411] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Osteoarthritis is a degenerative joint disease and a leading cause of adult disability. Our previous study has reported that mesenchymal stem cell-derived exosomes (MSC-Exo) mediated long non-coding RNA KLF3-AS1 improves osteoarthritis. This study aims to investigate the molecular mechanism of KLF3-AS1 in osteoarthritis. Chondrocytes were treated with IL-1β to induce chondrocyte injury, followed by MSC-Exo treatment. We found that MSC-Exo enhanced KLF3-AS1 expression in IL-1β-treated chondrocytes. IL-1β treatment reduced cell viability and enhanced apoptosis in chondrocytes. MSC-Exo-mediated KLF3-AS1 promoted cell viability and repressed apoptosis of IL-1β-treated chondrocytes. Rapamycin (autophagy activator) promoted cell viability and suppressed apoptosis of chondrocytes by activating autophagy. Moreover, KLF3-AS1 interacted with YBX1 in chondrocytes. MSC-Exo-mediated KLF3-AS1 activated PI3K/Akt/mTOR signaling pathway, which was abrogated by YBX1 silencing. MSC-Exo-mediated KLF3-AS1 repressed autophagy and apoptosis of chondrocytes by activating PI3K/Akt/mTOR signaling pathway. In conclusion, our data demonstrate that MSC-Exo-mediated KLF3-AS1 inhibits autophagy and apoptosis of IL-1β-treated chondrocyte through PI3K/Akt/mTOR signaling pathway. KLF3-AS1 activates PI3K/Akt/mTOR signaling pathway by targeting YBX1 to improve the progression of osteoarthritis. Thus, this work suggests that MSC-Exo-mediated KLF3-AS1 may be a potential therapeutic target for osteoarthritis.
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Affiliation(s)
- Chuanyang Wen
- Department of Orthopaedics, Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Lupan Lin
- Department of Orthopaedics, Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Rui Zou
- Department of Orthopaedics, Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Fuqing Lin
- Department of Orthopaedics, Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Yubao Liu
- Department of Orthopaedics, Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China,CONTACT Yubao Liu Luhe People’s Hospital of Nanjing, Nanjing, Jiangsu, China
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32
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Daou F, Cochis A, Leigheb M, Rimondini L. Current Advances in the Regeneration of Degenerated Articular Cartilage: A Literature Review on Tissue Engineering and Its Recent Clinical Translation. MATERIALS (BASEL, SWITZERLAND) 2021; 15:31. [PMID: 35009175 PMCID: PMC8745794 DOI: 10.3390/ma15010031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 12/23/2022]
Abstract
Functional ability is the basis of healthy aging. Articular cartilage degeneration is amongst the most prevalent degenerative conditions that cause adverse impacts on the quality of life; moreover, it represents a key predisposing factor to osteoarthritis (OA). Both the poor capacity of articular cartilage for self-repair and the unsatisfactory outcomes of available clinical interventions make innovative tissue engineering a promising therapeutic strategy for articular cartilage repair. Significant progress was made in this field; however, a marked heterogeneity in the applied biomaterials, biofabrication, and assessments is nowadays evident by the huge number of research studies published to date. Accordingly, this literature review assimilates the most recent advances in cell-based and cell-free tissue engineering of articular cartilage and also focuses on the assessments performed via various in vitro studies, ex vivo models, preclinical in vivo animal models, and clinical studies in order to provide a broad overview of the latest findings and clinical translation in the context of degenerated articular cartilage and OA.
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Affiliation(s)
- Farah Daou
- Department of Health Sciences, Center for Translational Research on Autoimmune and Allergic Diseases-CAAD, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (F.D.); (A.C.); (M.L.)
| | - Andrea Cochis
- Department of Health Sciences, Center for Translational Research on Autoimmune and Allergic Diseases-CAAD, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (F.D.); (A.C.); (M.L.)
| | - Massimiliano Leigheb
- Department of Health Sciences, Center for Translational Research on Autoimmune and Allergic Diseases-CAAD, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (F.D.); (A.C.); (M.L.)
- Department of Orthopaedics and Traumatology, “Maggiore della Carità” Hospital, 28100 Novara, Italy
| | - Lia Rimondini
- Department of Health Sciences, Center for Translational Research on Autoimmune and Allergic Diseases-CAAD, Università del Piemonte Orientale UPO, 28100 Novara, Italy; (F.D.); (A.C.); (M.L.)
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33
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Guan Y, Yang B, Xu W, Li D, Wang S, Ren Z, Zhang J, Zhang T, Liu XZ, Li J, Li C, Meng F, Han F, Wu T, Wang Y, Peng J. Cell-derived extracellular matrix materials for tissue engineering. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:1007-1021. [PMID: 34641714 DOI: 10.1089/ten.teb.2021.0147] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The involvement of cell-derived extracellular matrix (CDM) in assembling tissue engineering scaffolds has yielded significant results. CDM possesses excellent characteristics, such as ideal cellular microenvironment mimicry and good biocompatibility, which make it a popular research direction in the field of bionanomaterials. CDM has significant advantages as an expansion culture substrate for stem cells, including stabilization of phenotype, reversal of senescence, and guidance of specific differentiation. In addition, the applications of CDM-assembled tissue engineering scaffolds for disease simulation and tissue organ repair are comprehensively summarized; the focus is mainly on bone and cartilage repair, skin defect or wound healing, engineered blood vessels, peripheral nerves, and periodontal tissue repair. We consider CDM a highly promising bionic biomaterial for tissue engineering applications and propose a vision for its comprehensive development.
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Affiliation(s)
- Yanjun Guan
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, Beijing, China;
| | - Boyao Yang
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, Beijing, China;
| | - Wenjing Xu
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, Beijing, China;
| | - Dongdong Li
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, Beijing, China;
| | - Sidong Wang
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, Beijing, China;
| | - Zhiqi Ren
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Jian Zhang
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Tieyuan Zhang
- Chinese PLA General Hospital, 104607, Institute of Orthopedics, Chinese PLA, General Hospital; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Xiu-Zhi Liu
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Junyang Li
- Nankai University School of Medicine, 481107, Tianjin, Tianjin, China.,Chinese PLA General Hospital, 104607, Beijing, Beijing, China;
| | - Chaochao Li
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Fanqi Meng
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China.,Peking University People's Hospital, 71185, Department of spine surgery, Beijing, China;
| | - Feng Han
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Tong Wu
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China;
| | - Yu Wang
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China.,Nantong University, 66479, Co-innovation Center of Neuroregeneration, Nantong, Jiangsu, China;
| | - Jiang Peng
- Chinese PLA General Hospital, 104607, Institute of Orthopedics; Beijing Key Lab of Regenerative Medicine in Orthopedics; Key Lab of Musculoskeletal Trauma & War Injuries, Beijing, China.,Nantong University, 66479, Co-innovation Center of Neuroregeneration, Nantong, Jiangsu, China;
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34
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The potential utility of hybrid photo-crosslinked hydrogels with non-immunogenic component for cartilage repair. NPJ Regen Med 2021; 6:54. [PMID: 34508081 PMCID: PMC8433347 DOI: 10.1038/s41536-021-00166-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 08/19/2021] [Indexed: 12/12/2022] Open
Abstract
Finding a suitable biomaterial for scaffolding in cartilage tissue engineering has proved to be far from trivial. Nonetheless, it is clear that biomimetic approaches based on gelatin (Gel) and hyaluronic acid (HA) have particular promise. Herein, a set of formulations consisting of photo-polymerizable Gel; photo-polymerizable HA, and allogenic decellularized cartilage matrix (DCM), is synthesized and characterized. The novelty of this study lies particularly in the choice of DCM, which was harvested from an abnormal porcine with α-1,3-galactose gene knockout. The hybrid hydrogels were prepared and studied extensively, by spectroscopic methods, for their capacity to imbibe water, for their behavior under compression, and to characterize microstructure. Subsequently, the effects of the hydrogels on contacting cells (in vitro) were studied, i.e., cytotoxicity, morphology, and differentiation through monitoring the specific markers ACAN, Sox9, Coll2, and Col2α1, hypertrophy through monitoring the specific markers alkaline phosphatase (ALP) and Col 10A1. In vivo performance of the hydrogels was assessed in a rat knee cartilage defect model. The new data expand our understanding of hydrogels built of Gel and HA, since they reveal that a significant augmenting role can be played by DCM. The data strongly suggest that further experimentation in larger cartilage-defect animal models is worthwhile and has potential utility for tissue engineering and regenerative medicine.
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35
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Li H, Li P, Yang Z, Gao C, Fu L, Liao Z, Zhao T, Cao F, Chen W, Peng Y, Yuan Z, Sui X, Liu S, Guo Q. Meniscal Regenerative Scaffolds Based on Biopolymers and Polymers: Recent Status and Applications. Front Cell Dev Biol 2021; 9:661802. [PMID: 34327197 PMCID: PMC8313827 DOI: 10.3389/fcell.2021.661802] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Knee menisci are structurally complex components that preserve appropriate biomechanics of the knee. Meniscal tissue is susceptible to injury and cannot heal spontaneously from most pathologies, especially considering the limited regenerative capacity of the inner avascular region. Conventional clinical treatments span from conservative therapy to meniscus implantation, all with limitations. There have been advances in meniscal tissue engineering and regenerative medicine in terms of potential combinations of polymeric biomaterials, endogenous cells and stimuli, resulting in innovative strategies. Recently, polymeric scaffolds have provided researchers with a powerful instrument to rationally support the requirements for meniscal tissue regeneration, ranging from an ideal architecture to biocompatibility and bioactivity. However, multiple challenges involving the anisotropic structure, sophisticated regenerative process, and challenging healing environment of the meniscus still create barriers to clinical application. Advances in scaffold manufacturing technology, temporal regulation of molecular signaling and investigation of host immunoresponses to scaffolds in tissue engineering provide alternative strategies, and studies have shed light on this field. Accordingly, this review aims to summarize the current polymers used to fabricate meniscal scaffolds and their applications in vivo and in vitro to evaluate their potential utility in meniscal tissue engineering. Recent progress on combinations of two or more types of polymers is described, with a focus on advanced strategies associated with technologies and immune compatibility and tunability. Finally, we discuss the current challenges and future prospects for regenerating injured meniscal tissues.
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Affiliation(s)
- Hao Li
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Pinxue Li
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhen Yang
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Cangjian Gao
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Liwei Fu
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhiyao Liao
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Tianyuan Zhao
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Fuyang Cao
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China
| | - Wei Chen
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yu Peng
- School of Medicine, Nankai University, Tianjin, China
| | - Zhiguo Yuan
- Department of Bone and Joint Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang Sui
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China
| | - Shuyun Liu
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China
| | - Quanyi Guo
- The First Medical Center, Chinese PLA General Hospital, Institute of Orthopedics, Beijing, China.,Beijing Key Lab of Regenerative Medicine in Orthopedics, Beijing, China.,Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
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36
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Zhang F, Lin F, Xu Z, Huang Z. Circular RNA ITCH promotes extracellular matrix degradation via activating Wnt/β-catenin signaling in intervertebral disc degeneration. Aging (Albany NY) 2021; 13:14185-14197. [PMID: 34015763 PMCID: PMC8202898 DOI: 10.18632/aging.203036] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/27/2021] [Indexed: 12/24/2022]
Abstract
Intervertebral disc degeneration (IDD) is the prevailing spine disorder and is associated with musculoskeletal disease. The extracellular matrix (ECM) degradation is an essential hallmark of IDD progression. Circular RNAs (circRNAs), as crucial cellular regulators, participate in multiple pathological processes including IDD. Here, we tried to explore the effect of circITCH on the ECM degradation of IDD and the underlying mechanism. Significantly, the expression levels of circITCH were elevated in the IDD patients’ nucleus pulposus (NP) tissues relative to that of normal cases. CircITCH promoted apoptosis and decreased proliferation of NP cells. CircITCH contributed to ECM degradation, as demonstrated by increased ADAMTS4 and MMP13 expression and decreased aggrecan and collagen II expression. Mechanically, miR-17-5p could be sponged by circITCH and miR-17-5p inhibited ECM degradation by repressing SOX4 in degenerative NP cells. CircITCH could activate Wnt/β-catenin pathway by targeting miR-17-5p/SOX4 signaling. SOX4 overexpression, miR-17-5p inhibitor, or Wnt/β-catenin signaling activator LiCl was able to reverse circITCH knockdown-inhibited apoptosis and ECM degradation, and circITCH knockdown-enhanced proliferation in NP cells. Thus, we conclude that circITCH promotes ECM degradation in IDD by activating Wnt/β-catenin through miR-17-5p/SOX4 signaling. Our finding presents novel insight into the mechanism that circITCH modulates the IDD progression. CircITCH and SOX4 may serve as potential targets for IDD therapy.
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Affiliation(s)
- Feng Zhang
- Department of Orthopaedic, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Feili Lin
- Department of Nephrology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Zhiwen Xu
- Department of Orthopaedic, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Zheng Huang
- Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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37
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Yang Z, Li H, Tian Y, Fu L, Gao C, Zhao T, Cao F, Liao Z, Yuan Z, Liu S, Guo Q. Biofunctionalized Structure and Ingredient Mimicking Scaffolds Achieving Recruitment and Chondrogenesis for Staged Cartilage Regeneration. Front Cell Dev Biol 2021; 9:655440. [PMID: 33842484 PMCID: PMC8027342 DOI: 10.3389/fcell.2021.655440] [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: 01/18/2021] [Accepted: 03/05/2021] [Indexed: 11/13/2022] Open
Abstract
It remains scientifically challenging to regenerate injured cartilage in orthopedics. Recently, an endogenous cell recruitment strategy based on a combination of acellular scaffolds and chemoattractants to specifically and effectively recruit host cells and promote chondrogenic differentiation has brought new hope for in situ articular cartilage regeneration. In this study, a transforming growth factor-β3 (TGF-β3)-loaded biomimetic natural scaffold based on demineralized cancellous bone (DCB) and acellular cartilage extracellular matrix (ECM) was developed and found to improve chondral repair by enhancing cell migration and chondrogenesis. The DCB/ECM scaffold has porous microstructures (pore size: 67.76 ± 8.95 μm; porosity: 71.04 ± 1.62%), allowing the prolonged release of TGF-β3 (up to 50% after 42 days in vitro) and infrapatellar fat pad adipose-derived stem cells (IPFSCs) that maintain high cell viability (>96%) and favorable cell distribution and phenotype after seeding onto the DCB/ECM scaffold. The DCB/ECM scaffold itself can also provide a sustained release system to effectively promote IPFSC migration (nearly twofold in vitro). Moreover, TGF-β3 loaded on scaffolds showed enhanced chondrogenic differentiation (such as collagen II, ACAN, and SOX9) of IPFSCs after 3 weeks of culture. After implanting the composite scaffold into the knee joints of rabbits, enhanced chondrogenic differentiation was discovered at 1, 2, and 4 weeks post-surgery, and improved repair of cartilage defects in terms of biochemical, biomechanical, radiological, and histological results was identified at 3 and 6 months post-implantation. To conclude, our study demonstrates that the growth factor (GF)-loaded scaffold can facilitate cell homing, migration, and chondrogenic differentiation and promote the reconstructive effects of in vivo cartilage formation, revealing that this staged regeneration strategy combined with endogenous cell recruitment and pro-chondrogenesis is promising for in situ articular cartilage regeneration.
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Affiliation(s)
- Zhen Yang
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Hao Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yue Tian
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China
| | - Liwei Fu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Cangjian Gao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Tianyuan Zhao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Fuyang Cao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhiyao Liao
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhiguo Yuan
- Department of Bone and Joint Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
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