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Cai CW, Grey JA, Hubmacher D, Han WM. Biomaterial-Based Regenerative Strategies for Volumetric Muscle Loss: Challenges and Solutions. Adv Wound Care (New Rochelle) 2025; 14:159-175. [PMID: 38775429 PMCID: PMC11971559 DOI: 10.1089/wound.2024.0079] [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: 03/30/2024] [Accepted: 05/15/2024] [Indexed: 07/11/2024] Open
Abstract
Significance: Volumetric muscle loss (VML) is caused by the loss of significant amounts of skeletal muscle tissue. VML cannot be repaired by intrinsic regenerative processes, resulting in permanent loss of muscle function and disability. Current rehabilitative-focused treatment strategies lack efficacy and do not restore muscle function, indicating the need for the development of effective regenerative strategies. Recent Advances: Recent developments implicate biomaterial-based approaches for promoting muscle repair and functional restoration post-VML. Specifically, bioscaffolds transplanted in the injury site have been utilized to mimic endogenous cues of the ablated tissue to promote myogenic pathways, increase neo-myofiber synthesis, and ultimately restore contractile function to the injured unit. Critical Issues: Despite the development and preclinical testing of various biomaterial-based regenerative strategies, effective therapies for patients are not available. The unique challenges posed for biomaterial-based treatments of VML injuries, including its scalability and clinical applicability beyond small-animal models, impede progress. Furthermore, production of tissue-engineered constructs is technically demanding, with reproducibility issues at scale and complexities in achieving vascularization and innervation of large constructs. Future Directions: Biomaterial-based regenerative strategies designed to comprehensively address the pathophysiology of VML are needed. Considerations for clinical translation, including scalability and regulatory compliance, should also be considered when developing such strategies. In addition, an integrated approach that combines regenerative and rehabilitative strategies is essential for ensuring functional improvement.
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Affiliation(s)
- Charlene W. Cai
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Biology, The College of New Jersey, Ewing, New Jersey, USA
| | - Josh A. Grey
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Institute of Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dirk Hubmacher
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Woojin M. Han
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Institute of Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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2
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Arteel GE. Hepatic Extracellular Matrix and Its Role in the Regulation of Liver Phenotype. Semin Liver Dis 2024; 44:343-355. [PMID: 39191427 PMCID: PMC12057067 DOI: 10.1055/a-2404-7973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The hepatic extracellular matrix (ECM) is most accurately depicted as a dynamic compartment that comprises a diverse range of players that work bidirectionally with hepatic cells to regulate overall homeostasis. Although the classic meaning of the ECM referred to only proteins directly involved in generating the ECM structure, such as collagens, proteoglycans, and glycoproteins, the definition of the ECM is now broader and includes all components associated with this compartment. The ECM is critical in mediating phenotype at the cellular, organ, and even organismal levels. The purpose of this review is to summarize the prevailing mechanisms by which ECM mediates hepatic phenotype and discuss the potential or established role of this compartment in the response to hepatic injury in the context of steatotic liver disease.
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Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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Lai Z, Niu X, Chen X, Lu F, Zhang Y, Yuan Y. Composite Microparticles of Fat Graft and GFR Matrigel Improved Volume Retention by Promoting Cell Migration and Vessel Regeneration. Aesthetic Plast Surg 2024; 48:1993-2001. [PMID: 38302709 DOI: 10.1007/s00266-022-03145-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 10/09/2022] [Indexed: 02/03/2024]
Abstract
BACKGROUND The retention volume of autologous fat grafts decreases after transplantation due to limited nutrition infiltration and insufficient blood supply. Structural fat grafts and the 3M (multipoint, multitunnel, and multilayer) injection technique have been considered to improve the survival of grafts; however, it is difficult for surgeons to practice in the clinic because grafts tend to gather into a cluster, especially in large volume fat grafting. Therefore, we hypothesize that prefabricated microparticle fat grafts (PFMG) may improve the retention rate. METHODS The C57BL/6 mouse fat particles were embedded in growth factor-reduced (GFR)-Matrigel to detect cell migration by immunofluorescence staining in vitro. PFMG was prepared by mixing mouse fat particles and GFR Matrigel in a 1:1 volume ratio and injected subcutaneously into C57BL/6 mice. Fat particles mixed with PBS in equal volume served as control group. The grafts were harvested at 1, 4, 8, and 12 weeks after sacrifice. The retention rate of grafts at each time point was measured, and the structural alterations were detected by SEM. Fat necrosis and blood vessel density were evaluated by histological analysis. RESULTS CD34+ cells are migrated from the PFMG and formed a tree-like tubular network in the in vitro study. The retention rate was higher in the PFMG group than in the control group at week 12 (38% vs. 30%, p < 0.05). After transplantation, the dissociated structure of fat particles was maintained in PFMG by SEM analysis. Histological analysis of PFMG confirmed less fat necrosis and more blood vessel density in the PFMG group at the early stage than in the control group. The GFR Matrigel was displaced by adipose tissue with time. CONCLUSIONS In this study, we developed a novel fat grafting method, PFMG that dispersed fat grafts and maintained the structure after transplantation. High volume retention volume of PFMG was achieved by promoting cell migration and vessel regeneration. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Zhuhao Lai
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, 219 Moganshan Road, 310005, Hangzhou, People's Republic of China
| | - Xingtang Niu
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Xihang Chen
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Feng Lu
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Yuchen Zhang
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Yi Yuan
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China.
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Xu M, He Y, Li Y, Liu K, Zhang Y, Su T, Yao Y, Jin X, Zhang X, Lu F. Combined Use of Autologous Sustained-Release Scaffold of Adipokines and Acellular Adipose Matrix to Construct Vascularized Adipose Tissue. Plast Reconstr Surg 2024; 153:348e-360e. [PMID: 37171265 DOI: 10.1097/prs.0000000000010649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
BACKGROUND Adipose tissue engineering plays a key role in the reconstruction of soft-tissue defects. The acellular adipose matrix (AAM) is a promising biomaterial for the construction of engineered adipose tissue. However, AAM lacks sufficient adipoinduction potency because of the abundant loss of matrix-bound adipokines during decellularization. METHODS An adipose-derived extracellular matrix collagen scaffold, "adipose collagen fragment" (ACF), was prepared using a novel mechanical method that provides sustained release of adipokines. Here, the authors used label-free proteomics methods to detect the protein components in AAM and ACF. In vivo, ACF was incorporated into AAM or acellular dermal matrix and implanted into nude mice to evaluate adipogenesis. Neoadipocytes, neovessels, and corresponding gene expression were evaluated. The effects of ACF on adipogenic differentiation of human adipose-derived stem cells and tube formation by human umbilical vein endothelial cells were tested in vitro. RESULTS Proteomics analysis showed that ACF contains diverse adipogenic and angiogenic proteins. ACF can release diverse adipokines and induce highly vascularized, mature adipose tissue in AAM, and even in nonadipogenic acellular dermal matrix. Higher expression of adipogenic markers peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha and greater numbers of tubule structures were observed in ACF-treated groups in vitro. CONCLUSION The combination of ACF and AAM could serve as a novel and promising strategy to construct mature, vascularized adipose tissue for soft-tissue reconstruction. CLINICAL RELEVANCE STATEMENT The combined use of AAM and ACF has been proven to induce a highly vascularized, mature, engineered adipose tissue in the nude mouse model, which may serve as a promising strategy for soft-tissue reconstruction.
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Affiliation(s)
- Mimi Xu
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Yunfan He
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Yibao Li
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Kaiyang Liu
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Yuchen Zhang
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Ting Su
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Yao Yao
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Xiaoxuan Jin
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Xiangdong Zhang
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Feng Lu
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
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Noble A, Qubrosi R, Cariba S, Favaro K, Payne SL. Neural dependency in wound healing and regeneration. Dev Dyn 2024; 253:181-203. [PMID: 37638700 DOI: 10.1002/dvdy.650] [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: 02/13/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/29/2023] Open
Abstract
In response to injury, humans and many other mammals form a fibrous scar that lacks the structure and function of the original tissue, whereas other vertebrate species can spontaneously regenerate damaged tissues and structures. Peripheral nerves have been identified as essential mediators of wound healing and regeneration in both mammalian and nonmammalian systems, interacting with the milieu of cells and biochemical signals present in the post-injury microenvironment. This review examines the diverse functions of peripheral nerves in tissue repair and regeneration, specifically during the processes of wound healing, blastema formation, and organ repair. We compare available evidence in mammalian and nonmammalian models, identifying critical nerve-mediated mechanisms for regeneration and providing future perspectives toward integrating these mechanisms into a therapeutic framework to promote regeneration.
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Affiliation(s)
- Alexandra Noble
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Rozana Qubrosi
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Solsa Cariba
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Kayla Favaro
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Samantha L Payne
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
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Afzal Z, Huguet EL. Bioengineering liver tissue by repopulation of decellularised scaffolds. World J Hepatol 2023; 15:151-179. [PMID: 36926238 PMCID: PMC10011915 DOI: 10.4254/wjh.v15.i2.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/22/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Liver transplantation is the only curative therapy for end stage liver disease, but is limited by the organ shortage, and is associated with the adverse consequences of immunosuppression. Repopulation of decellularised whole organ scaffolds with appropriate cells of recipient origin offers a theoretically attractive solution, allowing reliable and timely organ sourcing without the need for immunosuppression. Decellularisation methodologies vary widely but seek to address the conflicting objectives of removing the cellular component of tissues whilst keeping the 3D structure of the extra-cellular matrix intact, as well as retaining the instructive cell fate determining biochemicals contained therein. Liver scaffold recellularisation has progressed from small rodent in vitro studies to large animal in vivo perfusion models, using a wide range of cell types including primary cells, cell lines, foetal stem cells, and induced pluripotent stem cells. Within these models, a limited but measurable degree of physiologically significant hepatocyte function has been reported with demonstrable ammonia metabolism in vivo. Biliary repopulation and function have been restricted by challenges relating to the culture and propagations of cholangiocytes, though advances in organoid culture may help address this. Hepatic vasculature repopulation has enabled sustainable blood perfusion in vivo, but with cell types that would limit clinical applications, and which have not been shown to have the specific functions of liver sinusoidal endothelial cells. Minority cell groups such as Kupffer cells and stellate cells have not been repopulated. Bioengineering by repopulation of decellularised scaffolds has significantly progressed, but there remain significant experimental challenges to be addressed before therapeutic applications may be envisaged.
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Affiliation(s)
- Zeeshan Afzal
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Laurent Huguet
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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7
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Proteomic Analysis of Decellularized Extracellular Matrix: Achieving a Competent Biomaterial for Osteogenesis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6884370. [PMID: 36267842 PMCID: PMC9578822 DOI: 10.1155/2022/6884370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 08/29/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022]
Abstract
Decellularized ECMs have been used as biological scaffolds for tissue repair due to their tissue-specific biochemical and mechanical composition, poorly simulated by other materials. It is used as patches and powders, and it could be further processed via enzymatic digestion under acidic conditions using pepsin. However, part of the bioactivity is lost during the digestion process due to protein denaturation. Here, stepwise digestion was developed to prepare a competent biomaterial for osteogenesis from three different ECM sources. In addition, three different proteases were compared to evaluate the most effective digestion protocol for specific cellular processes. GAGs and peptide quantification showed that the stepwise method yielded a higher concentration of bioactive residues. Circular dichroism analysis also showed that the stepwise approach preserved the secondary structures better. The protein profiles of the digested ECMs were analyzed, and it was found to be highly diverse and tissue-specific. The digestion of ECM from pericardium produced peptides originated from 94 different proteins, followed by 48 proteins in ECM from tendon and 35 proteins in ECM from bone. In addition, digested products from pericardium ECM yielded increased proliferation and differentiation of bone marrow mesenchymal stem cells to mature osteoblasts.
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8
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Turner NJ, Quijano LM, Hussey GS, Jiang P, Badylak SF. Matrix Bound Nanovesicles have Tissue Specific Characteristics that Suggest a Regulatory Role. Tissue Eng Part A 2022; 28:879-892. [PMID: 35946072 DOI: 10.1089/ten.tea.2022.0091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Recent studies have identified an extracellular vesicle population that is tightly anchored within the extracellular matrix of tissues and organs until released by matrix turnover events. Evidence suggests that these matrix-bound nanovesicles (MBV) are a ubiquitous component of the ECM, raising questions regarding their tissue specific identity and their biologic function(s). The primary objective of this study was to examine MBV isolated from six different tissues and compare their physical and compositional characteristics to determine the common and differentially expressed features. Accordingly, the results of this characterization show that while MBV are a ubiquitous component of the ECM they contain a protein and miRNA cargo that is tissue specific. The results furthermore suggest that MBV have an important role in regulating tissue homeostasis.
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Affiliation(s)
- Neill J Turner
- University of Pittsburgh, McGowan Institute for Regenerative Medicine, 450 Technology Drive, Suite 300, Pittsburgh, Pennsylvania, United States, 15212;
| | - Lina Maria Quijano
- University of Pittsburgh, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, United States;
| | - George S Hussey
- University of Pittsburgh, McGowan Institute for Regenerative Medicine, 450 Technology Dr., Pittsburgh, Pennsylvania, United States, 15219;
| | - Peng Jiang
- Cleveland State University, Center for Gene Regulation in Health and Disease, Cleveland, Ohio, United States;
| | - Stephen F Badylak
- University of Pittsburgh, McGowan Institute for Regenerative Medicine, 450 Technology Drive, Suite 300, Pittsburgh, Pennsylvania, United States, 15219;
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Talaei-Khozani T, Yaghoubi A. An overview of post transplantation events of decellularized scaffolds. Transpl Immunol 2022; 74:101640. [PMID: 35667545 DOI: 10.1016/j.trim.2022.101640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 12/19/2022]
Abstract
Regenerative medicine and tissue engineering are reasonable techniques for repairing failed tissues and could be a suitable alternative to organ transplantation. One of the most widely used methods for preparing bioscaffolds is the decellularization procedure. Although cell debris and DNA are removed from the decellularized tissues, important compositions of the extracellular matrix including proteins, proteoglycans, and glycoproteins are nearly preserved. Moreover, the obtained scaffolds have a 3-dimensional (3D) structure, appropriate naïve mechanical properties, and good biocompatibility. After transplantation, different types of host cells migrate to the decellularized tissues. Histological and immunohistochemical assessment of the different bioscaffolds after implantation reveals the migration of parenchymal cells, angiogenesis, as well as the invasion of inflammatory and giant foreign cells. In this review, the events after transplantation including angiogenesis, scaffold degradation, and the presence of immune and tissue-specific progenitor cells in the decellularized scaffolds in various hosts, are discussed.
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Affiliation(s)
- Tahereh Talaei-Khozani
- Histotomorphometry and stereology research center, Shiraz University of Medical Sciences, Shiraz, Iran; Tissue engineering lab, Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atefeh Yaghoubi
- Tissue engineering lab, Anatomy Department, Shiraz University of Medical Sciences, Shiraz, Iran.
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10
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Crum RJ, Hall K, Molina CP, Hussey GS, Graham E, Li H, Badylak SF. Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis. NPJ Regen Med 2022; 7:13. [PMID: 35110573 PMCID: PMC8810774 DOI: 10.1038/s41536-022-00208-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.
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Affiliation(s)
- Raphael J Crum
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA
| | - Kelsey Hall
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA
| | - Catalina Pineda Molina
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA.,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - George S Hussey
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA.,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.,ECM Therapeutics, Inc., 118 Marshall Dr., Warrendale, PA, 15086, USA
| | - Emma Graham
- Musculoskeletal Growth and Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, 450 Technology Drive, Suite 206, Pittsburgh, PA, 15219, USA
| | - Hongshuai Li
- Department of Orthopedics and Rehabilitation, University of Iowa, 25 Grand Ave, Iowa City, IA, 52246, USA
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA. .,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA. .,ECM Therapeutics, Inc., 118 Marshall Dr., Warrendale, PA, 15086, USA. .,Department of Bioengineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15261, USA.
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11
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Muscular and Tendon Degeneration after Achilles Rupture: New Insights into Future Repair Strategies. Biomedicines 2021; 10:biomedicines10010019. [PMID: 35052699 PMCID: PMC8773411 DOI: 10.3390/biomedicines10010019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/10/2021] [Accepted: 12/19/2021] [Indexed: 11/17/2022] Open
Abstract
Achilles tendon rupture is a frequent injury with an increasing incidence. After clinical surgical repair, aimed at suturing the tendon stumps back into their original position, the repaired Achilles tendon is often plastically deformed and mechanically less strong than the pre-injured tissue, with muscle fatty degeneration contributing to function loss. Despite clinical outcomes, pre-clinical research has mainly focused on tendon structural repair, with a lack of knowledge regarding injury progression from tendon to muscle and its consequences on muscle degenerative/regenerative processes and function. Here, we characterize the morphological changes in the tendon, the myotendinous junction and muscle belly in a mouse model of Achilles tendon complete rupture, finding cellular and fatty infiltration, fibrotic tissue accumulation, muscle stem cell decline and collagen fiber disorganization. We use novel imaging technologies to accurately relate structural alterations in tendon fibers to pathological changes, which further explain the loss of muscle mechanical function after tendon rupture. The treatment of tendon injuries remains a challenge for orthopedics. Thus, the main goal of this study is to bridge the gap between clinicians’ knowledge and research to address the underlying pathophysiology of ruptured Achilles tendon and its consequences in the gastrocnemius. Such studies are necessary if current practices in regenerative medicine for Achilles tendon ruptures are to be improved.
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12
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Ma J, Zhan H, Li W, Zhang L, Yun F, Wu R, Lin J, Li Y. Recent trends in therapeutic strategies for repairing endometrial tissue in intrauterine adhesion. Biomater Res 2021; 25:40. [PMID: 34819167 PMCID: PMC8611984 DOI: 10.1186/s40824-021-00242-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/31/2021] [Indexed: 12/25/2022] Open
Abstract
Intrauterine adhesion (IUA) is a common gynaecological disease that develops from infection or trauma. IUA disease may seriously affect the physical and mental health of women of childbearing age, which may lead to symptoms such as hypomenorrhea or infertility. Presently, hysteroscopic transcervical resection of adhesion (TCRA) is the principal therapy for IUAs, although its function in preventing the recurrence of adhesion and preserving fertility is limited. Pharmaceuticals such as hormones and vasoactive agents and the placement of nondegradable stents are the most common postoperative adjuvant therapy methods. However, the repair of injured endometrium is relatively restricted due to the different anatomical structures of the endometrium. Recently, the treatment outcome of IUAs has improved with the advancement of hysteroscopic techniques. In particular, the application of bioactive scaffolds combined with tissue engineering technology has proven to have high therapeutic potential or endometrial repair in IUA treatment. Herein, this review has summarized past therapeutic strategies, including postoperative adjuvant therapy, cell or therapeutic molecular delivery therapy methods and bioactive scaffold-based tissue engineering methods. Therefore, this review presented the recent therapeutic strategies for repairing endometrium treatment and pointed out the issues of clinical concern to provide alternative methods for the management of IUAs.
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Affiliation(s)
- Junyan Ma
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Major Gynecological Diseases, Hangzhou, 310006, Zhejiang Province, China
| | - Hong Zhan
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China
| | - Wen Li
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China
| | - Liqi Zhang
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China
| | - Feng Yun
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China
| | - Ruijin Wu
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China.
| | - Jun Lin
- Department of Gynecology and Obstetrics, Women' s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang Province, China.
| | - Yangyang Li
- Zhejiang Provincial Key Laboratory for Precision Diagnosis & Treatment of Major Gynecological Diseases, Hangzhou, 310006, Zhejiang Province, China.
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Samal J, Segura T. Injectable biomaterial shuttles for cell therapy in stroke. Brain Res Bull 2021; 176:25-42. [PMID: 34391821 PMCID: PMC8524625 DOI: 10.1016/j.brainresbull.2021.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 07/26/2021] [Accepted: 08/06/2021] [Indexed: 01/01/2023]
Abstract
Ischemic stroke (IS) is the leading cause of disability and contributes to a significant socio-economic cost in the western world. Brain repair strategies investigated in the pre-clinical models include the delivery of drug or cell-based therapeutics; which is hindered by the complex anatomy and functional organization of the brain. Biomaterials can be instrumental in alleviating some of these challenges by providing a structural support, localization, immunomodulation and/or modulating cellular cross-talk in the brain. This review addresses the significance of and challenges associated with cell therapy in an ischemic brain. This is followed by a detailed insight into the biomaterial-based delivery systems which have been designed to provide sustained trophic factor delivery for endogenous repair and to support transplanted cell survival and integration. A biomaterial intervention uses a multifaceted approach in enhancing the survival and engraftment of cells during transplantation and this has driven them as potential candidates for the treatment of IS. The biological processes that are activated as a response to the biomaterials and how to modulate them is one of the key factors contributing to the success of the biomaterial-based therapeutic approach. Future perspectives highlight the need of a combinative approach of merging the material design with disease biology to fabricate effective biomaterial-based intervention of stroke.
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Affiliation(s)
- Juhi Samal
- Department of Biomedical Engineering, 534 Research Drive, Durham, NC 27708, United States
| | - Tatiana Segura
- Department of Biomedical Engineering, 534 Research Drive, Durham, NC 27708, United States.
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T lymphocytes as critical mediators in tissue regeneration, fibrosis, and the foreign body response. Acta Biomater 2021; 133:17-33. [PMID: 33905946 DOI: 10.1016/j.actbio.2021.04.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/23/2021] [Accepted: 04/13/2021] [Indexed: 12/16/2022]
Abstract
Research on the foreign body response (FBR) to biomaterial implants has been focused on the roles that the innate immune system has on mediating tolerance or rejection of implants. However, the immune system also involves the adaptive immune response and it must be included in order to form a complete picture of the response to biomaterials and medical implants. In this review, we explore recent understanding about the roles of adaptive immune cells, specifically T cells, in modulating the immune response to biomaterial implants. The immune response to implants elicits a delicate balance between tissue repair and fibrosis that is mainly regulated by three types of T helper cell responses -T helper type 1, T helper type 2, and T helper type 17- and their crosstalk with innate immune cells. Interestingly, many T cell response mechanisms to implants overlap with the process of fibrosis or repair in different tissues. This review explores the fibrotic and regenerative T cell biology and draws parallels to T cell responses to biomaterials. Additionally, we also explore the biomedical engineering advancements in biomaterial applications in designing particle and scaffold systems to modulate T cell activity for therapeutics and devices. Not only do the deliberate engineering design of physical and chemical material properties and the direct genetic modulation of T cells not only offer insights to T cell biology, but they also present different platforms to develop immunomodulatory biomaterials. Thus, an in-depth understanding of T cells' roles can help to navigate the biomaterial-immune interactions and reconsider the long-lasting adaptive immune response to implants, which, in the end, contribute to the design of immunomodulatory medical implants that can advance the next generation of regenerative therapy. STATEMENT OF SIGNIFICANCE: This review article integrates knowledge of adaptive immune responses in tissue damage, wound healing, and medical device implantation. These three fields, often not discussed in conjunction, are important to consider when evaluating and designing biomaterials. Through incorporation of basic biological research alongside engineering research, we provide an important lens through which to evaluate adaptive immune contributions to regenerative medicine and medical device development.
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Xing Y, Varghese B, Ling Z, Kar AS, Reinoso Jacome E, Ren X. Extracellular Matrix by Design: Native Biomaterial Fabrication and Functionalization to Boost Tissue Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00210-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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16
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Guan G, Huo D, Li Y, Zhao X, Li Y, Qin Z, Sun D, Yang G, Yang M, Tan J, Zeng W, Zhu C. Engineering hiPSC-CM and hiPSC-EC laden 3D nanofibrous splenic hydrogel for improving cardiac function through revascularization and remuscularization in infarcted heart. Bioact Mater 2021; 6:4415-4429. [PMID: 33997517 PMCID: PMC8113784 DOI: 10.1016/j.bioactmat.2021.04.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Cell therapy has been a promising strategy for cardiac repair after myocardial infarction (MI), but a poor ischemic environment and low cell delivery efficiency remain significant challenges. The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI, but it is unclear whether it could be used for human pluripotent stem cell (hiPSC) cultivation and provide a proper microenvironment for cell grafts against the ischemic environment. Herein, we developed a splenic extracellular matrix derived thermoresponsive hydrogel (SpGel). Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway, cell-substrate adhesion, cardiac muscle contraction and oxidation-reduction processes. In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells (iECs) and cardiomyocytes (iCMs) with enhanced function on SpGel. The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven. Furthermore, in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival, revascularization and remuscularization. In conclusion, we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts, which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.
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Affiliation(s)
- Ge Guan
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Da Huo
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yanzhao Li
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiaolin Zhao
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yinghao Li
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Zhongliang Qin
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China.,Chongqing Institute of Zhong Zhi Yi Gu, Shapingba District, Chongqing, 400030, China
| | - Dayu Sun
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Guanyuan Yang
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Mingcan Yang
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Ju Tan
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Wen Zeng
- Department of Cell Biology, Third Military Army Medical University, Chongqing, 400038, China
| | - Chuhong Zhu
- Department of Anatomy, State Key Laboratory of Trauma, Burn and Combined Injury, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University (Third Military Medical University), Chongqing, 400038, China
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Promoting musculoskeletal system soft tissue regeneration by biomaterial-mediated modulation of macrophage polarization. Bioact Mater 2021; 6:4096-4109. [PMID: 33997496 PMCID: PMC8091177 DOI: 10.1016/j.bioactmat.2021.04.017] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/27/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Musculoskeletal disorders are common in clinical practice. Repairing critical-sized defects in musculoskeletal systems remains a challenge for researchers and surgeons, requiring the application of tissue engineering biomaterials. Successful application depends on the response of the host tissue to the biomaterial and specific healing process of each anatomical structure. The commonly-held view is that biomaterials should be biocompatible to minimize local host immune response. However, a growing number of studies have shown that active modulation of the immune cells, particularly macrophages, via biomaterials is an effective way to control immune response and promote tissue regeneration as well as biomaterial integration. Therefore, we critically review the role of macrophages in the repair of injured musculoskeletal system soft tissues, which have relatively poor regenerative capacities, as well as discuss further enhancement of target tissue regeneration via modulation of macrophage polarization by biomaterial-mediated immunomodulation (biomaterial properties and delivery systems). This active regulation approach rather than passive-evade strategy maximizes the potential of biomaterials to promote musculoskeletal system soft tissue regeneration and provides alternative therapeutic options for repairing critical-sized defects.
Different phenotypes of macrophages play a crucial role in musculoskeletal system soft tissue regeneration. Biomaterials and biomaterial-based delivery systems can be utilized to modulate macrophage polarization. This review summarizes immunomodulatory biomaterials to spur musculoskeletal system soft tissue regeneration.
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Alghutaimel H, Yang X, Drummond B, Nazzal H, Duggal M, Raïf E. Investigating the vascularization capacity of a decellularized dental pulp matrix seeded with human dental pulp stem cells: in vitro and preliminary in vivo evaluations. Int Endod J 2021; 54:1300-1316. [PMID: 33709438 DOI: 10.1111/iej.13510] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/17/2022]
Abstract
AIM To investigate the vascularization capacity of a decellularized dental pulp matrix (DDP) of bovine origin seeded with human dental pulp stem cells (hDPSCs) in vitro and to present preliminary in vivo findings. METHODOLOGY Bovine dental pulps were decellularized and then analysed using histological staining and DNA quantification. The resultant DDPs were characterized using immunohistochemical staining for the retention of vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF-2). Furthermore, DDPs were recellularized with hDPSCs and analysed histologically. The expression of markers involved in angiogenesis by hDPSCs colonizing the DDPs was assessed in vitro. A preliminary in vivo study was then conducted in which hDPSCs-seeded and unseeded DDPs were inserted in debrided human premolars root slices and implanted subcutaneously in immunodeficient mice. Samples were retrieved after 30 days and analysed using histological and immunohistochemical staining. The independent samples t-test, analysis of variance and a Kruskal-Wallis test were used to analyse the quantitative data statistically depending on the group numbers and normality of data distribution. The difference between the groups was considered significant when the P-value was less than 0.05. RESULTS Acellular dental pulp matrices were generated following bovine dental pulp decellularization. Evaluation of the developed DDPs revealed a significant DNA reduction (P < 0.0001) with preservation of the native histoarchitecture and vasculature and retention of VEGF-A and FGF-2. Upon recellularization of the DDPs with hDPSCs, the in vitro analyses revealed cell engraftment with progressive repopulation of DDPs' matrices and vasculature and with enhanced expression of markers involved in angiogenesis. In vivo implantation of root slices with hDPSCs-seeded DDPs revealed apparent vascularization enhancement as compared to the unseeded DDP group (P < 0.0001). CONCLUSIONS The developed decellularized dental pulp matrix had pro-angiogenic properties characterized by the retention of native vasculature and angiogenic growth factors. Seeding of hDPSCs into the DDP led to progressive repopulation of the vasculature, enhanced expression of markers involved in angiogenesis in hDPSCs and improved in vivo vascularization capacity. The se suggest that a combination of DDP and hDPSCs have the potential to provide a promising vascularization promoting strategy for dental pulp regeneration.
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Affiliation(s)
- H Alghutaimel
- Department of Paediatric Dentistry, School of Dentistry, University of Leeds, Leeds, UK.,Department of Paediatric Dentistry, School of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - X Yang
- Department of Oral Biology, School of Dentistry, University of Leeds, Leeds, UK
| | - B Drummond
- Department of Paediatric Dentistry, School of Dentistry, University of Leeds, Leeds, UK
| | - H Nazzal
- Paediatric Dentistry Section, Hamad Dental Centre, Hamad Medical Corporation, Doha, Qatar
| | - M Duggal
- College of Dental Medicine, QU Health, Qatar University, Doha, Qatar
| | - E Raïf
- Department of Oral Biology, School of Dentistry, University of Leeds, Leeds, UK
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Bankoti K, Rameshbabu AP, Datta S, Roy M, Goswami P, Roy S, Das AK, Ghosh SK, Dhara S. Carbon nanodot decorated acellular dermal matrix hydrogel augments chronic wound closure. J Mater Chem B 2020; 8:9277-9294. [PMID: 32996553 DOI: 10.1039/d0tb01574a] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Impaired skin regeneration in chronic wounds like in diabetes corresponds to high oxidative stress, poor angiogenesis and insufficient collagen hyperplasia. Therefore, a multifaceted strategy for treatment is required to address critical issues associated with chronic wound healing. Fascinating application of nanomaterials in chronic wounds is still limited; hence, in the present work bioactive solubilized decellularized dermal matrix (sADM) was employed to form a hydrogel with chitosan (CTS) at physiological pH/temperature and modified with reactive oxygen species (ROS) scavenging carbon nanodots (ND). A detailed in vitro investigation found that the ND modified bioactive hydrogel (CsADMND) is suitable for human amniotic membrane derived stem cell (hAMSC) delivery. Also, CsADMND was observed to possess a good ROS scavenging property, hemocompatibility and pro-angiogenic potential as demonstrated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), haemolysis and chick chorioallantoic membrane (CAM) assay, respectively. The hybrid hydrogel promoted migration of cells in vitro in scratch assay owing to its antioxidant potential and the presence of bioactive moieties. Further, its efficacy in healing full thickness (FT) chronic wounds was evaluated in a streptozotocin (STZ) induced diabetic model. The CsADMND hydrogel after association with hAMSCs led to stimulation of early angiogenesis, superior collagen deposition, rapid wound closure, complete reepithelialisation, and formation of distinct organized dermal epidermal junctions (DEJ) post 21 days of healing. These results suggest that the hAMSC laden CsADMND hydrogel may serve as a promising therapeutic strategy for the management of chronic wounds.
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Affiliation(s)
- Kamakshi Bankoti
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Arun Prabhu Rameshbabu
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Sayanti Datta
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
| | - Madhurima Roy
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Piyali Goswami
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Sabyasachi Roy
- Department of Gynaecology, Midnapore Medical College, Paschim Medinipur-721101, India
| | - Amit Kumar Das
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Sudip Kumar Ghosh
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
| | - Santanu Dhara
- Biomaterials and Tissue Engineering, Laboratory School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India.
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The Physician's Guide to Platelet-Rich Plasma in Dermatologic Surgery Part I: Definitions, Mechanisms of Action, and Technical Specifications. Dermatol Surg 2020; 46:348-357. [PMID: 31714381 DOI: 10.1097/dss.0000000000002147] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Platelet-rich plasma (PRP) is an increasingly popular treatment modality for various dermatologic conditions, but there are limitations in both the published literature and clinician knowledge. OBJECTIVE To create a high-yield, in-depth analysis of PRP in procedural dermatology by reviewing available data on its role in hair restoration, soft-tissue remodeling, resurfacing, and rejuvenation; identifying practice gaps and controversies; and making suggestions for future research that will establish dermatologists as pioneers of regenerative medicine. MATERIALS AND METHODS A 2-part systematic review and expert analysis of publications before October 2018. RESULTS AND CONCLUSION Most studies on PRP report favorable outcomes with the strongest level of evidence existing for androgenetic alopecia followed by postprocedure wound healing, scar revision, striae, rejuvenation, and dermal filling. There is a dearth of large randomized controlled trials, considerable heterogeneity in the variables studied, and lack of specificity in the preparatory protocols, which may influence clinical outcomes. Future investigations should use consistent nomenclature, find ideal solution parameters for each cutaneous indication, determine significant outcome metrics, and follow double-blinded, randomized, controlled methodologies. Addressing these deficiencies will take sound scientific inquiry but ultimately has the potential to benefit the authors' specialty greatly.
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Cramer MC, Badylak SF. Extracellular Matrix-Based Biomaterials and Their Influence Upon Cell Behavior. Ann Biomed Eng 2020; 48:2132-2153. [PMID: 31741227 PMCID: PMC7231673 DOI: 10.1007/s10439-019-02408-9] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 11/08/2019] [Indexed: 01/16/2023]
Abstract
Biologic scaffold materials composed of allogeneic or xenogeneic extracellular matrix (ECM) are commonly used for the repair and remodeling of injured tissue. The clinical outcomes associated with implantation of ECM-based materials range from unacceptable to excellent. The variable clinical results are largely due to differences in the preparation of the material, including characteristics of the source tissue, the method and efficacy of decellularization, and post-decellularization processing steps. The mechanisms by which ECM scaffolds promote constructive tissue remodeling include mechanical support, degradation and release of bioactive molecules, recruitment and differentiation of endogenous stem/progenitor cells, and modulation of the immune response toward an anti-inflammatory phenotype. The methods of ECM preparation and the impact of these methods on the quality of the final product are described herein. Examples of favorable cellular responses of immune and stem cells associated with constructive tissue remodeling of ECM bioscaffolds are described.
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Affiliation(s)
- Madeline C Cramer
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
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22
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Naranjo JD, Saldin LT, Sobieski E, Quijano LM, Hill RC, Chan PG, Torres C, Dziki JL, Cramer MC, Lee YC, Das R, Bajwa AK, Nossair R, Klimak M, Marchal L, Patel S, Velankar SS, Hansen KC, McGrath K, Badylak SF. Esophageal extracellular matrix hydrogel mitigates metaplastic change in a dog model of Barrett's esophagus. SCIENCE ADVANCES 2020; 6:eaba4526. [PMID: 32656339 PMCID: PMC7329334 DOI: 10.1126/sciadv.aba4526] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 04/16/2020] [Indexed: 05/17/2023]
Abstract
Chronic inflammatory gastric reflux alters the esophageal microenvironment and induces metaplastic transformation of the epithelium, a precancerous condition termed Barrett's esophagus (BE). The microenvironmental niche, which includes the extracellular matrix (ECM), substantially influences cell phenotype. ECM harvested from normal porcine esophageal mucosa (eECM) was formulated as a mucoadhesive hydrogel, and shown to largely retain basement membrane and matrix-cell adhesion proteins. Dogs with BE were treated orally with eECM hydrogel and omeprazole (n = 6) or omeprazole alone (n = 2) for 30 days. eECM treatment resolved esophagitis, reverted metaplasia to a normal, squamous epithelium in four of six animals, and downregulated the pro-inflammatory tumor necrosis factor-α+ cell infiltrate compared to control animals. The metaplastic tissue in control animals (n = 2) did not regress. The results suggest that in vivo alteration of the microenvironment with a site-appropriate, mucoadhesive ECM hydrogel can mitigate the inflammatory and metaplastic response in a dog model of BE.
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Affiliation(s)
- Juan Diego Naranjo
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Lindsey T. Saldin
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Eric Sobieski
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Lina M. Quijano
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Ryan C. Hill
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Patrick G. Chan
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Cardiothoracic Surgery, UPMC, Pittsburgh, PA 15213, USA
| | - Crisanto Torres
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Cardiothoracic Surgery, UPMC, Pittsburgh, PA 15213, USA
| | - Jenna L. Dziki
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Madeline C. Cramer
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yoojin C. Lee
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Rohit Das
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, UPMC, Pittsburgh, PA 15213, USA
| | - Anant K. Bajwa
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Rania Nossair
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Molly Klimak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Lucile Marchal
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Shil Patel
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Sachin S. Velankar
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Chemical Engineering, Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Kirk C. Hansen
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kevin McGrath
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, UPMC, Pittsburgh, PA 15213, USA
| | - Stephen F. Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Hernandez MJ, Zelus EI, Spang MT, Braden RL, Christman KL. Dose optimization of decellularized skeletal muscle extracellular matrix hydrogels for improving perfusion and subsequent validation in an aged hindlimb ischemia model. Biomater Sci 2020; 8:3511-3521. [PMID: 32432574 PMCID: PMC7375022 DOI: 10.1039/c9bm01963d] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Peripheral artery disease (PAD) affects more than 27 million individuals in North America and Europe, and current treatment strategies mainly aim to restore blood perfusion. However, many patients are ineligible for existing procedures, and these therapies are often ineffective. Previous studies have demonstrated success of an injectable decellularized skeletal muscle extracellular matrix (ECM) hydrogel in a young rat hindlimb ischemia model of PAD, but further pre-clinical studies are necessary prior to clinical translation. In this study, varying concentrations of a skeletal muscle ECM hydrogel were investigated for material properties and in vivo effects on restoring blood perfusion. Rheological measurements indicated an increase in viscosity and mechanical strength with the higher concentrations of the ECM hydrogels. When injecting dye-labelled ECM hydrogels into a healthy rat, differences were also observed for the spreading and degradation rate of the various concentrations. The three concentrations for the ECM hydrogel were then further examined in a young rat hindlimb ischemia model. The efficacy of the optimal ECM hydrogel concentration was then further confirmed in an aged mouse hindlimb ischemia model. These results further validate the use of decellularized skeletal muscle ECM hydrogels for improving blood perfusion in small animal models of PAD.
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Affiliation(s)
- Melissa J Hernandez
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Dr., La Jolla, CA 92037, USA.
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Hussein KH, Park KM, Yu L, Kwak HH, Woo HM. Decellularized hepatic extracellular matrix hydrogel attenuates hepatic stellate cell activation and liver fibrosis. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 116:111160. [PMID: 32806289 DOI: 10.1016/j.msec.2020.111160] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/31/2020] [Accepted: 06/03/2020] [Indexed: 12/21/2022]
Abstract
Liver fibrosis results from excessive accumulation of extracellular matrix (ECM) proteins that distort the hepatic architecture. Progression of liver fibrosis results in cirrhosis and liver failure, and often, liver transplantation is required. The decellularized liver tissue contains different components that mimic the natural hepatic environment. We hypothesized that a decellularized liver hydrogel can be used to replace the necrotic hepatocytes and damaged ECM. Therefore, our aim in this study is to develop a therapy for treating liver fibrosis. Mice livers were decellularized and processed to form a hepatic hydrogel. We evaluated the biocompatibility and bioactivity of the hydrogel. The ability of the hydrogel to enhance the migration of hepatocytes and endothelial cells was investigated. Human hepatic stellate cell line (LX-2) activated by transforming growth factor-β1 (TGF-β1) was used as in vitro model for fibrogenesis. Then, the hydrogel was injected into the liver parenchyma of mice after the induction of liver fibrosis using thioacetamide. The resulting hydrogel maintained a complex composition, which included glycosaminoglycans, collagen, elastin, and growth factors. Hepatocytes and endothelial cells were shown to migrate toward the hydrogel in vitro. Liver hydrogel improved TGF-β1-induced LX-2 cells activation via blocking the TGF-β1/Smad pathway. The matrix was delivered successfully in vivo and enhanced the reduction of fibrosis and recovery to a nearly normal structure. In conclusion, we have demonstrated that the liver hydrogel can be utilized as an injectable biomaterial for liver tissue engineering in order to reduce the degree of fibrosis.
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Affiliation(s)
- Kamal H Hussein
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Department of Animal Surgery, College of Veterinary Medicine, Assiut University, Assiut 71515, Egypt
| | - Kyung-Mee Park
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Lina Yu
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Ho-Hyun Kwak
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
| | - Heung-Myong Woo
- Stem Cell institute, College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
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The Antimicrobial Effectiveness and Cytotoxicity of the Antibiotic-Loaded Chitosan: ECM Scaffolds. APPLIED SCIENCES-BASEL 2020. [DOI: 10.3390/app10103446] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: The development of multifunctional wound dressings with the ability to control hemostasis, limit infection and promote rapid wound healing and constructive tissue remodeling has been a challenge for many years. In view of these challenges, a hybrid scaffold platform was developed that combined two different extracellular matrices (ECM): ECM from decellularized mammalian tissue and ECM (chitosan) from crustaceans. Both types of ECM have well established clinical benefits that support and promote wound healing and control hemostasis. This scaffold platform could also be augmented with antibiotics to provide bactericidal activity directly to the wound site. Methods: Four different scaffold formulations were developed containing chitosan supplemented with either 20% or 50% urinary bladder matrix (UBM) hydrogel or 1% (w/v) or 10% (w/v) UBM–ECM particulates. 100% chitosan scaffolds were used as controls. The scaffolds were augmented with either minocycline or rifampicin. Escherichia Coli and Staphylococcus Aureus were used to assesses antimicrobial efficacy and duration of activity, while neutral red uptake assays were performed to establish direct and indirect cytotoxicity. Results: Results showed that scaffold handling properties, scaffold integrity over time and the efficacy and release rate of loaded antibiotics could be modified by altering scaffold composition. Moreover, antibiotics were easily released from the scaffold and could remain effective for up to 24 h by modifying the scaffold composition. Variable results with cytotoxicity testing show that further work is required to optimize the scaffold formulations but these proof of principle experiments suggest that these scaffolds have potential as bioactive wound dressings.
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Xu CC, Mau T. A tissue-specific, injectable acellular gel for the treatment of chronic vocal fold scarring. Acta Biomater 2019; 99:141-153. [PMID: 31425889 PMCID: PMC6851489 DOI: 10.1016/j.actbio.2019.08.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/27/2019] [Accepted: 08/13/2019] [Indexed: 02/08/2023]
Abstract
Gel-based injectable biomaterials have significant potential for treating vocal fold defects such as scarring. An ideal injectable for vocal fold lamina propria restoration should mimic the microenvironment of the lamina propria to induce scarless wound healing and functional tissue regeneration. Most current synthetic or natural injectable biomaterials do not possess the same level of complex, tissue-specific constituents as the natural vocal fold lamina propria. In this study we present a newly-developed injectable gel fabricated from decellularized bovine vocal fold lamina propria. Blyscan assay and mass spectrometry indicated that the vocal fold-specific gel contained a large amount of sulfated glycosaminoglycans and over 250 proteins. Gene Ontology overrepresentation analysis revealed that the proteins in the gel dominantly promote antifibrotic biological process. In vivo study using a rabbit vocal fold injury model showed that the injectable gel significantly reduced collagen density and decreased tissue contraction of the lamina propria in vocal folds with chronic scarring. Furthermore, this acellular gel only elicited minimal humoral immune response after injection. Our findings suggested that the tissue-specific, injectable extracellular matrix gel could be a promising biomaterial for treating vocal fold scarring, even after the formation of mature scar. STATEMENT OF SIGNIFICANCE: Vocal fold lamina propria scarring remains among the foremost therapeutic challenges in the management of patients with voice disorders. Surgical excision of scar may cause secondary scarring and yield inconsistent results. The present study reports an extracellular matrix-derived biomaterial that demonstrated antifibrotic effect on chronic scarring in vocal fold lamina propria. Its injectability minimizes the invasiveness of the delivery procedure and the degree of mucosal violation. In this work we also describe a new methodology which can more accurately identify proteins from the complex mixture of an acellular extracellular matrix gel by excluding interfering peptides produced during the enzymatic digestion in gel fabrication.
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Affiliation(s)
- Chet C Xu
- Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Biomedical Engineering Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Ted Mau
- Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Khatibzadeh SM, Menarim BC, Nichols AEC, Werre SR, Dahlgren LA. Urinary Bladder Matrix Does Not Improve Tenogenesis in an In Vitro Equine Model. J Orthop Res 2019; 37:1848-1859. [PMID: 31042311 DOI: 10.1002/jor.24320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Extracellular matrix (ECM) is responsible for tendon strength and elasticity. Healed tendon ECM lacks structural integrity, leading to reinjury. Porcine urinary bladder matrix (UBM) provides a scaffold and source of bioactive proteins to improve tissue healing, but has received limited attention for treating tendon injuries. The objective of this study was to evaluate the ability of UBM to induce matrix organization and tenogenesis using a novel in vitro model. We hypothesized that addition of UBM to tendon ECM hydrogels would improve matrix organization and cell differentiation. Hydrogels seeded with bone marrow cells (n = 6 adult horses) were cast using rat tail tendon ECM ± UBM, fixed under static tension and harvested at 7 and 21 days for construct contraction, cell viability, histology, biochemistry, and gene expression. By day 7, UBM constructs contracted significantly from baseline, whereas control constructs did not. Both control and UBM constructs contracted significantly by day 21. In both groups, cells remained viable over time and changed from round and randomly oriented to elongated along lines of tension with visible compaction of the ECM. There were no differences over time or between treatments for nuclear aspect ratio, DNA, or glycosaminoglycan content. Decorin, matrix metalloproteinase 13, and scleraxis expression increased significantly over time, but not in response to UBM treatment. Mohawk expression was constant over time. Cartilage oligomeric matrix protein expression decreased over time in both groups. Using a novel ECM hydrogel model, substantial matrix organization and cell differentiation occurred; however, the addition of UBM failed to induce greater matrix organization than tendon ECM alone. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1848-1859, 2019.
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Affiliation(s)
- Sarah M Khatibzadeh
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, 24061, Blacksburg, Virginia
| | - Bruno C Menarim
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, 24061, Blacksburg, Virginia
| | - Anne E C Nichols
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, 24061, Blacksburg, Virginia
| | - Stephen R Werre
- Laboratory for Statistical Design and Study Analysis, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia
| | - Linda A Dahlgren
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, 24061, Blacksburg, Virginia
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29
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Lin MJ, Dubin DP, Farberg AS, Khorasani H. Acellular porcine transitional cell matrix xenograft for surgical defects. Australas J Dermatol 2019; 60:e345-e346. [PMID: 31119721 DOI: 10.1111/ajd.13080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Matthew J Lin
- Division of Dermatologic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Danielle P Dubin
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aaron S Farberg
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hooman Khorasani
- Division of Dermatologic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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30
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Paige JT, Kremer M, Landry J, Hatfield SA, Wathieu D, Brug A, Lightell DJ, Spiller KL, Woods TC. Modulation of inflammation in wounds of diabetic patients treated with porcine urinary bladder matrix. Regen Med 2019; 14:269-277. [PMID: 31020913 PMCID: PMC6886567 DOI: 10.2217/rme-2019-0009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Aim: To determine if porcine urinary bladder matrix (UBM) treatment is associated with modulation of wound inflammation in diabetic patients. Patients & methods: mRNA associated with M1 and M2 macrophages were measured in wounds of diabetic and nondiabetic patients pre- and post-treatment with UBM and an M1:M2 score was calculated. Results: Wound tissue from diabetic subjects exhibited elevated M1:M2 scores compared with nondiabetic patients, suggesting a greater pro-inflammatory state prior to treatment. Post-treatment, there was significantly greater reduction in the magnitude of the individual M1:M2 scores in the diabetic patients resulting in similar levels in both groups of patients. Conclusions: UBM may assist in diabetic wound healing by restoring an inflammatory state similar to that of nondiabetic patients.
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Affiliation(s)
- John T Paige
- Department of Surgery, LSU Health New Orleans, School of Medicine, New Orleans, LA 70112, USA
| | - Michael Kremer
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA
| | - Jace Landry
- Department of Surgery, LSU Health New Orleans, School of Medicine, New Orleans, LA 70112, USA
| | - Samuel A Hatfield
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA
| | - Donald Wathieu
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA
| | - Aaron Brug
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA
| | - Daniel J Lightell
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA
| | - Kara L Spiller
- School of Biomedical Engineering Science & Health Systems, Drexel University, Philadelphia, 19104 PA, USA
| | - T Cooper Woods
- Departments of Physiology & Medicine, Tulane School of Medicine, New Orleans, LA 70112, USA,*Author for correspondence: Tel.: +1 504 988 2588;
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31
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Joutoku Z, Onodera T, Matsuoka M, Homan K, Momma D, Baba R, Hontani K, Hamasaki M, Matsubara S, Hishimura R, Iwasaki N. CCL21/CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults. Sci Rep 2019; 9:5165. [PMID: 30914733 PMCID: PMC6435673 DOI: 10.1038/s41598-019-41621-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 03/14/2019] [Indexed: 12/12/2022] Open
Abstract
Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the chemokine receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
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Affiliation(s)
- Zenta Joutoku
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tomohiro Onodera
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. .,Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GSS, GI-CoRE), Hokkaido University, Sapporo, Japan.
| | - Masatake Matsuoka
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kentaro Homan
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Daisuke Momma
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Rikiya Baba
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazutoshi Hontani
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masanari Hamasaki
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shinji Matsubara
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Ryosuke Hishimura
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Norimasa Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GSS, GI-CoRE), Hokkaido University, Sapporo, Japan
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32
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Campo H. Bioengineering strategies of the uterus towards improving current investigative models and female reproductive health. Facts Views Vis Obgyn 2019; 11:87-99. [PMID: 31695861 PMCID: PMC6822955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Ever since the inception of artificial reproductive technologies (ART), new advances have been developed in the lab and translated to the clinic to improve the reproductive outcome of patients. Tissue engineering (TE) adopts ideas and concepts from biology, bioengineering and material science amongst others, resulting in a promising and burgeoning multidisciplinary field of investigation within regenerative medicine. The main objective of the work presented in this thesis was to use TE based approaches to create different types of natural biomaterials obtained from decellularized porcine or rabbit uteri. We investigated if these different bioscaffolds could improve current investigative in vitro models while also showing potential to be used as therapeutic solutions. Decellularized whole organs are acellular vascularized scaffolds that could be used to create tissue-engineered, transplantable organs. However, they can also be processed further into thin sections, ECM hydrogels and coatings, and were used as biocompatible tissue-specific substrates for cell and embryo culture. Two animal models were used, the pig model demonstrated that our perfusion-based protocol (with or without a freeze/thaw step) successfully decellularizes large uteri, yielding a biocompatible material. Secondly, we adapted this protocol for the rabbit uterus and converted the acellular endometrium into tissue-specific ECM hydrogels and coatings. After characterization of these substrates their effect on in vitro embryo development was also examined. While DC organs could one day be used to resolve the main issues plaguing transplantations, endometrial ECM sections, hydrogels and coatings have shown the potential to become a platform used in the culture of stem/progenitor cells and primary culture cells to better maintain their tissue-specific phenotype, improving in vitro models. Furthermore, ECM hydrogels could possibly be used in the future in vivo, as part of a treatment of Asherman's syndrome and endometrial atrophy.
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Affiliation(s)
- H Campo
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
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33
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Liu W, Cao N, Fan S, Zhang H, Shao H, Song L, Cao C, Huang J, Zhang Y. Angiogenesis Potential of Bladder Acellular Matrix Hydrogel by Compounding Endothelial Cells. ACS APPLIED BIO MATERIALS 2019; 2:1158-1167. [DOI: 10.1021/acsabm.8b00760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Wenjing Liu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-Dimension Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Nailong Cao
- Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, P. R. China
| | - Suna Fan
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-Dimension Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Huihui Zhang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-Dimension Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Huili Shao
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-Dimension Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Lujie Song
- Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, P. R. China
- Shanghai Eastern
Institute of Urologic Reconstruction, Shanghai 200233, P. R. China
| | - Chengbo Cao
- School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China
- School of Chemistry and Chemical Engineering, YanTai University, YanTai 264005, P. R. China
| | - Jianwen Huang
- Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, P. R. China
- Shanghai Eastern
Institute of Urologic Reconstruction, Shanghai 200233, P. R. China
| | - Yaopeng Zhang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-Dimension Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
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Chen C, Zhang X, Lin Q, Remlinger NT, Gilbert TW, Di YP. Urinary Bladder Matrix Protects Host in a Murine Model of Bacterial-Induced Lung Infection. Tissue Eng Part A 2019; 25:257-270. [DOI: 10.1089/ten.tea.2018.0080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Chen Chen
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaoping Zhang
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Qiao Lin
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Thomas W. Gilbert
- ACell, Inc., Columbia, Maryland
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yuanpu Peter Di
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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Nguyen L, Lu P, Boehm D, Bourke P, Gilmore BF, Hickok NJ, Freeman TA. Cold atmospheric plasma is a viable solution for treating orthopedic infection: a review. Biol Chem 2018; 400:77-86. [PMID: 30138104 PMCID: PMC12105529 DOI: 10.1515/hsz-2018-0235] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/06/2018] [Indexed: 12/15/2022]
Abstract
Bacterial infection and antibiotic resistance are major threats to human health and very few solutions are available to combat this eventuality. A growing number of studies indicate that cold (non-thermal) plasma treatment can be used to prevent or eliminate infection from bacteria, bacterial biofilms, fungi and viruses. Mechanistically, a cold plasma discharge is composed of high-energy electrons that generate short-lived reactive oxygen and nitrogen species which further react to form more stable compounds (NO2, H2O2, NH2Cl and others) depending on the gas mixture and plasma parameters. Cold plasma devices are being developed for medical applications including infection, cancer, plastic surgery applications and more. Thus, in this review we explore the potential utility of cold plasma as a non-antibiotic approach for treating post-surgical orthopedic infections.
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Affiliation(s)
- Ly Nguyen
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA
| | - Peng Lu
- College of Science and Health, Dublin Institute of Technology, Dublin, Ireland
| | - Daniela Boehm
- College of Science and Health, Dublin Institute of Technology, Dublin, Ireland
| | - Paula Bourke
- College of Science and Health, Dublin Institute of Technology, Dublin, Ireland
| | - Brendan F. Gilmore
- School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Noreen J. Hickok
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA
| | - Theresa A. Freeman
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA
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Morris AH, Lee H, Xing H, Stamer DK, Tan M, Kyriakides TR. Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2018; 10:41892-41901. [PMID: 30424595 PMCID: PMC9996546 DOI: 10.1021/acsami.8b08920] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Hydrogels composed of solubilized decellularized extracellular matrix (ECM) are attractive materials because they combine the complexity of native ECM with injectability and ease of use. Nevertheless, these materials are typically only tunable by altering the concentration, which alters the ligand landscape, or by incorporating synthetic components, which can result in an unfavorable host response. Herein, we demonstrate the fabrication of genetically tunable ECM-derived materials, by utilizing wild type (WT) and (thrombospondin-2 knockout) TSP-2 KO decellularized skins to prepare hydrogels. The resulting materials exhibited distinct mechanical properties characterized by rheology and different concentrations of collagens when characterized by quantitative proteomics. Mixtures of the gels achieved intermediate effects between the WT and the KO, permitting tunability of the gel properties. In vivo, the hydrogels exhibited tunable cell invasion with a correlation between the content of TSP-2 KO hydrogel and the extent of cell invasion. Additionally, TSP-2 KO hydrogels significantly improved diabetic wound healing at 10 and 21 days. Furthermore, hydrogels derived from genetically engineered in vitro cell-derived matrix mimicked the trends observed for tissue-derived matrix, providing a platform for faster screening of novel manipulations and easier clinical translation. Overall, we demonstrate that genetic engineering approaches impart tunability to ECM-based hydrogels and can result in materials capable of enhanced regeneration.
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Affiliation(s)
- Aaron H. Morris
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States
- Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut 06511, United States
| | - Hudson Lee
- Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut 06511, United States
| | - Hao Xing
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States
- Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut 06511, United States
| | - Danielle K. Stamer
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States
| | - Marina Tan
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States
| | - Themis R. Kyriakides
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States
- Department of Pathology, Yale University, New Haven, Connecticut 06511, United States
- Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut 06511, United States
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Guruswamy Damodaran R, Vermette P. Tissue and organ decellularization in regenerative medicine. Biotechnol Prog 2018; 34:1494-1505. [PMID: 30294883 DOI: 10.1002/btpr.2699] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 04/30/2018] [Indexed: 12/22/2022]
Abstract
The advancement and improvement in decellularization methods can be attributed to the increasing demand for tissues and organs for transplantation. Decellularized tissues and organs, which are free of cells and genetic materials while retaining the complex ultrastructure of the extracellular matrix (ECM), can serve as scaffolds to subsequently embed cells for transplantation. They have the potential to mimic the native physiology of the targeted anatomic site. ECM from different tissues and organs harvested from various sources have been applied. Many techniques are currently involved in the decellularization process, which come along with their own advantages and disadvantages. This review focuses on recent developments in decellularization methods, the importance and nature of detergents used for decellularization, as well as on the role of the ECM either as merely a physical support or as a scaffold in retaining and providing cues for cell survival, differentiation and homeostasis. In addition, application, status, and perspectives on commercialization of bioproducts derived from decellularized tissues and organs are addressed. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1494-1505, 2018.
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Affiliation(s)
- Rajesh Guruswamy Damodaran
- Laboratoire de bio-ingénierie et de biophysique de l'Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, Université de Sherbrooke, 2500 Boul. de l'Université, Sherbrooke, QC, J1K 2R1, Canada.,Pharmacology Institute of Sherbrooke, Faculté de médecine et des sciences de la santé, 3001 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.,Research Centre on Aging, Institut universitaire de gériatrie de Sherbrooke, 1036 rue Belvédère Sud, Sherbrooke, Québec, J1H 4C4, Canada
| | - Patrick Vermette
- Laboratoire de bio-ingénierie et de biophysique de l'Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, Université de Sherbrooke, 2500 Boul. de l'Université, Sherbrooke, QC, J1K 2R1, Canada.,Pharmacology Institute of Sherbrooke, Faculté de médecine et des sciences de la santé, 3001 12ième Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada.,Research Centre on Aging, Institut universitaire de gériatrie de Sherbrooke, 1036 rue Belvédère Sud, Sherbrooke, Québec, J1H 4C4, Canada
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White LJ, Keane TJ, Smoulder A, Zhang L, Castleton AA, Reing JE, Turner NJ, Dearth CL, Badylak SF. The impact of sterilization upon extracellular matrix hydrogel structure and function. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.regen.2018.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Porcine Small Intestinal Submucosa May Be a Suitable Material for Norwood Arch Reconstruction. Ann Thorac Surg 2018; 106:1847-1852. [PMID: 30055141 DOI: 10.1016/j.athoracsur.2018.06.033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 05/31/2018] [Accepted: 06/07/2018] [Indexed: 11/24/2022]
Abstract
BACKGROUND Norwood palliation typically requires patch augmentation of the ascending aorta and aortic arch. Patients having undergone Norwood palliation are at risk of recurrent arch obstruction, the risk of which may be affected by the type of patch material used at the time of Norwood palliation. We sought to determine the freedom from neoaortic arch reintervention and overall survival in patients who underwent Norwood palliation utilizing porcine small intestinal submucosa (PSIS) as the patch material. METHODS Retrospective chart review was performed to identify patients who underwent a Norwood operation utilizing PSIS material at our institution. Cardiac diagnosis, age at surgery, shunt type, need for reintervention, and outcome (survival, transplant, and death) were evaluated. RESULTS Forty-four patients had PSIS material utilized for arch reconstruction at the time of Norwood palliation. There were only five neoaortic arch reinterventions in 4 patients (11.4%). An additional 10 reinterventions, unrelated to the PSIS patch, were performed, including five shunt revisions and five branch pulmonary artery interventions. There were 3 deaths, and 5 patients underwent transplantation. Median follow-up was 387.5 days (range, 4 to 1,513). CONCLUSIONS Freedom from neoaortic arch reintervention and survival after Norwood palliation with PSIS patch material is promising. The PSIS appears noninferior and may be an appropriate tissue choice for Norwood palliation. Studies with longer follow-up are needed to determine the rate of neoaortic reintervention over time.
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Wang Y, Papagerakis S, Faulk D, Badylak SF, Zhao Y, Ge L, Qin M, Papagerakis P. Extracellular Matrix Membrane Induces Cementoblastic/Osteogenic Properties of Human Periodontal Ligament Stem Cells. Front Physiol 2018; 9:942. [PMID: 30072915 PMCID: PMC6058254 DOI: 10.3389/fphys.2018.00942] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 06/26/2018] [Indexed: 01/09/2023] Open
Abstract
Objective: Periodontitis affects nearly 90% of adults over the age of 70, resulting to periodontal tissue infection, destruction, and ultimately tooth loss. Guided tissue regeneration (GTR) is a method widely used to treat severe periodontal disease, and involves placement of an occlusive barrier to facilitate regeneration of the damaged area by periodontal ligament stem cells (PDLSCs). In this study, we evaluate natural extracellular matrix (ECM) as a scaffold material to provide a suitable microenvironment to support the proliferation, differentiation, and tissue-regenerating properties of PDLSCs. Design: The viability, proliferation, apoptosis, and migration of PDLSCs cultured on ECM membrane, that was isolated from porcine urinary bladders, were compared with those cultured on type I collagen membrane, a commonly used scaffold in GTR. To evaluate the effects of ECM vs. type I collagen on the tissue-regenerating properties of PDLSCs, the bio-attachment and cementoblastic/osteogenic differentiation of PDLSCs were evaluated. Results: Incubation of PDLSCs with ECM resulted in increased viability, proliferation, and reduced apoptosis, compared with type I collagen treated PDLSCs. Co-culture with ECM membrane also increased the migration and bio-attachment of PDLSCs. Incubation of PDLSCs with ECM membrane increased expression of the cementoblastic/osteogenic differentiation markers BSP, RUNX2, ALP, OPN, OCN, and periostin. Conclusion: ECM membrane enhances the proliferation and regenerative properties of PDLSCs, indicating that ECM membrane can serve as a suitable scaffold in the application of GTR to treat periodontal disease.
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Affiliation(s)
- Yuanyuan Wang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Silvana Papagerakis
- Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.,Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, United States
| | - Denver Faulk
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
| | - Yuming Zhao
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Lihong Ge
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Man Qin
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Beijing, China
| | - Petros Papagerakis
- Colleges of Dentistry and Biomedical Engineering, Toxicology, Pharmacy, Nutrition, Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada.,Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, United States
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Decellularised skeletal muscles allow functional muscle regeneration by promoting host cell migration. Sci Rep 2018; 8:8398. [PMID: 29849047 PMCID: PMC5976677 DOI: 10.1038/s41598-018-26371-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 04/06/2018] [Indexed: 01/30/2023] Open
Abstract
Pathological conditions affecting skeletal muscle function may lead to irreversible volumetric muscle loss (VML). Therapeutic approaches involving acellular matrices represent an emerging and promising strategy to promote regeneration of skeletal muscle following injury. Here we investigated the ability of three different decellularised skeletal muscle scaffolds to support muscle regeneration in a xenogeneic immune-competent model of VML, in which the EDL muscle was surgically resected. All implanted acellular matrices, used to replace the resected muscles, were able to generate functional artificial muscles by promoting host myogenic cell migration and differentiation, as well as nervous fibres, vascular networks, and satellite cell (SC) homing. However, acellular tissue mainly composed of extracellular matrix (ECM) allowed better myofibre three-dimensional (3D) organization and the restoration of SC pool, when compared to scaffolds which also preserved muscular cytoskeletal structures. Finally, we showed that fibroblasts are indispensable to promote efficient migration and myogenesis by muscle stem cells across the scaffolds in vitro. This data strongly support the use of xenogeneic acellular muscles as device to treat VML conditions in absence of donor cell implementation, as well as in vitro model for studying cell interplay during myogenesis.
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Hernandez MJ, Gaetani R, Pieters VM, Ng NW, Chang AE, Martin TR, van Ingen E, Mol EA, Sluijter JPG, Christman KL. Decellularized Extracellular Matrix Hydrogels as a Delivery Platform for MicroRNA and Extracellular Vesicle Therapeutics. ADVANCED THERAPEUTICS 2018; 1. [PMID: 31544132 DOI: 10.1002/adtp.201800032] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the last decade, the use of microRNA (miRNA) and extracellular vesicle (EV) therapies has emerged as an alternative approach to mitigate the negative effects of several disease pathologies ranging from cancer to tissue and organ regeneration; however, delivery approaches towards target tissues have not been optimized. To alleviate these challenges, including rapid diffusion upon injection and susceptibility to degradation, porcine-derived decellularized extracellular matrix (ECM) hydrogels are examined as a potential delivery platform for miRNA and EV therapeutics. The incorporation of EVs and miRNA antagonists, including anti-miR and antago-miR, in ECM hydrogels results in a prolonged release as compared to the biologic agents alone. In addition, individual in vitro assessments confirm the bioactivity of the therapeutics upon release from the ECM hydrogels. This work demonstrates the feasibility of encapsulating miRNA and EV therapeutics in ECM hydrogels to enhance delivery and potentially efficacy in later in vivo applications.
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Affiliation(s)
- Melissa J Hernandez
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Roberto Gaetani
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Vera M Pieters
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Nathan W Ng
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Audrey E Chang
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Taylor R Martin
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Eva van Ingen
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Emma A Mol
- Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, 3584CX, NL
| | - Joost P G Sluijter
- Department of Cardiology, Experimental Cardiology Laboratory, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, 3584CX, NL
| | - Karen L Christman
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
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Burkhardt MA, Gerber I, Moshfegh C, Lucas MS, Waser J, Emmert MY, Hoerstrup SP, Schlottig F, Vogel V. Clot-entrapped blood cells in synergy with human mesenchymal stem cells create a pro-angiogenic healing response. Biomater Sci 2018; 5:2009-2023. [PMID: 28809406 DOI: 10.1039/c7bm00276a] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Blood clots stop bleeding and provide cell-instructive microenvironments. Still, in vitro models used to study implant performance typically neglect any possible interactions of recruited cells with surface-adhering blood clots. Here we study the interaction and synergies of bone marrow derived human mesenchymal stem cells (hMSCs) with surface-induced blood clots in an in vitro model by fluorescence microscopy, scanning and correlative light and electron microscopy, ELISA assays and zymography. The clinically used alkali-treated rough titanium (Ti) surfaces investigated here are known to enhance blood clotting compared to native Ti and to improve the healing response, but the underlying mechanisms remain elusive. Here we show that the presence of blood clots synergistically increased hMSC proliferation, extracellular matrix (ECM) remodelling and the release of matrix fragments and angiogenic VEGF, but did not increase the osteogenic differentiation of hMSCs. While many biomaterials are nowadays engineered to release pro-angiogenic factors, we show here that clot-entrapped blood cells on conventional materials in synergy with hMSCs are potent producers of pro-angiogenic factors. Our data might thus not only explain why alkali-treatment is beneficial for Ti implant integration, but they suggest that the physiological importance of blood clots to create pro-angiogenic environments on implants has been greatly underestimated. The importance of blood clots might have been missed because the pro-angiogenic functions get activated only upon stimulation by synergistic interactions with the invading cells.
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Affiliation(s)
- Melanie A Burkhardt
- Department of Health Sciences and Technology, Institute of Translational Medicine, Laboratory of Applied Mechanobiology, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, 8093, Switzerland.
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Feng W, Lu H, Xu Z, Chen L, Yang X, Qi Z. [Effect of cells in the epimysium conduit on the regeneration of peripheral nerve]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:617-624. [PMID: 29806353 PMCID: PMC8430018 DOI: 10.7507/1002-1892.201712092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 03/22/2018] [Indexed: 11/03/2022]
Abstract
Objective To investigate the effect of cells in the epimysium conduit (EMC) on the regeneration of sciatic nerve of mice. Methods The epimysium of the 8-week-old male C57BL/6J enhanced green fluorescent protein (EGFP) mouse was trimmed to a size of 5 mm×3 mm, and prepared in a tubular shape (ie, EMC). Some epimysia were treated with different irradiation doses (0, 15, 20, 25, 30, 35 Gy) to inhibit cells migration. Then the number of migrating cells were counted, and the epimysia with the least migrating cells were selected to prepare EMC. Some epimysia were subjected to decellularization treatment and prepared EMC. HE and Masson staining were used to identify the decellularization effect. Twenty-four C57BL/6J wild-type mice were used to prepare a 3-mm-long sciatic nerve defect of right hind limb model and randomly divided into 3 groups ( n=8). EMC (group A), EMC after cell migration inhibition treatment (group B), and decellularized EMC (group C) were used to repair defects. At 16 weeks after operation, the midline of the regenerating nerve was taken for gross, toluidine blue staining, immunofluorescence staining, and transmission electron microscopy. Results At 15 days, the number of migrating cells gradually decreased with the increase of irradiation dose. There was no significant difference between 30 Gy group and 35 Gy group ( P>0.05); there were significant differences between the other groups ( P<0.05). The epimysium after treatment with 35 Gy irradiation dose was selected for the in vivo experiment. After the decellularization of the epimysium, no nucleus was found in the epimysium and the epimysium could be sutured to prepare EMC. At 16 weeks after operation, the nerves in all groups were recanalized. The sciatic nerve was the thickest in group A, followed by group B, and the finest in group C. Immunofluorescence staining showed that the EGFP cells in group A were surrounded by regenerated axons. Toluidine blue staining and transmission electron microscopy observation showed that the number of regenerated axons and the thickness of regenerated myelin sheath in group A were significantly better than those in groups B and C ( P<0.05). There was no significant difference between groups B and C ( P>0.05). Conclusion The cellular components of the epimysium participate in and promote the regeneration of the sciatic nerve in mice.
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Affiliation(s)
- Weifeng Feng
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, P.R.China
| | - Haibin Lu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, P.R.China
| | - Zhuqiu Xu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, P.R.China
| | - Lulu Chen
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, P.R.China
| | - Xiaonan Yang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144,
| | - Zuoliang Qi
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144,
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Hussein KH, Saleh T, Ahmed E, Kwak HH, Park KM, Yang SR, Kang BJ, Choi KY, Kang KS, Woo HM. Biocompatibility and hemocompatibility of efficiently decellularized whole porcine kidney for tissue engineering. J Biomed Mater Res A 2018; 106:2034-2047. [PMID: 29569325 DOI: 10.1002/jbm.a.36407] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 02/15/2018] [Accepted: 03/15/2018] [Indexed: 12/14/2022]
Abstract
Whole kidney decellularization is a promising approach in regenerative medicine for engineering a functional organ. The reaction of the potential host depends on the biocompatibility of these decellularized constructs. Despite the proven ability of decellularized kidney scaffolds to guide cell attachment and growth, little is known about biocompatibility and hemocompatibility of these scaffolds. Our aim is to prepare decellularized kidneys of a clinically relevant size and evaluate its biocompatibility and hemocompatibility. Porcine kidneys were cannulated via the renal artery, and then perfused with 0.1% sodium dodecyl sulfate solution. Hematoxylin and eosin as well as DAPI staining confirmed cellular clearance from native kidneys in addition to preservation of the microstructure. SEM confirmed the absence of any cellular content within the scaffold, which is maintained in a well-organized 3D architecture. Decellularized kidneys retained the intact renal vasculature upon examination with contrast radiography. The essential structural extracellular matrix molecules were well-preserved. Scaffolds were susceptible to enzymatic degradation upon collagenase treatment. Scaffolds showed a good hemocompatibility when exposed to porcine blood. Decellularization was efficient to remove 97.7% of DNA from native kidneys in addition to the immunogenic and pathogenic antigens. Scaffolds did not induce the human immune response in vitro. Decellularized kidneys were non-cytotoxic to pig kidney cells (PKs). PKs were able to grow and proliferate within the decellularized renal scaffolds with maintaining a higher function than cells grown as monolayers. Thus, we have developed a rapid decellularization technique for generating biocompatible kidney scaffolds that represents a step toward development of a transplantable organ. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2034-2047, 2018.
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Affiliation(s)
- Kamal Hany Hussein
- Department of Animal Surgery, College of Veterinary Medicine, Assiut University, Assiut, 71515, Egypt
| | - Tarek Saleh
- Stem Cell Institute, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea.,Department of Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Ebtehal Ahmed
- Stem Cell Institute, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea.,Department of Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Ho-Hyun Kwak
- Stem Cell Institute, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea.,Department of Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Kyung-Mee Park
- Department of Surgery, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Se-Ran Yang
- Stem Cell Institute, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea.,Department of Thoracic and Cardiovascular Surgery, College of Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Byung-Jae Kang
- Department of Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Ki-Young Choi
- Department of Controlled Agriculture, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
| | - Kyung-Sun Kang
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Heung-Myong Woo
- Stem Cell Institute, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea.,Department of Surgery, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 200-701, Republic of Korea
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Stradecki-Cohan HM, Cohan CH, Raval AP, Dave KR, Reginensi D, Gittens RA, Youbi M, Perez-Pinzon MA. Cognitive Deficits after Cerebral Ischemia and Underlying Dysfunctional Plasticity: Potential Targets for Recovery of Cognition. J Alzheimers Dis 2018; 60:S87-S105. [PMID: 28453486 DOI: 10.3233/jad-170057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cerebral ischemia affects millions of people worldwide and survivors suffer from long-term functional and cognitive deficits. While stroke and cardiac arrest are typically considered when discussing ischemic brain injuries, there is much evidence that smaller ischemic insults underlie neurodegenerative diseases, including Alzheimer's disease. The "regenerative" capacity of the brain relies on several aspects of plasticity that are crucial for normal functioning; less affected brain areas may take over function previously performed by irreversibly damaged tissue. To harness the endogenous plasticity mechanisms of the brain to provide recovery of cognitive function, we must first understand how these mechanisms are altered after damage, such as cerebral ischemia. In this review, we discuss the long-term cognitive changes that result after cerebral ischemia and how ischemia alters several plasticity processes. We conclude with a discussion of how current and prospective therapies may restore brain plasticity and allow for recovery of cognitive function, which may be applicable to several disorders that have a disruption of cognitive processing, including traumatic brain injury and Alzheimer's disease.
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Affiliation(s)
- Holly M Stradecki-Cohan
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Charles H Cohan
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA
| | - Ami P Raval
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA
| | - Kunjan R Dave
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Diego Reginensi
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama, Republic of Panama
| | - Rolando A Gittens
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama, Republic of Panama
| | - Mehdi Youbi
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA
| | - Miguel A Perez-Pinzon
- Department of Neurology Cerebral Vascular Disease Research Laboratories, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
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Reisbig NA, Hussein HA, Pinnell E, Bertone AL. Evaluation of equine synovial-derived extracellular matrix scaffolds seeded with equine synovial-derived mesenchymal stem cells. Am J Vet Res 2018; 79:124-133. [DOI: 10.2460/ajvr.79.1.124] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Ford AJ, Rajagopalan P. Extracellular matrix remodeling in 3D: implications in tissue homeostasis and disease progression. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2017; 10:e1503. [PMID: 29171177 DOI: 10.1002/wnan.1503] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/15/2017] [Accepted: 10/11/2017] [Indexed: 12/16/2022]
Abstract
The extracellular matrix (ECM) plays a critical role in regulating cell behavior during tissue homeostasis and in disease progression. Through a combination of adhesion, contraction, alignment of ECM proteins and subsequent degradation, cells change the chemical, mechanical, and physical properties of their surrounding matrix. Other contributing factors to matrix remodeling are the de novo synthesis of ECM proteins, post-translational modifications and receptor-mediated internalization. In this review, we highlight how each of these processes contributes to the maintenance of homeostasis and in disease conditions such as cancer and liver fibrosis. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement.
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Affiliation(s)
- Andrew J Ford
- Department of Chemical Engineering, Virginia Tech, Blacksburg, VA, USA
| | - Padmavathy Rajagopalan
- Department of Chemical Engineering, Virginia Tech, Blacksburg, VA, USA.,School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, VA, USA.,ICTAS Center for Systems Biology of Engineered Tissues, Virginia Tech, Blacksburg, VA, USA
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50
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Dziki JL, Sicari BM, Wolf MT, Cramer MC, Badylak SF. Immunomodulation and Mobilization of Progenitor Cells by Extracellular Matrix Bioscaffolds for Volumetric Muscle Loss Treatment. Tissue Eng Part A 2017; 22:1129-1139. [PMID: 27562630 DOI: 10.1089/ten.tea.2016.0340] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Acellular bioscaffolds composed of extracellular matrix (ECM) have been effectively used to promote functional tissue remodeling in both preclinical and clinical studies of volumetric muscle loss, but the mechanisms that contribute to such outcomes are not fully understood. Thirty-two C57bl/6 mice were divided into eight groups of four animals each. A critical-sized defect was created in the quadriceps muscle and was repaired with a small intestinal submucosa ECM bioscaffold or left untreated. Animals were sacrificed at 3, 7, 14, or 56 days after surgery. The spatiotemporal cellular response in both treated and untreated groups was characterized by immunolabeling methods. Early time points showed a robust M2-like macrophage phenotype following ECM treatment in contrast to the predominant M1-like macrophage phenotype present in the untreated group. ECM implantation promoted perivascular stem cell mobilization, increased presence of neurogenic progenitor cells, and was associated with myotube formation. These cell types were present not only at the periphery of the defect near uninjured muscle, but also in the center of the ECM-filled defect. ECM bioscaffolds modify the default response to skeletal muscle injury, and provide a microenvironment conducive to a constructive healing response.
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Affiliation(s)
- Jenna L Dziki
- 1 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania.,2 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Brian M Sicari
- 2 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.,3 Department of Surgery, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Matthew T Wolf
- 1 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania.,2 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Madeline C Cramer
- 2 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Stephen F Badylak
- 1 Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania.,2 McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.,3 Department of Surgery, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
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