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Article ; Online: Bone formation by human paediatric marrow stromal cells in a functional allogeneic immune system.

Palomares Cabeza, Virginia / Fahy, Niamh / Kiernan, Caoimhe H / Lolli, Andrea / Witte-Bouma, Janneke / Fahmy Garcia, Shorouk / Merino, Ana / Kops, Nicole / Ridwan, Yanto / Wolvius, Eppo B / Brama, Pieter A J / Hoogduijn, Martin J / Farrell, Eric

Biomaterials

2024 Volume 306, Page(s) 122471

Abstract: Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in ... ...

Abstract	Allogeneic stem-cell based regenerative medicine is a promising approach for bone defect repair. The use of chondrogenically differentiated human marrow stromal cells (MSCs) has been shown to lead to bone formation by endochondral ossification in immunodeficient pre-clinical models. However, an insight into the interactions between the allogeneic immune system and the human MSC-derived bone grafts has not been fully achieved yet. The choice of a potent source of MSCs isolated from pediatric donors with consistent differentiation and high proliferation abilities, as well as low immunogenicity, could increase the chance of success for bone allografts. In this study, we employed an immunodeficient animal model humanised with allogeneic immune cells to study the immune responses towards chondrogenically differentiated human pediatric MSCs (ch-pMSCs). We show that ch-differentiated pMSCs remained non-immunogenic to allogeneic CD4 and CD8 T cells in an in vitro co-culture model. After subcutaneous implantation in mice, ch-pMSC-derived grafts were able to initiate bone mineralisation in the presence of an allogeneic immune system for 3 weeks without the onset of immune responses. Re-exposing the splenocytes of the humanised animals to pMSCs did not trigger further T cell proliferation, suggesting an absence of secondary immune responses. Moreover, ch-pMSCs generated mature bone after 8 weeks of implantation that persisted for up to 6 more weeks in the presence of an allogeneic immune system. These data collectively show that human allogeneic chondrogenically differentiated pediatric MSCs might be a safe and potent option for bone defect repair in the tissue engineering and regenerative medicine setting.
MeSH term(s)	Humans ; Mice ; Animals ; Child ; Osteogenesis ; Bone Marrow ; Mesenchymal Stem Cells ; Stromal Cells ; Cell Differentiation ; Hematopoietic Stem Cell Transplantation ; Bone Marrow Cells ; Cells, Cultured
Language	English
Publishing date	2024-01-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2024.122471
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Article ; Online: Shear and Dynamic Compression Modulates the Inflammatory Phenotype of Human Monocytes

Fahy, Niamh / Menzel, Ursula / Alini, Mauro / Stoddart, Martin J

Frontiers in immunology

2019 Volume 10, Page(s) 383

Abstract: Monocytes and their derived macrophages are found at the site of remodeling tissue, such as fracture hematoma, that is exposed to mechanical forces and have been previously implicated in the reparative response. However, the mechanoresponsive of ... ...

Abstract	Monocytes and their derived macrophages are found at the site of remodeling tissue, such as fracture hematoma, that is exposed to mechanical forces and have been previously implicated in the reparative response. However, the mechanoresponsive of monocytes and macrophages to skeletal tissue-associated mechanical forces and their subsequent contribution to skeletal repair remains unclear. The aim of this study was to investigate the potential of skeletal tissue-associated loading conditions to modulate human monocyte activation and phenotype. Primary human monocytes or the human monocyte reporter cell line, THP1-Blue, were encapsulated in agarose and exposed to a combination of shear and compressive loading for 1 h a day for 3 consecutive days. Exposure of monocytes to mechanical loading conditions increased their pro-inflammatory gene and protein expression. Exposure of undifferentiated monocytes to mechanical loading conditions significantly upregulated gene expression levels of interleukin(IL)-6 and IL-8 compared to free swelling controls. Additionally, multiaxial loading of unstimulated monocytes resulted in increased protein secretion of TNF-α (17.1 ± 8.9 vs. 8 ± 7.4 pg/ml) and MIP-1α (636.8 ± 471.1 vs. 124.1 ± 40.1 pg/ml), as well as IL-13 (42.1 ± 19.8 vs. 21.7 ± 13.6) compared monocytes cultured under free-swelling conditions. This modulatory effect was observed irrespective of previous activation with the M1/pro-inflammatory differentiation stimuli lipopolysaccharide and interferon-γ or the M2/anti-inflammatory differentiation factor interleukin-4. Furthermore, mechanical shear and compression were found to differentially regulate nitric oxide synthase 2 (NOS2) and IL-12B gene expression as well as inflammatory protein production by THP1-Blue monocytes. The findings of this study indicate that human monocytes are responsive to mechanical stimuli, with a modulatory effect of shear and compressive loading observed toward pro-inflammatory mediator production. This may play a role in healing pathways that are mechanically regulated. An in depth understanding of the impact of skeletal tissue-associated mechanical loading on monocyte behavior may identify novel targets to maximize inflammation-mediated repair mechanisms.
MeSH term(s)	Cell Differentiation/physiology ; Gene Expression Regulation/physiology ; Humans ; Inflammation ; Macrophages/physiology ; Monocytes/physiology ; Phenotype ; Shear Strength/physiology ; Stress, Mechanical ; Wound Healing/physiology
Language	English
Publishing date	2019-03-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00383
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Article: The response of human macrophages to 3D printed titanium antibacterial implants does not affect the osteogenic differentiation of hMSCs.

Garmendia Urdalleta, Amaia / Van Poll, Mathijs / Fahy, Niamh / Witte-Bouma, Janneke / Van Wamel, Willem / Apachitei, Iulian / Zadpoor, Amir A / Fratila-Apachitei, Lidy E / Farrell, Eric

Frontiers in bioengineering and biotechnology

2023 Volume 11, Page(s) 1176534

Abstract: Macrophage responses following the implantation of orthopaedic implants are essential for successful implant integration in the body, partly through intimate crosstalk with human marrow stromal cells (hMSCs) in the process of new bone formation. Additive ...

Abstract	Macrophage responses following the implantation of orthopaedic implants are essential for successful implant integration in the body, partly through intimate crosstalk with human marrow stromal cells (hMSCs) in the process of new bone formation. Additive manufacturing (AM) and plasma electrolytic oxidation (PEO) in the presence of silver nanoparticles (AgNPs) are promising techniques to achieve multifunctional titanium implants. Their osteoimmunomodulatory properties are, however, not yet fully investigated. Here, we studied the effects of implants with AgNPs on human macrophages and the crosstalk between hMSCs and human macrophages when co-cultured
Language	English
Publishing date	2023-06-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2023.1176534
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Article ; Online: Mechanical stimulation of mesenchymal stem cells: Implications for cartilage tissue engineering.

Fahy, Niamh / Alini, Mauro / Stoddart, Martin J

Journal of orthopaedic research : official publication of the Orthopaedic Research Society

2017 Volume 36, Issue 1, Page(s) 52–63

Abstract: Articular cartilage is a load-bearing tissue playing a crucial mechanical role in diarthrodial joints, facilitating joint articulation, and minimizing wear. The significance of biomechanical stimuli in the development of cartilage and maintenance of ... ...

Abstract	Articular cartilage is a load-bearing tissue playing a crucial mechanical role in diarthrodial joints, facilitating joint articulation, and minimizing wear. The significance of biomechanical stimuli in the development of cartilage and maintenance of chondrocyte phenotype in adult tissues has been well documented. Furthermore, dysregulated loading is associated with cartilage pathology highlighting the importance of mechanical cues in cartilage homeostasis. The repair of damaged articular cartilage resulting from trauma or degenerative joint disease poses a major challenge due to a low intrinsic capacity of cartilage for self-renewal, attributable to its avascular nature. Bone marrow-derived mesenchymal stem cells (MSCs) are considered a promising cell type for cartilage replacement strategies due to their chondrogenic differentiation potential. Chondrogenesis of MSCs is influenced not only by biological factors but also by the environment itself, and various efforts to date have focused on harnessing biomechanics to enhance chondrogenic differentiation of MSCs. Furthermore, recapitulating mechanical cues associated with cartilage development and homeostasis in vivo, may facilitate the development of a cellular phenotype resembling native articular cartilage. The goal of this review is to summarize current literature examining the effect of mechanical cues on cartilage homeostasis, disease, and MSC chondrogenesis. The role of biological factors produced by MSCs in response to mechanical loading will also be examined. An in-depth understanding of the impact of mechanical stimulation on the chondrogenic differentiation of MSCs in terms of endogenous bioactive factor production and signaling pathways involved, may identify therapeutic targets and facilitate the development of more robust strategies for cartilage replacement using MSCs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:52-63, 2018.
MeSH term(s)	Animals ; Biomechanical Phenomena ; Cartilage, Articular/cytology ; Cartilage, Articular/physiology ; Cell Differentiation ; Chondrogenesis ; Humans ; Mesenchymal Stem Cells/physiology ; Signal Transduction/physiology ; Tissue Engineering/methods
Language	English
Publishing date	2017-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605542-4
ISSN	1554-527X ; 0736-0266
ISSN (online)	1554-527X
ISSN	0736-0266
DOI	10.1002/jor.23670
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Article ; Online: Parathyroid Hormone-Related Protein Gradients Affect the Progression of Mesenchymal Stem Cell Chondrogenesis and Hypertrophy.

Fahy, Niamh / Gardner, Oliver F W / Alini, Mauro / Stoddart, Martin J

Tissue engineering. Part A

2018 Volume 24, Issue 9-10, Page(s) 849–859

Abstract: Introduction: Mesenchymal stem cells (MSCs) are considered a promising cell source for cartilage repair strategies due to their chondrogenic differentiation potential. However, their in vitro tendency to progress toward hypertrophy limits their clinical ...

Abstract	Introduction: Mesenchymal stem cells (MSCs) are considered a promising cell source for cartilage repair strategies due to their chondrogenic differentiation potential. However, their in vitro tendency to progress toward hypertrophy limits their clinical use. This unfavorable result may be due to the fact that MSCs used in tissue engineering approaches are all at the same developmental stage, and have lost crucial spatial and temporal signaling cues. In this study, we sought to investigate the effect of a spatial parathyroid hormone-related protein (PTHrP) signaling gradient on the chondrogenic differentiation of MSCs and progression to hypertrophy. Methods: Human bone marrow-derived MSCs were transduced with adenoviral vectors overexpressing PTHrP and seeded into fibrin-poly(ester-urethane) scaffolds. To investigate the effect of a spatial PTHrP signaling gradient, scaffolds were seeded with PTHrP-overexpressing MSCs positioned on top of the scaffold, with untransduced MSCs seeded evenly within. Scaffolds were cultured with or without 2 ng/mL transforming growth factor (TGF)-β1 for 28 days. Results: PTHrP overexpression increased glycosaminoglycan (GAG) production by MSCs irrespective of TGF-β1 treatment, and exerted differential effects on chondrogenic and hypertrophic gene expression when MSCs were cultured in the presence of a PTHrP signaling gradient. Furthermore, PTHrP-overexpressing MSCs were associated with an increase of endogenous TGF-β1 production and reduced total MMP-13 secretion compared to controls. Conclusion: The presence of a spatial PTHrP signaling gradient may support chondrogenic differentiation of MSCs and promote the formation of a more stable cartilage phenotype in tissue engineering applications.
MeSH term(s)	Adenoviridae/genetics ; Alkaline Phosphatase/metabolism ; Cells, Cultured ; Chondrogenesis/physiology ; Enzyme-Linked Immunosorbent Assay ; Genetic Vectors/genetics ; Humans ; Hypertrophy/metabolism ; Mesenchymal Stem Cells/cytology ; Parathyroid Hormone-Related Protein/metabolism ; Tissue Engineering/methods
Chemical Substances	Parathyroid Hormone-Related Protein ; Alkaline Phosphatase (EC 3.1.3.1)
Language	English
Publishing date	2018-01-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2017.0337
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Zs.A 5500/A: Show issues

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Article ; Online: Intra-articular injection of triamcinolone acetonide sustains macrophage levels and aggravates osteophytosis during degenerative joint disease in mice.

Ferrao Blanco, Mauricio N / Bastiaansen Jenniskens, Yvonne M / Kops, Nicole / Chavli, Athina / Narcisi, Roberto / Botter, Sander M / Leenen, Pieter J M / van Osch, Gerjo J V M / Fahy, Niamh

British journal of pharmacology

2022 Volume 179, Issue 11, Page(s) 2771–2784

Abstract: Background and purpose: Corticosteroids such as triamcinolone acetonide (TAA) are potent drugs administered intra-articularly as an anti-inflammatory therapy to relieve pain associated with osteoarthritis (OA). However, the ability of early TAA ... ...

Abstract	Background and purpose: Corticosteroids such as triamcinolone acetonide (TAA) are potent drugs administered intra-articularly as an anti-inflammatory therapy to relieve pain associated with osteoarthritis (OA). However, the ability of early TAA intervention to mitigate OA progression and modulate immune cell subsets remains unclear. Here, we sought to understand the effect of early intra-articular injection of TAA on OA progression, local macrophages, and peripheral blood monocytes. Experimental approach: Degenerative joint disease was induced by intra-articular injection of collagenase into the knee joint of male C57BL/6 mice. After 1 week, TAA or saline was injected intra-articularly. Blood was taken throughout the study to analyse monocyte subsets. Mice were killed at days 14 and 56 post-induction of collagenase-induced OA (CiOA) to examine synovial macrophages and structural OA features. Key results: The percentage of macrophages relative to total live cells present within knee joints was increased in collagenase- compared with saline-injected knees at day 14 and was not altered by TAA treatment. However, at day 56, post-induction of CiOA, TAA-treated knees had increased levels of macrophages compared with the knees of untreated CiOA-mice. The distribution of monocyte subsets present in peripheral blood was not altered by TAA treatment during the development of CiOA. Osteophyte maturation was increased in TAA-injected knees at day 56. Conclusion and implications: Intra-articular injection of TAA increases long-term synovial macrophage numbers and osteophytosis. Our findings suggest that TAA accentuates the progression of osteoarthritis-associated features when applied to an acutely inflamed knee.
MeSH term(s)	Animals ; Collagenases ; Injections, Intra-Articular ; Macrophages ; Male ; Mice ; Mice, Inbred C57BL ; Osteoarthritis/chemically induced ; Osteoarthritis/drug therapy ; Triamcinolone Acetonide
Chemical Substances	Collagenases (EC 3.4.24.-) ; Triamcinolone Acetonide (F446C597KA)
Language	English
Publishing date	2022-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15780
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Article ; Online: Allogeneic Chondrogenic Mesenchymal Stromal Cells Alter Helper T Cell Subsets in CD4+ Memory T Cells.

Kiernan, Caoimhe H / Asmawidjaja, Patrick S / Fahy, Niamh / Witte-Bouma, Janneke / Wolvius, Eppo B / Brama, Pieter A J / Lubberts, Erik / Farrell, Eric

Tissue engineering. Part A

2020 Volume 26, Issue 9-10, Page(s) 490–502

Abstract: Implantation of chondrogenically differentiated mesenchymal stromal cells (MSCs) leads to bone ... ...

Abstract	Implantation of chondrogenically differentiated mesenchymal stromal cells (MSCs) leads to bone formation
MeSH term(s)	CD4-Positive T-Lymphocytes/metabolism ; Cell Differentiation/physiology ; Cells, Cultured ; Chondrogenesis/genetics ; Chondrogenesis/physiology ; Coculture Techniques ; Humans ; Interleukin-6/metabolism ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/metabolism ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/metabolism ; T-Lymphocytes, Helper-Inducer/metabolism
Chemical Substances	Interleukin-6
Language	English
Publishing date	2020-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2019.0177
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Article ; Online: Joint mimicking mechanical load activates TGFβ1 in fibrin-poly(ester-urethane) scaffolds seeded with mesenchymal stem cells.

Gardner, Oliver F W / Fahy, Niamh / Alini, Mauro / Stoddart, Martin J

Journal of tissue engineering and regenerative medicine

2016 Volume 11, Issue 9, Page(s) 2663–2666

Abstract: Transforming growth factor-β1 (TGF-β1) is widely used in an active recombinant form to stimulate the chondrogenic differentiation of mesenchymal stem cells (MSCs). Recently, it has been shown that the application of multiaxial load, that mimics the ... ...

Abstract	Transforming growth factor-β1 (TGF-β1) is widely used in an active recombinant form to stimulate the chondrogenic differentiation of mesenchymal stem cells (MSCs). Recently, it has been shown that the application of multiaxial load, that mimics the loading within diarthrodial joints, to MSCs seeded in to fibrin-poly(ester-urethane) scaffolds leads to the endogenous production and secretion of TGF-β1 by the mechanically stimulated cells, which in turn drives the chondrogenic differentiation of the cells within the scaffold. The work presented in this short communication provides further evidence that the application of joint mimicking multiaxial load induces the secretion of TGF-β1 by mechanically stimulated MSCs. The results of this work also show that joint-like multiaxial mechanical load activates latent TGF-β1 in response to loading in the presence or absence of cells; this activation was not seen in non-loaded control scaffolds. Despite the application of mechanical load to scaffolds with different distributions/numbers of cells no significant differences were seen in the percentage of active TGF-β1 quantified in the culture medium of scaffolds from different groups. The similar level of activation in scaffolds containing different numbers of cells, cells at different stages of differentiation or with different distributions of cells suggests that this activation results from the mechanical forces applied to the culture system rather than differences in cellular behaviour. These results are relevant when considering rehabilitation protocols after cell therapy or microfracture, for articular cartilage repair, where increased TGF-β1 activation in response to joint mobilization may improve the quality of developing cartilaginous repair material. Copyright © 2016 John Wiley & Sons, Ltd.
MeSH term(s)	Adolescent ; Adult ; Female ; Fibrin/chemistry ; Humans ; Joints ; Male ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Middle Aged ; Polyesters/chemistry ; Polyurethanes/chemistry ; Stress, Mechanical ; Tissue Scaffolds/chemistry ; Transforming Growth Factor beta1/metabolism
Chemical Substances	Polyesters ; Polyurethanes ; TGFB1 protein, human ; Transforming Growth Factor beta1 ; microthane foam ; Fibrin (9001-31-4)
Language	English
Publishing date	2016-07-22
Publishing country	England
Document type	Journal Article
ISSN	1932-7005
ISSN (online)	1932-7005
DOI	10.1002/term.2210
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Article ; Online: Chondrogenically Primed Human Mesenchymal Stem Cells Persist and Undergo Early Stages of Endochondral Ossification in an Immunocompetent Xenogeneic Model.

Fahy, Niamh / Palomares Cabeza, Virginia / Lolli, Andrea / Witte-Bouma, Janneke / Merino, Ana / Ridwan, Yanto / Wolvius, Eppo B / Hoogduijn, Martin J / Farrell, Eric / Brama, Pieter A J

Frontiers in immunology

2021 Volume 12, Page(s) 715267

Abstract: Tissue engineering approaches using progenitor cells such as mesenchymal stromal cells (MSCs) represent a promising strategy to regenerate bone. Previous work has demonstrated the potential of chondrogenically primed human MSCs to recapitulate the ... ...

Abstract	Tissue engineering approaches using progenitor cells such as mesenchymal stromal cells (MSCs) represent a promising strategy to regenerate bone. Previous work has demonstrated the potential of chondrogenically primed human MSCs to recapitulate the process of endochondral ossification and form mature bone
MeSH term(s)	Animals ; Biomarkers ; Bone Regeneration ; Calcification, Physiologic ; Cell Differentiation/genetics ; Cells, Cultured ; Chondrogenesis/genetics ; Humans ; Immunity ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mice ; Models, Animal ; Monocytes/immunology ; Monocytes/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Tissue Engineering ; X-Ray Microtomography
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-09-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.715267
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Article ; Online: Macrophage phenotypes and monocyte subsets after destabilization of the medial meniscus in mice.

Utomo, Lizette / Fahy, Niamh / Kops, Nicole / van Tiel, Sandra T / Waarsing, Jan / Verhaar, Jan A N / Leenen, Pieter J M / van Osch, Gerjo J V M / Bastiaansen-Jenniskens, Yvonne M

Journal of orthopaedic research : official publication of the Orthopaedic Research Society

2020 Volume 39, Issue 10, Page(s) 2270–2280

Abstract: Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial ... ...

Abstract	Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial meniscus (DMM), and the association of macrophage subsets with OA features. DMM, sham, and non-operated knees were histologically assessed between 1 and 56 days for macrophage polarization states by immunohistochemistry (IHC), cartilage damage, synovial thickening, and osteophytes (n = 9 per timepoint). Naive knees (n = 6) were used as controls. Monocyte and polarized synovial macrophage subsets were evaluated by flow cytometry. CD64 and CD206 levels on IHC were higher at early timepoints in DMM and sham knees compared to naive knees. iNOS labeling intensity was higher in DMM and sham knees than in naive knees from d3 onwards. CD163 expression was unaltered at all timepoints. Even though macrophage polarization profiles were similar in DMM and sham knees, only in DMM knees the presence of iNOS and CD206 associated with synovial thickness, and CD163 staining inversely correlated with osteophyte presence. At day 14, monocyte subset distribution was different in peripheral blood of DMM mice compared with sham mice. In conclusion, monocyte subsets in blood and synovial macrophage phenotypes vary after joint surgery. High levels of iNOS
MeSH term(s)	Animals ; Disease Models, Animal ; Macrophages/metabolism ; Menisci, Tibial/pathology ; Mice ; Mice, Inbred C57BL ; Monocytes/metabolism ; Osteoarthritis/metabolism ; Osteophyte/pathology ; Phenotype
Language	English
Publishing date	2020-12-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605542-4
ISSN	1554-527X ; 0736-0266
ISSN (online)	1554-527X
ISSN	0736-0266
DOI	10.1002/jor.24958
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