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Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component
Open accessAbstract
Recently, macrophages have been characterized as having an M1 or M2 phenotype based on receptor expression, cytokine and effector molecule production, and function. The effects of macrophage phenotype upon tissue remodeling following the implantation of a biomaterial are largely unknown. The objectives of this study were to determine the effects of a cellular component within an implanted extracellular matrix (ECM) scaffold upon macrophage phenotype, and to determine the relationship between macrophage phenotype and tissue remodeling. Partial-thickness defects in the abdominal wall musculature of Sprague-Dawley rats were repaired with autologous body wall tissue, acellular allogeneic rat body wall ECM, xenogeneic pig urinary bladder tissue, or acellular xenogeneic pig urinary bladder ECM. At 3, 7, 14, and 28 days the host tissue response was characterized using histologic, immunohistochemical, and RT-PCR methods. The acellular test articles were shown to elicit a predominantly M2 type response and resulted in constructive remodeling, while those containing a cellular component, even an autologous cellular component, elicited a predominantly M1 type response and resulted in deposition of dense connective tissue and/or scarring. We conclude that the presence of cellular material within an ECM scaffold modulates the phenotype of the macrophages participating in the host response following implantation, and that the phenotype of the macrophages participating in the host response appears to be related to tissue remodeling outcome.
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“What is more, it is widely accepted that during the degradation of implanted ECM bioscaffolds, ECM components are released into the environment and promote the transition to a remodeling phase [18,44,74,78].”
From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [74]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mechanistically, inadequate decellularization retains high amounts of damage-associated molecular patterns (DAMPs) or endotoxin, and excessive crosslinking biases macrophages toward pro-inflammatory phenotypes that drive fibrosis and poor remodeling [73,74].”
From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [74]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Immunohistochemical and gene expression analysis using CCR7 and iNOS for M1 and CD163 and Arg for M2 macrophages revealed that cellular scaffolds had a majority of M1 phenotype and provided a dense, poorly organized collagenous FBC, while decellularized scaffolds favored the M2 phenotype, and displayed both neomatrix formation and early angiogenesis.”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [180]
Experimental — accuracy not yet measuredIn the citing paper
“Recognition of the predominant MΦ phenotypic profile can provide a tool by which a tissue regenerative outcome can be predicted and possibly promoted [4].”
From Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds (2013) · cites this paper as [4]
In the citing paper
“Brown et al. [83], who demonstrated that the presence of even an autologous cellular component attracted M1 cells, which was not observed in cell free constructs.”
From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [83]
In the citing paper
“Briefly, scaffold materials composed of extracellular matrix (ECM) have been shown to promote a switch from a predominantly M1 cell population immediately following implantation to a population enriched in M2 cells by 7–14 days post implantation [154–156].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [156]
In the citing paper
“This constructive remodeling response has been directly linked to the ability of the material to modulate macrophage phenotype [154–157].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [156]
In the citing paper
“Here we find that MΦ activation depends on biomaterial architecture in addition to previously implicated biomaterial chemistry and bioactivity (34–36).”
From Proangiogenic scaffolds as functional templates for cardiac tissue engineering (2010) · cites this paper as [34]
In the citing paper
“Previous in vivo studies demonstrated concurrent expression of M1 and M2 markers (37), and enhanced expression of M2 markers has been associated with improved outcomes for implanted biologic scaffolds (34).”
From Proangiogenic scaffolds as functional templates for cardiac tissue engineering (2010) · cites this paper as [34]
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Citations
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“In this study, we found that HIF-1α mediates MCP1, TNFα, and IFNγ production and that HIF-1α-mediated impairment of liver and EWAT increases IL-1β production [49–51], which induced M1 polarization [19,51] in mice contributing to obesity-induced NAFLD.”
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Differentiation of the Mammary Epithelial Cell during Involution: Implications for Breast Cancer
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Extracellular matrix grafts: From preparation to application (Review)
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A Balance between Pro‐Inflammatory and Pro‐Reparative Macrophages is Observed in Regenerative D‐MAPS
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“Further, the phenotype of the macrophages recruited into the implanted scaffold can potentially forecast the direction of the in vivo remodeling response to either chronic inflammation or healing [73].”
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“…shown to modulate the inflammatory response from the body, eliciting a more prominent M2 macrophage phenotype, which has been associated with constructive ECM and functional remodelling of the tissue, including organized connective tissue and vasculature (Badylak et al., 2008; Brown et al., 2009).”
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Absence of Immune Responses with Xenogeneic Collagen and Elastin
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“Whereas the acellular scaffold alone elicits a constructive remodeling response, the presence of cellular components, even autologous, on acellular scaffold shifts the macrophage phenotype to proinflammatory, leading to scar and connective tissue deposition (Brown et al., 2009).”
BackgroundBioactive Inks Development for Osteochondral Tissue Engineering: A Mini-Review
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“Besides the counteracting inflammatory factors, macrophages can regulate protein expression for cell growth and regeneration [45,46].”
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“…time points were chosen to evaluate the early (innate), mid, and late - phase immune response, respectively, given that previous studies have indicated that the macrophage response and polarization during this timeframe are indicative of long - term biocompatibility and tissue repair (79, 80).”
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BackgroundPhotoreactive Hydrogel Stiffness Influences Volumetric Muscle Loss Repair
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Matrix Bound Nanovesicles Have Tissue-Specific Characteristics That Suggest a Regulatory Role
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Metadata
- Authors
- Brown, B. N., Valentin, J. E., Stewart-Akers, A. M., McCabe, G. P., & Badylak, S. F.
- Affiliations
- University of Pittsburgh (US)
- Purdue University West Lafayette (US)
- Corresponding author
- Badylak, Stephen F.
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 30
- Issue
- 8
- Pages
- 1482-1491
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC2805023
- OpenAlex
- W1999579326
- Cited by
- 896
- References
- 38
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 37 · 2023: 46 · 2022: 61 · 2021: 73 · 2020: 47 · 2019: 69 · 2018: 63 · 2017: 73 · 2016: 59 · 2015: 70 · 2014: 76 · 2013: 60 · 2012: 38
- FWCI
- 36.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Biomedical Imaging and Bioengineering (F31EB007914)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Keywords
- macrophage phenotype, macrophage polarization, tissue remodeling, extracellular matrix scaffolds, acellular scaffolds, cellular scaffolds, host tissue response, scar formation, connective tissue deposition
- MeSH terms
- Animals, Cell Nucleus, Gene Expression Regulation, Immunohistochemistry, Indoles, Macrophages, Phenotype, Transplantation, Autologous, Transplantation, Heterologous, Transplantation, Homologous, Rats, Sprague-Dawley, Muscle, Skeletal, Prosthesis Implantation, Sus scrofa, Rats, Tissue Scaffolds
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