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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During degradation of implanted ECM bioscaffolds, ECM components are released and promote the transition to a remodeling phase.
“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]
The Introduction identifies biomaterial degradation products as possible stimuli for macrophages, and the Discussion says rapid ECM-scaffold degradation is followed by constructive tissue remodeling (page numbers not provided). The paper does not establish that released ECM components promote the transition to a remodeling phase; that causal mechanism is stronger than its evidence. (LLM, conf=0.83)
Experimental — accuracy not yet measuredInadequate decellularization retains high amounts of DAMPs or endotoxin, and excessive crosslinking biases macrophages toward pro-inflammatory phenotypes that drive fibrosis and poor remodeling.
“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]
The Discussion (page not provided) reports that chemically crosslinked scaffolds elicited a predominantly M1 macrophage response and chronic inflammation, whereas non-crosslinked scaffolds elicited an M2 response and constructive remodeling. It also notes residual DNA fragments after decellularization, but does not say inadequate decellularization retains high amounts of DAMPs or endotoxin. The reported crosslinking comparison does not establish that excessive crosslinking drives fibrosis specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCellular 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.
“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]
The Results (§3.2) report an M1-skewed response to cellular scaffolds and an M2-skewed response to acellular scaffolds. The histopathology Results (§3.1) describe dense, poorly organized collagenous connective tissue after a cellular xenograft, and neomatrix deposition and early angiogenesis after acellular scaffolds. They do not identify the dense tissue as a foreign body capsule (FBC), so that characterization is not supported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRecognizing the predominant macrophage phenotypic profile can provide a tool to predict and possibly promote a tissue regenerative outcome.
“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]
The presence of even an autologous cellular component attracted M1 cells, which was not observed in cell-free constructs.
“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]
ECM-based scaffold materials promote a switch from predominantly M1 cells immediately after implantation to a population enriched in M2 cells by 7-14 days post implantation.
“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]
This constructive remodeling response is directly linked to the material's ability to modulate macrophage phenotype.
“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]
MΦ activation depends on biomaterial architecture in addition to previously implicated biomaterial chemistry and bioactivity.
“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]
Previous in vivo studies demonstrated concurrent expression of M1 and M2 markers, and enhanced expression of M2 markers has been associated with improved outcomes for implanted biologic scaffolds.
“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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Self-citationBiologic Scaffolds for Regenerative Medicine: Mechanisms of In vivo Remodeling
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Extracellular matrix scaffold devices for rotator cuff repair
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Self-citationEuropium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent
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Self-citationMacrophages Are Key Regulators of Stem Cells during Skeletal Muscle Regeneration and Diseases
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“Multiple studies have shown that ECM based scaffold materials which are properly prepared facilitate a transition from an M1 to an M2 phenotype around 7–14 days post-implantation (3, 92, 93).”
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Self-citationA Murine Model of Volumetric Muscle Loss and a Regenerative Medicine Approach for Tissue Replacement
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Self-citationThe host response to naturally-derived extracellular matrix biomaterials
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“We found that our composite had a similar fibrillary microarchitecture as native spinal cord ECM and resulted in 85% of the injury occupied by cells and structures.”
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Decellularized extracellular matrix mediates tissue construction and regeneration
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Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response
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- 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 › Rehabilitation › 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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