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Macrophage Phenotype as a Determinant of Biologic Scaffold Remodeling
Abstract
Macrophage phenotype can be characterized as proinflammatory (M1) or immunomodulatory and tissue remodeling (M2). The present study used a rat model to determine the macrophage phenotype at the site of implantation of two biologic scaffolds that were derived from porcine small intestinal submucosa (SIS) and that differed mainly according to their method of processing: the Restore device (SIS) and the CuffPatch device (carbodiimide crosslinked form of porcine-derived SIS (CDI-SIS)). An autologous tissue graft was used as a control implant. Immunohistologic methods were used to identify macrophage surface markers CD68 (pan macrophages), CD80 and CCR7 (M1 profile), and CD163 (M2 profile) during the remodeling process. All graft sites were characterized by the dense population of CD68+ mononuclear cells present during the first 4 weeks. The SIS device elicited a predominantly CD163+ response (M2 profile, p < 0.001) and showed constructive remodeling at 16 weeks. The CDI-SIS device showed a predominately CD80+ and CCR7+ response (M1 profile, p < 0.03), and at 16 weeks was characterized by chronic inflammation. The autologous tissue graft showed a predominately CD163+ response (M2) at 1 week, with a dual M1/M2 population (CD80+, CCR7+, and CD163+) by 2 and 4 weeks and moderately well organized connective tissue by 16 weeks. The processing methods used during the manufacturing of a biologic scaffold can have a profound influence upon the macrophage phenotype profile and downstream remodeling events. Routine histologic examination alone is inadequate to determine the phenotype of mononuclear cells that participate in the host response to the scaffold.
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“promotion of M2-like phenotypes in vitro [40,44,153] and in vivo [152,154,155].”
From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [40]
In the citing paper
“Macrophages that polarized toward to the M2 phenotype are identified by high expression levels of IL‐10, CD163, and amplification of the Arginase 1 (Arg1) enzyme, hereby switching the focus to releasing signals for constructive tissue remodeling.[ 68 ]”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [68]
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 [154]
In the citing paper
“However, modification of such scaffold materials with chemical crosslinking agents which delay or prevent macrophage mediated degradation inhibits the formation of the beneficial M2 response and results in downstream scar tissue formation [154].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [154]
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 [154]
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 [35]
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Self-citation
Metadata
- Authors
- Badylak, S. F., Valentin, J. E., Ravindra, A. K., McCabe, G. P., & Stewart-Akers, A. M.
- Affiliations
- University of Pittsburgh (US)
- Purdue University West Lafayette (US)
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Corresponding author
- Badylak, Stephen F.
- Venue
- Tissue Engineering Part A
- Publisher
- SAGE Publications
- Published
- 2008-11
- Volume
- 14
- Issue
- 11
- Pages
- 1835-1842
- ISSN
- 1937-3341 (ISSN-L)
- 1937-335X
- OpenAlex
- W2042569529
- Cited by
- 729
- References
- 51
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 31 · 2023: 25 · 2022: 28 · 2021: 50 · 2020: 49 · 2019: 46 · 2018: 41 · 2017: 67 · 2016: 62 · 2015: 47 · 2014: 71 · 2013: 63 · 2012: 34
- FWCI
- 28.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Tissue Engineering Part A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054940)
- 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, M1/M2 macrophages, porcine small intestinal submucosa, carbodiimide crosslinking, chronic inflammation, CD163, CD80, CCR7, CD68, tissue grafts
- MeSH terms
- CD163 Antigen, Animals, Immunohistochemistry, Macrophages, Random Allocation, Receptors, Cell Surface, Swine, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Rats, Sprague-Dawley, B7-1 Antigen, Tissue Engineering, Rats, Receptors, CCR7, Tissue Scaffolds
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