title: Response of human macrophages to wound matrices in vitro.
abstract: Chronic wounds remain a major burden to the global healthcare system. Myriad wound matrices are commercially available but their mechanisms of action are poorly understood. Recent studies have shown that macrophages are highly influenced by their microenvironment, but it is not known how different biomaterials affect this interaction. Here, it was hypothesized that human macrophages respond differently to changes in biomaterial properties in vitro with respect to phenotype, including pro-inflammatory M1, anti-inflammatory M2a, known for facilitating extracellular matrix deposition and proliferation, and M2c, which has recently been associated with tissue remodeling. Using multiple donors, it was found that collagen scaffolds cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (EDC/NHS) promoted the least inflammatory phenotype in primary human macrophages compared with scaffolds cross-linked with formaldehyde or glutaraldehyde. Importantly, gene expression analysis trends were largely conserved between donors, especially TNFa (M1), CCL22 (M2a), and MRC1 (M2a). Then the response of primary and THP1 monocyte-derived macrophages to four commercially available wound matrices were compared-Integra Dermal Regeneration Template (Integra), PriMatrix Dermal Repair Scaffold (PriMatrix), AlloMend Acellular Dermal Matrix (AlloMend), and Oasis Wound Matrix (Oasis). Gene expression trends were different between primary and THP1 monocyte-derived macrophages for all six genes analyzed in this study. Finally, the behavior of primary macrophages cultured onto the wound matrices over time was analyzed. Integra and Oasis caused down-regulation of M2a markers CCL22 and TIMP3. PriMatrix caused up-regulation of TNFa (M1) and CD163 (M2c) and down-regulation of CCL22 and TIMP3 (both M2a). AlloMend caused up-regulation in CD163 (M2c). Lastly, Oasis promoted the largest increase in the combinatorial M1/M2 score, defined as the sum of M1 genes divided by the sum of M2 genes. This preliminary study suggested that biomaterials influenced the wound microenvironment to affect macrophage phenotype.
authors.affiliation: School of Biomedical Engineering, Biomaterials & Regenerative Medicine Laboratory, Drexel University, Philadelphia, Pennsylvania, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Witherel
authors.affiliation: School of Biomedical Engineering, Biomaterials & Regenerative Medicine Laboratory, Drexel University, Philadelphia, Pennsylvania, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Graney
authors.affiliation: New York Stem Cell Foundation, New York, New York, USA.|Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.|North Carolina State University, Raleigh, North Carolina, 27695, USA.
authors.forename: Donald O
authors.initials: DO
authors.lastname: Freytes
authors.affiliation: College of Medicine, Drexel University, Philadelphia, Pennsylvania, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Weingarten
authors.affiliation: School of Biomedical Engineering, Biomaterials & Regenerative Medicine Laboratory, Drexel University, Philadelphia, Pennsylvania, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Spiller
mesh_terms: D062088:Acellular Dermis; D001672:Biocompatible Materials / Q000494:pharmacology*; D001684:Biological Dressings; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008422:Materials Testing; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D054457:Tissue Scaffolds; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*
chemical_list: D001672:Biocompatible Materials