title: Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels.
abstract: Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties including an anti-inflammatory cytokine profile and the promotion of angiogenesis via expression of growth factors in pre-clinical models. MSCs encapsulated in poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) crosslinked hydrogels have led to controlled cellular presentation at wound sites with favorable wound healing outcomes. However, the therapeutic potential of MSC-loaded hydrogels may be limited by non-specific protein adsorption on the delivery matrix that could facilitate the initial adhesion of microorganisms and subsequent virulent biofilm formation. Antimicrobials loaded concurrently in the hydrogels with MSCs could reduce microbial bioburden and promote healing, but the antimicrobial effect on the MSC wound healing capacity and the antibacterial efficacy of the hydrogels is unknown. We demonstrate that minocycline specifically induces a favorable change in MSC migration capacity, proliferation, gene expression, extracellular matrix (ECM) attachment, and adhesion molecule and growth factor release with subsequent increased angiogenesis. We then demonstrate that hydrogels loaded with MSCs, minocycline, vancomycin, and linezolid can significantly decrease bacterial bioburden. Our study suggests that minocycline can serve as a dual mechanism for the regenerative capacity of MSCs and the reduction of bioburden in triple antimicrobial-loaded hydrogels.
  
  
  
  Wound healing is a complex biological process that can be hindered by bacterial infection, excessive inflammation, and inadequate microvasculature. In this study, we develop a new formulation of poly(ethylene glycol) diacrylate and thiolated gelatin poly(ethylene glycol) crosslinked hydrogels loaded with minocycline, vancomycin, linezolid, and mesenchymal stromal/stem cells that induces a favorable wound healing phenotype in mesenchymal stromal/stem cells and prevents bacterial bioburden on the hydrogel. This combinatorial approach to biomaterial development has the potential to impact wound healing for contaminated full thickness cutaneous wounds.
authors.affiliation: School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA. Electronic address: aguerra@wisc.edu.
authors.forename: Alberto Daniel
authors.initials: AD
authors.lastname: Guerra
authors.affiliation: School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA. Electronic address: warren.rose@wisc.edu.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Rose
authors.affiliation: School of Medicine and Public Health, Department of Medicine, Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA. Electronic address: pxh@medicine.wisc.edu.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.affiliation: School of Pharmacy, Division of Pharmaceutical Sciences, Pharmacy Practice Division, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; College of Engineering, Department of Biomedical Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, WI 53706, USA; School of Medicine and Public Health, Department of Surgery, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA. Electronic address: WJKao@wisc.edu.
authors.forename: W John
authors.initials: WJ
authors.lastname: Kao
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D020100:Hydrogels; D036341:Intercellular Signaling Peptides and Proteins; D008911:Minocycline
keywords: Hydrogel; Mesenchymal stromal/stem cells; Minocycline; Staphylococcus aureus; Wound healing