title: Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kit(w-Sh) murine model.
abstract: Mast cells (MCs)_are recognized for their functional role in wound-healing and allergic and inflammatory responses - host responses that are frequently detrimental to implanted biomaterials if extended beyond acute reactivity. These tissue reactions impact especially on the performance of sensing implants such as continuous glucose monitoring (CGM) devices. Our hypothesis that effective blockade of MC activity around implants could alter the host foreign body response (FBR) and enhance the in vivo lifetime of these implantable devices motivated this study. Stem cell factor and its ligand c-KIT receptor are critically important for MC survival, differentiation and degranulation. Therefore, an MC-deficient sash mouse model was used to assess MC relationships to the in vivo performance of CGM implants. Additionally, local delivery of a tyrosine kinase inhibitor (TKI) that inhibits c-KIT activity was also used to evaluate the role of MCs in modulating the FBR. Model sensor implants comprising polyester fibers coated with a rapidly dissolving polymer coating containing drug-releasing degradable microspheres were implanted subcutaneously in sash mice for various time points, and the FBR was evaluated for chronic inflammation and fibrous capsule formation around the implants. No significant differences were observed in the foreign body capsule formation between control and drug-releasing implant groups in MC-deficient mice. However, fibrous encapsulation was significantly greater around the drug-releasing implants in sash mice compared to drug-releasing implants in wild-type (e.g. MC-competent) mice. These results provide insights into the role of MCs in the FBR, suggesting that MC deficiency provides alternative pathways for host inflammatory responses to implanted biomaterials.
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Avula
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Rao
authors.affiliation: Associated Regional and University Pathologist Laboratories, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: McGill
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: david.grainger@utah.edu.
authors.forename: D W
authors.initials: DW
authors.lastname: Grainger
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: F
authors.initials: F
authors.lastname: Solzbacher
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects*; D002452:Cell Count; D004195:Disease Models, Animal; D005355:Fibrosis; D005547:Foreign Bodies / Q000276:immunology / Q000473:pathology; D005549:Foreign-Body Reaction / Q000276:immunology* / Q000473:pathology; D020007:Implants, Experimental / Q000009:adverse effects*; D007249:Inflammation / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008407:Mast Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000276:immunology* / Q000473:pathology
chemical_list: D001672:Biocompatible Materials; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D019009:Proto-Oncogene Proteins c-kit
keywords: Combination device; Continuous glucose monitoring sensors; Host response; Inflammation; Local drug delivery