The pivotal role of fibrocytes and mast cells in mediating fibrotic reactions to biomaterials

Abstract

Almost all biomaterial implants are surrounded by a fibrotic capsule, although the mechanism of biomaterial-mediated fibrotic reactions is mostly unclear. To search for the types of cells responsible for triggering the tissue responses, we used poly-L glycolic acid polymers capable of releasing various reagents. We first identified that CD45+ /Collagen 1+ fibrocytes are recruited and resided within the fibrotic capsule at the implant interface. Interestingly, we found that the recruitment of fibrocytes and the extent of fibrotic tissue formation (collagen type I production) were substantially enhanced and reduced by the localized release of compound 48/80 and cromolyn, respectively. Since it is well established that compound 48/80 and cromolyn alter mast cell reactions, we hypothesized that mast cells are responsible for triggering fibrocyte recruitment and subsequent fibrotic capsule formation surrounding biomaterial implants. To directly test this hypothesis, similar studies were carried out using mast cell deficient mice, WBB6F1/J-KitW/KitW-v/, and their congenic controls. Indeed, mast cell deficient mice prompted substantially less fibrocyte and myofibroblast responses in comparison to C-57 wild type mice controls. Most interestingly, subcutaneous mast cell reconstitution of WBB6F1/J-KitW/KitW-v/J mice almost completely restored the fibrocyte response in comparison to the C-57 wild type response. These results indicate that the initial biomaterial interaction resulting in the stimulation of mast cells and degranulation byproducts not only stimulates the inflammatory cascade but significantly alters the downstream fibrocyte response and degree of fibrosis.

El papel de los mastocitos en la evaluación de la respuesta inflamatoria posoperatoria, al implantar mallas protésicas para la reparación de defectos de la pared abdominal en biomodelos rata Wistar

“…Thevenot et al (2011), plantearon la hipótesis de que la activación de los mastocitos está directamente asociados con la patogénesis fibrótica de los implantes de los biomateriales 16 . Para modelar la formación de tejido fibrótico mediada por el implante, se emplearon las películas hechas de poli-L de ácido glicólico (PLGA), materiales comúnmente utilizados para la fabricación de andamios de ingeniería de tejidos.…”

Effect of propranolol on capsular reaction around silicone implants in guinea pigs

“…In patient populations, this condition is accompanied by overt symptoms and loss of esthetic results of breast augmentation 13 Since the first reports on capsular contracture in the literature, a number of preclinical studies have been conducted in an attempt to prevent its development, using different drugs (such as leukotriene receptor antagonists, antibiotics, anti-neoplastic and antifibroticagents, steroids and non-steroidal anti-inflammatory drugs) administered locally or systemically, but with disappointing results [3][4][5][6][7][8][9][13][14][15][16] . Thus, there is currently no proven pharmacological therapy for ACC 13 .…”

“…Both the wound healing and immune system have very complex interconnections and implanting biomaterials are likely to affect many of these pathways [3][4][5] . Despite silicone has being considered relatively inert, as any biomaterial implanted in the human body, its elicits this protective immune-inflammatory reaction from the organism, starting a rejection process that interferes with wound healing process and finish by encapsulating this foreign body too large to be eliminated by phagocytosis [6][7][8][9][10][11] .…”

“…Foreign body reaction often interferes with the longterm functionality and performance of implanted biomedical devices through fibrous capsule formation 3,4 . Both the wound healing and immune system have very complex interconnections and implanting biomaterials are likely to affect many of these pathways [3][4][5] .…”

Liver tissue engineering: From implantable tissue to whole organ engineering

“…In addition, human cocultured encapsulated cells were transplanted in immunocompetent mice without causing immune rejection for at least 24 days 21. However, the actual applicability of the encapsulated coculture system approach needs to be further explored in specific disease models where additional parallel strategies aimed at reducing potential foreign body fibrotic reactions22, 23 and improving neovascularization24, 25 should be considered.…”