The purpose of this study was to better understand whether interleukin-13 (IL-13) and connective tissue growth factor (CTGF) are highly expressed during foreign body encapsulation of subcutaneous devices. Mock biosensors were implanted into rats for three lengths of time (7-, 21- and 48-55 days) to address different stages of the foreign body response. Using quantitative real-time PCR and immunofluorescence, the expression of IL13, CTGF, collagen 1, decorin and fibronectin were measured in this tissue. IL-13, a product of Th2 cells, was highly expressed at all time points, with greatest expression at day 21. The IL-13 expression was paralleled by increased presence of T-cells at all time points. CTGF was also found to be more highly expressed in foreign body tissue than in controls. Collagen and decorin were highly expressed at the middle and later stages. Given the increased expression of IL-13 and CTGF in foreign body tissue, and their roles in other fibrotic disorders, these cytokines may well contribute to the formation of the foreign body capsule. Since the peak gene expression of IL-13 occurred later than the previously-reported TGFbeta expression peak, IL-13 is probably not the major stimulus to TGFbeta expression during foreign body encapsulation and may contribute to fibrosis independently.
"As mentioned above, we have shown that inhibition of TGF-β signalling either by siRNA knockdown of TGFβRII or chemical inhibition of TGFβRII (ALK5) inhibits myofibroblast differentiation in vitro and peritoneal tissue capsule formation in vivo (Chau et al, unpublished data). However in light of the pleiotropic roles of TGF-β, a more suitable target for selective intervention may be the downstream effector, connective tissue growth factor (CTGF) which is responsible for many of the pro-fibrogenic effects of TGF-β (Ward et al., 2008; Brigstock, 2009). Conversely, chemokines/growth factors may be incorporated into biomaterials to promote tissue production for replacement/repair. "
[Show abstract][Hide abstract] ABSTRACT: The biological response to implanted biomaterials in mammals is a complex series of events that involves many biochemical pathways. Shortly after implantation, fibrinogen and other proteins bind to the device surface, a process known as biofouling. Macrophages then bind to receptors on the proteins, join into multinucleated giant cells, and release transforming growth factor beta and other inflammatory cytokines. In response to these signals, quiescent fibroblasts are transformed into myofibroblasts, which synthesize procollagen via activation of Smad mediators. The procollagen becomes crosslinked after secretion into the extracellular space. Mature crosslinked collagen and other extracellular matrix proteins gradually contribute to formation of a hypocellular dense fibrous capsule that becomes impermeable or hypopermeable to many compounds. Porous substrates and angiogenic growth factors can stimulate formation of microvessels, which to some extent can maintain analyte delivery to implanted sensors. However, stimulation by vascular endothelial growth factor alone may lead to formation of leaky, thin-walled, immature vessels. Other growth factors are most probably needed to act upon these immature structures to create more robust vessels.During implantation of foreign bodies, the foreign-body response is difficult to overcome, and thousands of biomaterials have been tested. Biomimicry (i.e., creating membranes whose chemical structure mimics natural cellular compounds) may diminish the response, but as of this writing, it has not been possible to create a stealth material that circumvents the ability of the mammalian surveillance systems to distinguish foreign from self.
Journal of diabetes science and technology 09/2008; 2(5):768-77. DOI:10.1177/193229680800200504
[Show abstract][Hide abstract] ABSTRACT: The proteoglycan decorin putatively inhibits cell adhesion and cell migration on various extracellular matrix substrates through interactions with beta(1) integrins. This study, therefore, examined the adhesive, migration, and proliferative characteristics of decorin knockout (Dcn(-/-)) murine embryonic fibroblasts compared to wild-type controls on collagen-coated, fibronectin-coated, and uncoated tissue culture plates. The Dcn(-/-) cells showed significantly greater proliferation than wild-type controls on all substrates. The Dcn(-/-) cells also showed significantly greater adhesion to both collagen and fibronectin; both cell types showed greater adhesion to collagen. The addition of exogenous decorin had a differential effect on adhesion to collagen between cell types, but not on fibronectin. For collagen, blocking either alpha(2) or beta(1) integrin subunits significantly reduced adhesion for Dcn(-/-) cells; whereas for fibronectin, blocking either the alpha(5) or beta(1) integrin subunits reduced adhesion for both cell types. Decorin and the alpha(5)beta(1) integrin may have lesser roles in adhesion to fibronectin than previously presumed. Finally, compared to wild-type cells, Dcn(-/-) cells showed greater migration on both uncoated and collagen substrates. This study demonstrates that decorin affects the biology of various integrins that participate in cell proliferation, adhesion, and migration on various substrates.
Journal of Biomedical Materials Research Part A 01/2009; 93(2):419-28. DOI:10.1002/jbm.a.32545 · 3.37 Impact Factor
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