Role of plasma fibronectin in the foreign body response to biomaterials
Introduction
Host responses to biomaterials control the biological performance of implanted medical devices, tissue-engineered constructs, and delivery vehicles for therapeutics [1], [2]. Upon implantation, synthetic materials dynamically adsorb proteins and other biomolecules, which trigger an inflammatory cascade comprising blood coagulation, leukocyte recruitment and adhesion, foreign body reaction, and fibrous encapsulation [1], [2]. The foreign body reaction and ensuing fibrous encapsulation result in a physicochemical barrier that severely limits device integration and the in vivo performance of numerous devices, including chemical biosensors, electrical leads/electrodes, therapeutic delivery systems, and orthopedic and cardiovascular prostheses [3], [4], [5], [6]. Extensive research has identified mechanisms governing acute inflammatory responses to implanted synthetic materials. Adsorption of fibrinogen and complement fragments from plasma onto biomaterial surfaces results in integrin receptor-mediated leukocyte recruitment and adhesion [7], [8], [9]. Adherent monocytes/macrophages secrete cytokines and growth factors and mature into foreign body giant cells that coordinate the recruitment and activities of other cell types [10], [11], leading to neovascularization and connective tissue formation [2]. Despite our understanding of acute inflammation to implanted synthetic materials, mediators of chronic inflammation and fibrous encapsulation of implanted biomaterials remain poorly understood.
Fibronectins (FNs) are widely expressed, cell-adhesive glycoproteins present as soluble forms in body fluids (e.g., plasma FN, pFN) and insoluble fibrils in extracellular matrices (cellular FN, cFN) [12]. FNs are generated from a single gene, but alternative splicing gives rise to different isoforms [12]. Deletion of the FN gene is embryonically lethal due to defects in mesoderm, neural tube and vascular development [13]. FN is also required for cleft formation during epithelial branching morphogenesis [14]. Extensive in vitro analyses have demonstrated that FNs promote cell adhesion and regulate the survival, cell cycle progression, and expression of differentiated phenotypes in various cell types. Despite the vast amounts of studies on the role of FN in cellular functions, the role of the pFN isoform in adult physiology and pathology has been difficult to analyze because of the embryonic lethality of the FN gene deletion. Recent studies with FN conditional knock-out mice have shown that pFN promotes thrombus growth and stability in injured arterioles and supports neuronal survival following cerebral ischemia, but is not essential to skin-wound healing, likely due to contributions from cFN [15], [16]. In the present analysis, we used pFN conditional knock-out mice to examine the contributions of pFN to host responses to implanted biomaterials.
Section snippets
pFN conditional knock-out mice
pFN conditional knock-out mice based on the Cre-loxP system were previously developed by Erickson and Fässler [15] and rederived by Hynes [16]. The Cre-loxP system provides a genetic tool to control site-specific recombination events in genomic DNA, thereby affording a mechanism for deleting a specific gene in response to a stimulus that results in Cre recombinase expression. These mice have the FN gene flanked by loxP sites and express Cre recombinase under control of the interferon- and
Results
We used pFN conditional knock-out mice based on the Cre-loxP system [15], [16] to examine the role of pFN in host responses to implanted biomaterials. Deletion of the FN gene in these mice is induced by intraperitoneal injections of pI–pC and results in complete and stable deletion of FN in the liver (hepatocytes produce pFN) for at least 8 months [15]. The extent of FN deletion in other tissues is variable, and some cell types retain the ability to produce cFN. Importantly, these mice express
Discussion
Our results demonstrate that pFN modulates the foreign body response and fibrous encapsulation of implanted materials. This is the first report directly linking pFN to host inflammatory responses to implanted synthetic materials. Deletion of pFN, however, did not influence leukocyte recruitment and adhesion to the implanted biomaterial, indicating that pFN regulates chronic, but not acute, inflammatory responses to biomaterials. The lack of involvement of pFN in acute leukocyte adhesion to
Conclusion
Using plasma fibronectin (pFN) conditional knock-out mice, we demonstrate that pFN modulates the foreign body response to biomaterial disks implanted subcutaneously. Fibrous collagenous capsules were two-fold thicker and three-fold higher numbers of foreign body giant cells were observed in mice depleted of pFN compared to controls. In contrast, deletion of pFN did not alter acute leukocyte recruitment to the biomaterial, indicating that pFN modulates chronic fibrotic responses. These results
Acknowledgments
Funding provided by the NSF-sponsored Georgia Tech/Emory Center on the Engineering of Living Tissues (ECC-9731643) and NIH (R01 EB-004496). AWB is the recipient of a NSF Graduate Fellowship. Mice containing a floxed (fl; loxP-site containing) fibronectin allele and Mx-Cre were kindly provided by H.P. Erickson and R.O. Hynes.
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