Nanomedicine, Volume IIA: Biocompatibility

© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003 Cell and Tissue Response to Bulk Teflon

In general, bulk Teflon has little adhesion to living cells [1033] or tissues [5031], and is not cytotoxic [1141, 1190]. Indeed, Teflon is often used as an inert negative control [1172-1178] in cytotoxicity studies. Many different types of cells and tissues have been evaluated for their response to bulk Teflon:

(1) Monocytes and Macrophages. Human monocyte-derived macrophages cultured on non-adherent Teflon liners in Petri dishes [1210-1213], hydrophobic Teflon bags [1198-1200, 5030], beakers [1341] and membranes [1162], and other Teflon culture vessels [1160-1163] retain their immunocompetence [1213] and are not stimulated or activated. Thus they can be sustained in long-term culture [1212] for up to 200 days [1162]. Maturing macrophages are readily detached from the Teflon surfaces [1164, 1166] and show no obvious structural or functional defects [1162-1166]. Culturing in the presence of Teflon does not suppress succinic dehydrogenase activity of THP-1 human monocytes, nor does it elicit the expression of TNF-alpha or IL-1beta [1178]. In one study [1163], Teflon-cultured monocytes demonstrated a significantly enhanced CSF (colony stimulating factor) cytokine release over culturing on polystyrene plates. But nonadherent peripheral blood cells cultured in Teflon chambers express relatively low levels of IL-8, a potent neutrophil chemoattractant and activating cytokine [1342].

(2) Leukocytes and Inflammation. Inflammatory tissue reactions to Teflon have been observed in mice, rats, rabbits and other animal models since at least the 1970s [1343]. Early studies found that Teflon felts and fibers implanted in canine pleural cavities elicited mild to moderate inflammatory reactions, but hematocele (blood cyst) occurred only upon implantation in the aorta with direct blood contact and exposure to arterial pressures [1157]. Teflon tubes implanted percutaneously can cause an inflammatory reaction [1191]. But in another experiment, sterile Teflon tablets implanted subcutaneously on the backs of rats elicited only a few inflammatory (leukocyte) cells in the tissues bordering the Teflon for up to 3 weeks post-implantation [1185]. Teflon-coated catheters have significantly reduced superoxide radical production by human polymorphonuclear leukocytes, suggesting that Teflon may inhibit the bactericidal function (respiratory burst) of these leukocytes [1184]. However, in the same experiment the uptake of opsonized Staphylococcus aureus (e.g., phagocytic function) was unaffected by the Teflon [1184]. Teflon implanted in the quadriceps muscle of guinea pigs and assessed histologically after 2 days to 26 weeks showed no prominent tissue inflammation or foreign body giant cell response [1344]. Leukocytes are generally not activated by Teflon in vitro. For example, human leukocytes incubated with knitted Teflon or e-PTFE exhibited no peak metabolic activity (implying the material is noninflammatory) [1195]. In another experiment [1173], culturing neutrophils in Teflon bags did not trigger cell activity, whereas cells incubated in uncoated glass or plastic tubes adhered and released O2-. However, neutrophils incubated in the presence of lipopolysaccharide (LPS) could adhere to Teflon and release O2- [1173], and Teflon surfaces elicited a transient increase of cellular calcium levels, indicating a G protein-coupled activation of the granulocytes used as a biological test for inflammatory mediators [1189].

(3) Fibroblasts. Microporous e-PTFE Teflon implanted beneath the transversalis fascia in the groins of rabbits was completely invaded by fibroblasts at 8 weeks, with flat orientation of graft to the fibrous tissue forming a neofascia with local or peritoneal inflammatory reaction [1167]. Teflon membranes incubated in collagen promote attachment of fibroblasts [1172]. Porous or knitted Teflon material coated with collagen, fibronectin, gelatin or laminin promotes human fibroblast migration over and adherence to Teflon [1196]. Granulomatous reaction and tissue formation has been observed around cannulated Teflon cylinders implanted subdermally in rats, producing exudation with cell infiltration, granuloma growth, and formation of prostaglandins [1181]. Sterile Teflon tablets implanted subcutaneously on the backs of rats elicits a connective tissue capsula after 3 weeks [1185, 1186]. Fibrous tissue encapsulates subcutaneously implanted Teflon disks in rats [1187].

(4) Lymphocytes. Bovine lymphocytes exposed to bulk Teflon retain their ability to activate, hence bulk Teflon appears to be lymphocompatible [1345]. Teflon implanted in temporal (skull) bone elicits fibrous tissue formation and a few giant cells with some lymphocyte infiltration [1346].

(5) Platelets and Thrombogenesis. Platelet deposition on Teflon surfaces placed in sanguo is greatest immediately post-implantation, then declines over time [1202]. In short-term exposures, platelet adhesion was measured experimentally as 0.0037 platelets/micron2 on dePTFE, ~0.014/micron2 on e-PTFE, and 0.0168/micron2 on woven Dacron, after a 5-minute exposure to fresh human blood flowing at a wall shear rate (Section of 50 sec-1 [1680]. Tested for longer exposures, luminal platelet adherence to Teflon graft surface in a canine model was 0.564 platelets/micron2 at 4 weeks and 0.124 platelets/micron2 at 12 weeks [1326]. Teflon vascular grafts incorporated into femoral arterial-arterial shunts in baboons for 1 hour produced a platelet deposition of ~2 platelets/micron2 [1204]. Teflon may enhance platelet reactivity [1159], though some data appear contradictory. One experiment [1195] found that human platelets exposed to Teflon experience a rapid increase in metabolic activity, followed by a steady state for more than 1 hour, which suggests that bulk Teflon is thrombogenic. However, another experiment [1209] determined that platelet adhesion to Teflon is shear rate independent, with the large percentage of platelets not spread out on the surface, indicating that the material is a poor platelet activator. Studies of platelets on Teflon often employ anticoagulants [1326] because some forms of Teflon are so thrombogenic, more so than Dacron [1209]. Rotating disks [1180] and atrial septal defect patches [1347, 1348, 5020] made of Teflon are very mechanically hemolytic. Intense thrombogenicity was observed with Teflon-coated guidewires in both clinical [5010] and in vitro settings, with formed thrombi ranging from 50-100 microns in size [1317]. Gore-Tex used in vascular grafts is acutely thrombogenic, accumulating 8 platelets/micron2 in the first hour of exposure to human blood [1192]. The same study found that a series of plasma-modified polymers based on tetrafluoroethylene, hexafluoroethane and hexafluoroethane/H2, when deposited on silicone rubber, consumed platelets at rates ranging from 1.1-5.6 platelets/micron2-day, which was considered relatively nonthrombogenic [1192]. And a second study [1205] found that a graft of stretchable Teflon implanted in pig iliac arteries produced a 68% thrombus-free surface, compared to only 37% for standard Teflon fabric grafts. Surface roughness may play an important role. In one experiment [1315] very thin fluorocarbon films were plasma-deposited on rough but hemocompatible poly(hydroxybutyrate), and on smoother but more thrombogenic polysulphone, to study the relative influence of surface roughness and surface energy on polymer thrombogenicity. In vitro protein adsorption and blood clotting tests proved that surface roughness influences thrombogenicity more than other surface properties [1315]. Interestingly, centimeter-size nanoporous Teflon chambers implanted intraperitoneally have been tested in guinea pigs and rhesus monkeys as in vivo clotting factor dispensers, as a potential treatment for hemophilia [1407].

(6) Bone Cells and Tissues. Osseous tissue cell reactions to Teflon implants have been studied for decades [1214-1216]. For example, Teflon tubes implanted percutaneously in rats near demineralized bone matrix produced chondrogenesis and osteogenesis in the subcutaneous tissues [1191]. Osteogenesis was inhibited near the foreign material but there was good circumferential bone formation [1191]. Hollow Teflon capsules implanted in rat jaw bone were infiltrated by new bone to 31% of the cross-sectional area after 60 days and to 45% after 120 days [5012]. So bone tissue appears more sensitive to the presence of Teflon. One experiment with Teflon tubes implanted in the mandible of guinea pigs found that the Teflon elicited a soft tissue capsule which separated regenerated bone from the implant [1349]. An independent study using the same animal model found a persistent moderate inflammation reaction and a thick fibrous encapsulation after 4-12 weeks, except in areas where poorly condensed material was dispersed into the bony tissue where chronic inflammation and active phagocytosis was also observed along the surface of the material [1350]. Dental applications of Teflon have been investigated sporadically [1217-1220]. In one experiment [1220], exposed pulps of Rhesus monkey teeth received Teflon caps for 3 days to 8 weeks. Resolution of the soft tissue inflammatory response and healing were slow, with only 20% of teeth treated for 5-8 weeks showing hard tissue formation at the exposure site [1220].

(7) Endothelial Cells. Cultured human endothelial cells show poor attachment to hydrophobic polymers such as Teflon [1224, 1329]. In one experiment, human microvessel endothelial cell attachment compared to control was 47% for albumin-coated Dacron but only 3% for Teflon graft material [1351]. Precoating Dacron or Teflon with fibronectin allows endothelialization to occur, up to 500 cells/mm2, compared to ~70 cells/mm2 for uncoated surface, after culturing for 8 days [1329]. Alternatively, when Teflon is surface modified by exposure to nitrogen or oxygen plasmas, creating a 1 nm thick modified layer, the surface can then sustain a monolayer of cultured endothelial cells [1224]. (But Teflon precoated with albumin, high-density lipoprotein, or IgG inhibits endothelial adhesion [1329].) Teflon felt and Teflon-coated fibers tested in vitro with endothelial cells on cultured canine saphenous vein explants have shown no signs of toxic reactions [1157]. Culturing in the presence of Teflon does not suppress succinic dehydrogenase activity of human microvascular endothelial cells, nor does it elicit the expression of ICAM-1 [1178].

(8) Epithelial Cells. Porous or knitted Teflon material coated with collagen, fibronectin, gelatin or laminin promotes human conjunctival epithelial cell migration over and adherence to Teflon [1196]. In vitro human junctional epithelial cells do not attach to Teflon [1193]. In this experiment [1193], cells adjacent to the Teflon substrata were nonproliferative and did exhibit signs of degeneration or cell differentiation. However, an earlier study in mice had shown that subcutaneously implanted Teflon cylinders with etched surfaces produced closed tissue contact, with signs of toxic tissue reactions completely absent [1182]. There is one decades-old report [1179] of subcutaneous fibrosarcomas induced in 30-94% of BALB/c, C3Hf/Dp, and C57BL/He female mice by implantation of a Teflon disc, with mean latency of 61-82 weeks, but the reliability of this study is unknown and the results appear not to have been replicated.

(9) Neural Cells. Dissociated mouse cerebellar cells containing both glia and neurons in tissue culture were exposed to spongy and fibrous Teflon, which had little or no effect on the growth of these cells [1158]. Some adhesion of both glia and neurons to the Teflon surface was seen, but the attachment was not extensive [1158]. There is at least one case of aseptic meningitis that persisted for 5 months and did not resolve until after surgical removal of Teflon that had been used to pad the trigeminal nerve to provide microvascular decompression to relieve trigeminal neuralgia [1352]. There is also one reported case of recurrent trigeminal neuralgia caused by a Teflon prosthesis that had been inserted between the trigeminal nerve and the superior cerebellar artery, and which then became hard and compressed the trigeminal nerve 17 months after the initial surgery [1353]. The ability of amorphous Teflon copolymer to inhibit or bio-pattern cell adhesion has also been tested with various neural cell lines [1354].

(10) Sperm and Embryo Cells. Teflon is relatively inert with respect to its biocompatibility toward sperm motility and penetrability of zona-free hamster eggs, and toward the ability of two-cell mouse embryos to divide [1355]. Teflon coated catheters appear nonspermiotoxic to bull sperm, reducing sperm motility by only ~6% after 90 minutes exposure. Teflon embryonation capillaries are well tolerated by embryos [1356].

(11) Hematopoietic Cells. Human hematopoietic cells proliferate near-normally when cultured on Teflon perfluoroalkoxy or Teflon fluorinated ethylene propylene [1357].

(12) Bacterial Cells. Microbial tooth plaque accumulation and adhesion are reduced on Teflon-coated metal surfaces [1358]. Some bacteria such as S. epidermidis attach readily to Teflon surfaces [1225-1227], forming biofilms [1226, 1359]. Here again there are conflicting claims in the literature, suggesting further research is needed. For example, one study reported that adhesion of the staphylococci to fluorinated polyethylene-propylene films was not related to the relative surface charge or the hydrophobicity of the bacteria [1360], while another study reported that adherence to Teflon catheters was significantly influenced by the degree of hydrophobicity of the microbial strains [1361]. Preincubation in serum reduces bacteria adhesion on Teflon, mainly due to the inhibitory effects of adsorbed albumin [1360, 1361].

(13) Other Cells. Hepatocytes grow normally on Teflon membrane culture dishes [5025].


Last updated on 30 April 2004