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 Biocompatibility of Teflon Particles

Small-chain fluorocarbon molecules are generally biocompatible in low doses. However:

(a) macrophages which have ingested perfluoro compounds may show some loss of phagocytic function and possible release of cytokines and other immune mediators [1383];

(b) oxypherol, a commercially available perfluorochemical used in animal tests, is slightly adsorbed on the surface of red blood cells, causing a decrease in erythrocyte deformability [1384];

(c) tetrafluoroethylene (a monomer used in Teflon manufacture) is hepatocarcinogenic in inhalation studies in mice after 2-year exposures at 312-1250 ppm concentrations [1385];

(d) Fluosol (an oxygenatible fluorochemical) elicits anaphylactoid-type reactions in a small percentage of patients at blood concentrations as low as ~0.1 gm/liter [1386]; and

(e) biological enzymes modified by adding a large number of fluorocarbon residues do not undergo large conformational changes upon adsorption on a Teflon surface and thus are not deactivated [1337].

Pure fluorocarbons and fluorocarbon moieties have very strong intramolecular bonds and very weak intermolecular interactions [1387], hence should display low particle aggregation.* The stability and permeability of fluorinated liposomes has been widely studied [1306-1309]. For example, aqueous-suspended 30-70 nm fluorovesicles have a maximum tolerated IV dose up to 0.5 gm/kg body weight in mice (~5 gm/liter blood volume) [1308]. Hemolytic activity sharply decreases with increasing degree of fluorination [1308].

* Fluorocarbons have much weaker intermolecular interactions than hydrocarbons. Their intermolecular interactions are among the weakest known for organic molecules. This is manifested most prominently in the low boiling points of fluorocarbons, since a comparison of boiling points for compounds of similar molecular weight gives a good idea of the magnitude of intermolecular interactions. For example, the fluorocarbon perfluorocyclobutane (MW = 200) has a boiling point of -6 oC, whereas the hydrocarbon tetradecane (MW = 198) has a boiling point of 253 oC; even the non-fluorinated hydrocarbon cyclobutane (MW = 56) has a boiling point of 13 oC.

There are no confirmed reports of Teflon particle inhalation toxicity. Polymer fume fever [1683, 2120, 2121] due to inhalation of Teflon pyrolysis products is well known, though pyrolysis products are very different chemically from Teflon and are inevitably toxic due to their high reactivity. (This is true for other polymers as well, and does not directly relate to the biological performance of the polymer material.) For example, in one case [1388] two men were occupationally exposed to Teflon powder and experienced episodes at work of fever, leukocytosis and general malaise, all of short duration, which ceased after there was no further exposure to Teflon. It was concluded that the cause was inhalation of Teflon combustion products originating from Teflon-contaminated cigarettes. There are also reports of bird toxicity from heated Teflon fumes [1683]. Ultrafine (<100 nm) particle fumes produced by heating Teflon to 486 oC in air are extremely toxic to rats in concentrations of ~50 µg/m3 when inhaled for only 15 minutes [4846], possibly due to the presence of radicals on the surface. Ultrafine Teflon particles rapidly translocate across the epithelium after their deposition in the lungs [4846]. But when these particles are generated by heating in an argon atmosphere they are no longer toxic, implicating possible radicals on the particle surface for the toxicity. Interestingly, the researchers [4846] noted that “the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-minute exposures on 3 days prior to a 15-minute exposure.” Particles larger than 100 nm no longer caused toxicity in exposed animals [4846].

Teflon particle injections have been used for decades to treat a variety of human medical conditions, as summarized below. The most common injectant is a commercial preparation known as polytef paste. Polytef paste consists of pyrolyzed Teflon particles measuring 4-100 microns in diameter and irregular in shape, suspended in a glycerin carrier [1256, 1389]. The principal intended therapeutic effect of the implanted particles is to passively increase local tissue volume. Experimental and clinical doses typically range from 0.1-1 cm3 of paste [1390], representing 0.1-10 billion Teflon particles per dose.

But when injected in particulate form, Teflon can sometimes provoke severe inflammatory reactions [900, 901] and can elevate serum levels of allergen-specific IgE and IgG2a [5026]. In one experiment with Teflon particles [1389], mice received subcutaneous dorsal injections, rabbits received subareolar injections, and dogs received subareolar and periurethral injections. Subsequent histological examination of the biopsy sites revealed a persistent chronic inflammatory reaction with progressive growth of the involved tissue volume, evoking inflammatory pseudo-tumors [1389]. In addition to giant cells and macrophages, lymphocytes became apparent at 3 months and constituted up to 40% of the cellular infiltrate by 1 year. Plasma cells were also noted in the rabbits after 1 year [1389]. In another experiment [1391], 48 days after submucosal injections of Teflon paste into the peritoneum of mice, many particles were found (1) in peritoneal macrophages, (2) in microphages and macrophages of regional lymph nodes and the spleen, and (3) in Kupffer cells of the liver [1391]. Phagocytes containing Teflon particles can induce local inflammation and fibrosis [1391].

Implanted Teflon particle migration from the site of injection to lungs and brain has been reported in many animal studies [1392]. For example, small amounts of Teflon paste particles injected intravascularly into peripheral veins and the right carotid artery of dogs were found in cerebral vessels 6 months after arterial but not venous injections [1392]. Brain tissue sections showed particles in vessels with focal foreign-body reaction but no infarction, no nerve fiber abnormality, no astrocytosis, and no demyelination around vessels containing the particles and the parenchyma – in summary, no brain parenchymal tissue damage [1392]. Nevertheless, concerns with particle migration [1280] led the FDA in 1984 to prohibit the medical use of Teflon particles in the U.S. [1311].

Medical conditions which have been treated (with varying degrees of success) by Teflon particle injections, or experimentally evaluated in animal models for possible human treatment, include:

(1) Vocal Cord Paralysis (first used, 1962). Since the 1920s, reinnervation attempts have been unsuccessful in restoring motion to paralyzed vocal cords [1240]. In 1962, Arnold [1682] used injectable Teflon particles to reintroduce Brunings’ technique for rehabilitating the paralyzed vocal cord [1237]. Since then, transcutaneous Teflon injection of paralyzed and bowed vocal cords has been used to treat unilateral paralytic dysphonia [900, 1232-1251, 1260]. There are several good historical and literature reviews [1243-1246]. The major defect of unilateral vocal cord paralysis, which manifests as a soft and breathy voice, can be eliminated by moving the edge of the paralyzed vocal cord to the midline via Teflon injection [1240]. This allows the mobile vocal cord to adduct and vibrate firmly against the edge of the paralyzed vocal cord during phonation, eliminating the air leak between the vocal cords. The treatment is commonly performed by indirect laryngoscopy under local anesthesia so that the effect on the voice can be monitored during the injection. Teflon is easily removed from the vocal cord via direct laryngoscopy [1240]. Teflon particles appear to be noncarcinogenic [1237, 1249]. The foreign body reaction to the laryngeal Teflon implant shows giant cells, few lymphocytes, and no polymorphonuclear leukocytes. This reaction may be described as a bland, chronic type consistent with the age of the implant, and lacking any areas of florid, acute reaction [1249]. Partial extrusion of polytef through the cricothyroid space is sometimes observed, but usually without signs of unfavorable tissue reaction or intolerance [1249].

Failure or complications in this procedure are sometimes reported [1246-1248]. These complications may include: acute or chronic inflammatory reaction [900, 1251, 1262]; cough or choking [1262]; swallowing difficulties [1262]; laryngeal stenosis [900] or airway obstruction [1250, 1260-1262]; acute foreign-body giant cell reaction [1252-1255]; extravasation and infiltration into the soft tissues of the neck [1260]; particle migration into the lymphatics [900, 1390] or surrounding muscle tissues [1253]; persistent hoarseness or voice changes [1260]; and even dysphonia [1252, 1262]. A rare complication is “teflonoma” [1255-1260, 5021] or large granuloma formation [1248-1253]. Teflonomas have been initially been mistaken for thyroid tumors [1249, 1258-1260] or carotid body tumors [1256]. Today, collagen particles [1237], autologous lipids [5014], and other materials [5032] show more promise as possibly safer particle-implantation tissue-bulking alternatives.

(2) Urinary Incontinence (first used, 1973). Periurethral Teflon injection is commonly used to control urinary incontinence [1267-1280], stress incontinence [1283-1286], and post-prostatectomy incontinence [1263-1265]. Tissue reactions in males are generally limited to modest infiltration of lymphocytes and monocytes, and a slight increase in collagen fibers. Particles are generally well tolerated [1393] with minimal migration to lungs or brain in pig and dog models [1394]. Complications have included: clumping of paste [1393]; pain [1263]; fever and malaise upon removal [1282]; inflammatory reaction [1268]; possible infection or intolerance [1268]; periurethral abscess and urethral diverticulum [1265, 1286]; elevated erythrocyte sedimentation rate [1282]; fibrosis [1268]; foreign-body giant cell granulomatous reaction [1266, 1267, 1280-1282] and polyps [1398]; pulmonary granuloma [1286-1288] with urethral wall prolapse [1286]; teflonoma [1264-1266] with urethral wall prolapse [1265]; migration of particles [1280, 1397, 1398] particularly into lymphatic [1280], perineal [1263], kidney [1280], spleen [1280], brain [1280], and pulmonary [1277, 1280] tissues, and to the skin [1282]; and even complete urinary obstruction [1266-1268]. These potential complications have led some to recommend that periurethral Teflon injections should only be used in special cases [1284], although autologous lipoinjection has an even poorer success rate [5022].

(3) Cosmetic Surgery (first used, 1976). Subcutaneous injection of facial wrinkles with Teflon paste in the 1970s produced granulomas [1395]. In another case [1396], granular Teflon paste was injected into the upper eyelid to remodel the upper palpebral furrow which had been retracted by scars. Large foreign-body granulomas developed a few weeks later, necessitating excision and leading the surgeons to advise against using Teflon injections in well-vascularized loose tissue [1396].

(4) Vesicoureteric Reflux (first used, 1981). Vesicoureteric reflux or VUR is the reflux of urine up the ureter during micturition. Endoscopic submucosal Teflon injection (STING) to correct VUR was performed for the first time by Matouschek [1289] in 1981. The procedure has since been widely employed in clinical practices by Puri and O’Donnell [1399] and others [1305, 1312] for treatment of ureteric, vesicorenal or vesicoureteral reflux [1289-1305, 5011]. The procedure is also used to correct VUR prior to renal transplantation procedures [1304] and to treat ureteroceles [1291]. STING gives a high cure rate in children [1297-1303, 5029, 5033] and adults [1294, 1303] with generally good results [1292, 1298], although a second injection is often required [1301-1305]. There is no major morbidity or risk of nephroureterectomy [1304], and there are no signs or symptoms of embolization of the implant material [1296]. Possible carcinogenic risks have been noted [1312] but no carcinogenic degeneration has yet been observed [1385] and Teflon powder is not considered to be carcinogenic [1311].

Complications may include: postoperative Teflon leakage from the injection site [1296, 1400]; encapsulation of the implant by a thin layer of fibrous tissue [1399]; foreign body granulomatous reaction locally involving histiocytes and giant cells within the implant [1399, 1401] and also involving locoregional lymph nodes [1401]; ureteral stenosis in 1% of cases [1312]; and one possible case of ischemic brain injury (stroke) [1402]. The risk of particle migration has been noted [1304, 1312] although most studies have detected no migration [1296, 1399] to liver [1312], lungs [1312], or brain [1312]. In one animal study [1401], rare particles of Teflon were observed in the lungs but not in the brains of rabbits that had received Teflon injections in the bladder submucosa. In another animal study [1403], numerous particles were recovered from lungs and brain within 2 weeks of Teflon particle injection in the manner used to treat VUR. Particles in the brain measured up to 15 microns, indicating that the pulmonary bed is an inefficient filter of particles gaining access to the venous circulation [1403]. No adverse neurological effects have been reported clinically, but the authors warned that some particles could lodge in the brain where they could block the cerebral microcirculation [1403]. In a human clinical study, most of the Teflon particles injected for VUR in one child of 83 treated were observed by CT scan to have disappeared from the original site of injection. It was speculated that the material had been extruded into the bladder [1400]. A few practitioners have now abandoned polytef injection for treating VUR [1295]. Collagen particles have given disappointing results, but microparticulate silicone [1312] and bioresorbable microspheres [5453] appear more promising.

(5) Velopharyngeal Incompetence (first used, 1985). Teflon injection into the submucosa of a child’s posterior pharyngeal wall was used to treat severe open nasality due to velopharyngeal incompetence. A biopsy after 8 years revealed a marked foreign body reaction with a persistent inflammation and fibrosis [1404]. Lipoinjection may be a preferable alternative here [5019].

(6) Partial Fecal Incontinence (first used, 1993). Perianal injection of polytef particle paste into the rectal neck submucosa in patients with partial fecal incontinence resulted in an increase in rectal neck pressure produced by the cushion effect of the Teflon particles. All patients showed at least partial improvement, and two-thirds experienced long-term cure [1405].

(7) Low Esophageal Sphincter Pressure (first used, 1996). Intraabdominal injection of Teflon paste at the gastroesophageal junction produced a well defined Teflon mass at the site of the injection. The implant was encapsulated by a thin layer of fibrous tissue and a benign foreign body granulomatous reaction with round cells surrounded the implant. The procedure increased lower esophageal sphincter pressure from 29.7 mmHg preoperative to 37.6 mmHg postoperative in rabbits [1313].


Last updated on 30 April 2004