| Biocompatibility evaluation of nickel-titanium shape memory metal alloy: | ||
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Only a few in vitro studies of cell response to NiTi have been reported. The results have been slightly contradictory. These differences may be due to differences in test protocols, including different cell types, different observed factors, variations in surface treatments, surface area, surface roughness, etc.
A preliminary report intending to evaluate the acceptance of NiTi in vitro was published by Castleman & Motzkin (1981). Human fetal lung fibroblasts were used in that study. The results were surprising: 316L stainless steel and Co-Cr alloy did not differ in cell growth from the control cultures, but NiTi and more titanium significantly reduced cell growth. The morphological changes of cells with NiTi and titanium were also more pronounced. As far as titanium is concerned, these findings are contradictory to most later studies. Titanium is considered one of the best accepted metals in vitro and in vivo (Trentz et al. 1997, Doran et al. 1998).
In a well-monitored study by Putters et al. (1992), the effects of increasing dose exposure to NiTi, nickel or titanium in cell cultures were examined. The results showed that nickel induces a significant inhibition of mitosis in human fibroblasts, whereas no significant effects of this kind were found for titanium or NiTi. NiTi was considered biocompatible and comparable to titanium.
More confusing results were also reported when direct contact and agar diffusion cytotoxicity assays were performed using Confluent L-929 fibroblasts. Cells were incubated in the presence of NiTi, titanium, Co-Cr-Mo and 316L stainless steel discs. The evaluation of cytotoxic reactions was done under light microscopy. Both assays indicated that all metals induced a mild biological reaction. The cytotoxicity of NiTi was found to be approximately equal to that of Co-Cr-Mo, both being more than that of pure titanium, Ti- 6A1-4V or 316L stainless steel. The authors of that study also used NiTi samples with plasma surface treatment, which was found to increase the cytocompatibility of NiTi (Assad et al. 1994).
Endo et al. (1995) reported that human plasma fibronectin (pFN), an adhesive protein, can be covalently immobilized onto NiTi substrate. Fibronectin significantly improved human gingival fibroblast spreading, suggesting that this chemical modification enables the controlling of metal/cell interactions.
The results of a study in which various surface treatment effects were studied in rat splenocytes showed that cells exposed to NiTi are critically affected by the surface preparation. The hydrogen peroxide surface treatment of NiTi caused a toxic effect comparable to that of pure nickel. However, the situation changed tremendously when NiTi was treated by autoclaving in water or steam. The reaction with these NiTi specimens was clearly non-toxic. The explanation for this was that the Ni surface concentration may vary from 0.4 to 27%, depending on the specific surface treatments used (Shabalovskaya 1996).
In conclusion, earlier in vitro studies have neither established the position of NiTi among the metallic biomaterials nor confirmed its ultimate cytocompatibility.
Weaver et al. (1997) evaluated the short-term biological safety of the NiTi alloy. They used an end-point dilution minimal essential medium extract cytotoxicity test, a guinea-pig sensitization test and two genotoxicity tests: the Salmonella reverse mutation test and the chromosomal aberration test. The NiTi alloy showed no cytotoxic, allergic or genotoxic activity. The findings were similar to those on AISI 316 LVM stainless steel. They concluded that the NiTi alloy can be regarded as a biologically safe implant material.
The in vitro genotoxicity of NiTi has also been evaluated using human peripheral blood lymphocytes. A comparison was made with commercially pure titanium and 316L stainless steel. Cells were cultured in a semiphysiological medium that had previously been exposed to the biomaterials. An electron microscopy in situ end-labeling assay was performed to provide quantification of in vitro chromatin DNA single-stranded breaks. NiTi, titanium and stainless steel induced similar DNA strand breaks of interphase chromatin, but stainless steel induction on metaphase chromatin was more intense than with NiTi or pure titanium. The authors concluded that NiTi genocompatibility is promising in view of its biocompatibility approval (Assad et al. 1998).
The influence of the corrosion products of different orthodontic wires on the cytotoxicity of a fibroblast culture was investigated by Rose et al (1998) using Mosmann"s MTT test. Ion release was assessed by ICP-AES analysis. NiTi, stainless steel and beta-titanium alloy wires had no effect on the rate of cell proliferation. The most severe growth inhibition was induced by the Co-Cr-Ni alloy. The degree of growth inhibition depended upon the concentration of corrosive cobalt and nickel ions in the elute.
The first published study on the reaction of tissue to 55-NiTi was reported in by Cutright et al. (1973). In that study, NiTi wire sutures were placed subcutaneously in forty-five rats, which were followed for 9 weeks. The tissue reaction was minimal at all checkup points. The reparative process was initiated within 1 to 2 weeks and resulted in a dense, relative avascular fibrous connective tissue capsule by 5 to 6 weeks, with little change beyond that. When compared to the tissue reaction to stainless steel seen in earlier experiments, NiTi was indistinguishable from stainless steel within similar time periods. It was concluded that 55-NiTi compares favorably with stainless steel and could be used in deep tissues. The lack of a simultaneous control group, the short implantation time (nine weeks) and the non-standardized (subcutis or muscle) implantation site may have caused some uncertainty to the results.
The first attempt at a profound biocompatibility evaluation of NiTi was made by Castleman et al. (1976). The methods of that study were versatile and the approach was well-advised. This study has often been used as a reference study when discussing the biocompatibility of NiTi. There were, however, some weaknesses in the study, which were also pointed out by the authors. These may have critically affected the final conclusions. First, the total number of test animals was quite small. There were three dogs in the NiTi implant group and one Co-Cr implant and one “sham” as a control at each killing point. The complete NiTi data consisted of 12 beagles examined after exposures of 3, 6, 12, and 17 months. The maximum follow-up time can be considered sufficient for the conclusions, at least as far as implant use in fracture fixation is concerned. The NiTi alloy used in the experiment was laboratory-prepared and had no commercial counterpart. The analysis of scar capsule membrane thickness seems to be based on an invalid hypothesis. Statistical tests were used, expecting no significant differences between the mean thickness values of the scar capsules associated with NiTi and those associated with the Co-Cr alloy. However, the authors admitted earlier that “considerable variation was evident between the capsules of different specimens of same material and between the capsules of different metals and also depending on implantation time”. Thus, it seems that the statistical data in this case cannot be used as a basis of relevant conclusions. The muscle tissue in dogs exposed to NiTi implants for 17 months showed some variability. The areas adjacent to or overlying the screw head showed a looser arrangement of striated muscle fiber bundles with larger areas of areolar connective tissue between the muscle fibers. Overall, the gross clinical, radiological, and morphological observations of tissue at the implantation sites at autopsy revealed no signs of adverse tissue reactions resulting from the implants. The study warranted the conclusion that NiTi had no clearly toxic effects in vivo. The authors concluded that no significant differences were noted between the samples taken from the controls and those taken from the dogs exposed to the implants, and that NiTi alloy is sufficiently compatible with dog tissue to warrant further investigation of its potential as a biomaterial.
It is astonishing that no further comprehensive studies on the tissue reaction to NiTi have been published so far.
Recently, one comparative study was published, in which the corrosion resistance and tissue biocompatibility of NiTi and Ti50Ni50-xCux (x = 1, 2, 4, 6, 8) alloy were investigated. Electrochemical and quantitative histomorphometric methods were used. The connective tissue layer covering the Ti50Ni42Cu8 plates was statistically significantly thicker than that of Ti50Ni50, Ti50Ni48Cu2, or Ti50Ni44Cu6 plates after one month. The numbers of connective tissue cells, polynucleated cells, macrophages and round cells were higher for Ti50Ni42Cu8 plates than those of the other three types of plates, but no statistically significant differences were detected. There were no significant differences in the tissue reaction parameters after two and three months between the four alloys. After three months’ implantation, no corrosion was observed on the plate surfaces. It was concluded that Ti50Ni50-xCux (x = 2, 6, 8) shape memory alloys also have good biocompatibility (Wen et al. 1997).
NiTi is one of the most innovative concepts introduced in the field of metallic biomaterials in the recent years, but its biocompatibility remains controversial, especially in bone.
The first attempts to study NiTi as a bone implant were made also by Castleman et al. (1976). A prototype of NiTi bone plates was made and implanted into the femurs of 12 beagles. Commercial cobalt-chromium (Co-Cr) alloy bone plates served as reference controls (1 per time period). The plates were removed from the animals and examined after exposure for 3, 6, 12, and 17 months. There was no evidence of either localized or general corrosion on the surfaces of the bone plates and screws. No signs of adverse tissue reactions resulting from the NiTi implants were seen. Decalcified histological samples showed no evidence of bone resorption in specimens adjacent to the plate. Nor were any significant differences noted in the sham-operated controls. The data used in neutron activation analyses suggested that there is no nickel contamination in bone due to the implants. However, the authors suggested that there does appear to be some chromium contamination from the Co-Cr alloy implants in the adjacent bone. The results of neutron activation analysis implied some uncertainty associating with the contamination of samples during the cutting procedure. In the NiTi group, some high nickel concentrations were also observed, but these were attributed to contamination.
Yang et al. (1992) made their own internal fixing device of NiTi and applied it to fractured femoral shafts of dogs. Comparison was made with a 316L stainless steel plate-screw system. Osteotomy on both sides of the femoral diaphyses was performed in 15 dogs. One side was plated with a bone plate and the other with a NiTi device. Five animals in each group were killed at 4, 8, 12 weeks after operation. Radiographic examination, light microscopy and transmission electron microscopy methods were used. The fracture healing and the course of callus remodeling were similar in these two groups, but the cortical bone remodeling underneath the fixator near the osteotomized area was significantly different. The authors suggested that since the elastic modulus of the NiTi shape memory alloy is lower, the stress-shielding effect in the bone underneath the NiTi device is less. The axial compression stress of the fracture line is kept greater and the contact of that NiTi device with the bone was not so close. This might be beneficial for the recovery of blood supply and bone remodeling.
A preliminary report on the use of porous NiTi was published by Simske & Sachdeva (1995). The material has a controllable open structure that provides a possibility for the ingrowth of bony tissue into the body of the implant, resulting in desirable firm fixation to bone. Eight uncoated porous NiTi implants (average pore size 300µm; 50% average void volume) were placed to either side of the frontal bone of rabbits. In the other frontal location, a coralline hydroxyapatite implant of was fitted as a control. The animals were killed at post-surgical intervals of 2 (n=2), 6 (n=2), and 12 (n=3) weeks. The implants were evaluated for gross biocompatibility, bony contact, and ingrowth. Overlaying soft tissues and connective tissues readily adhered to the implants even after 2 weeks. No adjacent macrophage cells were seen for either implant type. Both materials made bone contact with the surrounding cranial hard tissue, and the percentage of ingrowth increased with the surgical recovery time. The bone histology and microhardness parameters showed that the bone in contact with the implants was similar in quality to the surrounding cranial bone. Porous NiTi implants appear to allow for significant cranial bone ingrowth after as few as 12 weeks. Compared to HA, the NiTi implants demonstrated a trend for less total apposition and more total ingrowth after 6 and 12 weeks of implantation. The authors concluded that porous NiTi appears to be suitable for craniofacial applications. The small number of animals used in this study can be criticized. It allows no quantitative conclusions. The implantation time was also quite short, but the bone response was still good. Further studies are needed for the conclusions on final biocompatibility and the value of porous NiTi in craniofacial or other bone-related applications.
A new type of ear stapes prosthesis made of nickel-titanium shape memory alloy wire was developed by Kasano & Morimitsu (1997). Its biocompatibility was examined in 24 ears of 12 cats. The prosthesis was implanted at the long crus of the incus and the incus was examined 27-355 days after operation. In 23 ears, the prosthesis was found macroscopically well implanted at the intended position. In one ear, the prosthesis was found to be dislocated, and in another, it was slightly loosened. The incudes were removed, and five specimens were prepared for scanning electron microscopy, while the other specimens were observed under a light microscope. Histological studies revealed severe bone resorption of the long crus in the dislocated case and moderate bone resorption in the slightly loosened case. These instances of bone resorption were found to have been caused by inadvertent removal of the mucosal membrane during the implant operations. Slight bone resorption was seen at the contact area of the prosthesis in seven ears under a light microscope and in one ear under a scanning electron microscope. This bone resorption was induced by the mechanical pressure of the prosthesis and was not progressive due to the diminishing pressure. With the exception of pressure-induced bone erosions, there was no progressive bone resorption which was prosthesis-induced. The authors concluded that the biocompatibility of the nickel-titanium alloy stapes prosthesis with the long crus of the incus was hereby proven.
The above studies suggested that NiTi is quite well accepted into bone. However, there are two conflicting studies, in which NiTi has been found to have inferior properties compared to the other implant materials.
Berger-Gorbet et al. (1996) evaluated the biocompatibility of NiTi screws using immunohistochemical methods. The distribution of bone proteins during the bone remodeling process around a NiTi implant was observed. The control materials were screws made of Vitallium, c.p. titanium, Duplex austenitic-ferritic stainless steel (SAF), and stainless steel 316L. The test materials were implanted in rabbit tibias for 3 (n=2), 6 (n=2), and 12 (n=2) weeks. The embedding was done in hard resin, and undecalcified sections with bone-anchored implants were used for the immunohistochemical procedure. The authors concluded that the immunostaining method developed by them seemed to be a reliable technique for staining proteins in undecalcified sections. The biocompatibility results of the NiTi screws compared with the other screws showed a slower osteogenesis process characterized by no close contacts between the implant and bone, disorganized migration of osteoblasts around the implant, and a lower activity of osteonectin synthesis. The study included some uncertainties, however. The number of samples was too small to allow statistically significant histomorphometry. No characterization of the surface was done. Careful saline cooling was used while drilling the hole in the bone, but the material of the drill was not specified. Authors said that “on all NiTi sections black granules could be observed along the screws”. Microparticles from the drill are possible and may affect the results. The authors used mouse anti-osteonectin and goat anti-collagen type III antibodies. There might be some problems in cross-reaction if rabbits are used as test animals. The assessment of osteonectin was good because it is an important protein in the bone remodeling process. The role of CIII was considered to be less useful even by the authors.
The bone reaction to NiTi implants inserted transcortically and extending into the medullary canal of rat tibiae was quantitatively assessed using an image-processing system by Takeshita et al. (1997). The control materials were composed of pure titanium, anodic oxidized titanium (AO-Ti), Ti-6Al-4V alloy and pure nickel. Three rats were killed 7, 14, 28,84 and 168 days after operation (n=3). Essentially the same histological findings were made for NiTi, Ti, Ti-6Al-4V and AO-Ti implants. While NiTi and the other materials were progressively encapsulated with bone tissues, Ni was encapsulated with connective tissues and showed no bone contact through the 168-day experimental period. Histometric analysis revealed no significant differences between the tissue reactions to Ti, AO-Ti and Ti-6Al-4V, but NiTi implants showed a significantly lower percentage of bone contact and bone contact area than any of the other titanium or titanium alloy materials. In terms of bone contact thickness, however, there were no significant differences between NiTi and the other three materials (Ti, AO-Ti and Ti-6Al-4V).
NiTi has also be used as a bone implant material in humans, but worldwide medical applications have been hindered for a long time because of the lack of knowledge of the biocompatibility of NiTi. A bone anchor (Mitec G2®) which includes a small piece of superelastic NiTi wire has been lately approved by FDA. In the USA, FDA limits the marketing of long-term implanted NiTi devices because their biocompatibility has not been proved. There are reports that NiTi material has been successfully used in bone-related human applications in Russia and China in a large number of patients (Yang et al. 1987, Kuo et al. 1989, Shabalovskaya 1996, Dai et al. 1996). Very few well-monitored studies have been published in peer-reviewed journals up until now. Also, no controlled or randomized studies have been published so far.
Drugacz et al. (1995) tested the clinical application of Ti50Ni48.7Co1.3 alloy shape-memory clamps for the fixation of mandibular fractures using transoral access. The clamps were used to treat all types of fractures occurring between the mandibular angles. The clamps were removed after a period of at least 6 weeks, and tissue samples were taken for microscopic examination. Seventy-seven patients with mandibular fractures were treated using the clamps. Altogether 93 fractures were treated, involving 124 clamps. There were 56 cases of single fracture and 21 cases of multiple fracture. In 72 patients the treatment progressed satisfactorily, while in five cases infections occurred. Tissue samples for histologic examination were taken from 58 patients after removal of the clamps. There were no pathologic or atypical tissue reactions or signs of disturbed cell maturation. The authors concluded that the application of shape memory clamps for the surgical treatment of mandibular fractures facilitates treatment while ensuring stable fixation of the bone fragments.
There are also two other studies in which NiTi implants were used in the surgical correction of maxillo-facial fractures. The results showed that the surgical treatment of these fractures by NiTi devices was simple, ensured a good stability of the fracture surfaces, reduced the time needed for operative procedures and rehabilitation, and allowed rapid bone healing (Sysolyatin et al. 1994, Itro et al. 1997).
The results of ventral intercorporeal lumbar spondylodesis with a NiTi implant were reported by von Salis-Soglio (1989). The operative technique was characterized by primary stabilization of the moving segment by means of a memory implant that was inserted intercorporeally following ventral removal of the intervertebral disc. The results included 51 cases of bony fusion within an average postoperative period of 9 months, one case of pseudoarthrosis and 11 cases of delayed bony fusion. The author concluded that, in view of the easier operative technique, the earlier mobilization of the patients and the good fusion rate, the memory spondylodesis seems to have important advantages over the transplantation of bone chips only. The use of a NiTi staple to lock a tri-cortical iliac bone graft in cervical anterior fusion was used by Ricart (1997). Fifty patients with various clinical diagnoses were treated. Good and very good clinical results were reported in 80% of the cases and the average bone fusion rate was fast (7 weeks).
Silberstein (1997) reported a clinical study where 84 patients with fractures, tumors or intervertebral disc disease of the cervical and lumbal spine were treated with anterior fusion and porous NiTi implant grafts. They concluded that porous NiTi implants can be successfully used, probably because their mechanical properties are similar to those of the vertebral bodies, and the material itself shows a high degree of biocompatibility.
Thirty-six metatarsal osteotomies using internal fixation of a shape memory metal compression staple for hallux valgus were performed in a study by Tang et al. (1996). The recovery period preceding return to light work averaged 19 days, and normal work and normal walking were resumed an average of 41 days postoperatively. Twenty patients (35 feet) experienced complete pain relief. Only in one foot was the pain transferred under the second metatarsal head. Radiographic analysis of the feet showed that all the osteotomies united, and the average angle of hallux valgus and the intermetatarsal angle improved. The distal fragment during the healing of the osteotomy was stable. No external fixation by plaster splintage was needed. According to the authors, the benefits of this internal fixator were that the period of bone healing was shortened and the patients were allowed to bear weight earlier than usual.
Musialek et al. (1998) reported the fixation of small bone fragments with NiTi clamps in 64 patients. Clamps were used for compressive stabilization in several kinds of fractures. Three aspects were studied: bone union, wound healing problems and histology. Non-union occurred in 4 patients treated with only one fixative. Two clamps implanted in non-parallel planes seem to be advisable to exclude the need for longer immobilization. Neither toxic manifestation nor episodes of allergic reaction occurred. No suppuration appeared when a heat stimulus was applied by using a contact resistance heater. Histological evaluation of the tissue covering the implants in 22 patients did not reveal any adverse reactions. The study suggests that by using NiTi clamps in an appropriate way, satisfactory outcomes could be achieved with respect to both biofunctionality and biocompatibility.
In conclusion, on the basis of a few studies, it seems the NiTi material in itself has no deleterious effects in human use. The clinical relevance of the devices will not be discussed here.
In an early study by Castleman et al. (1976), neutron activation analyses were carried out on a small number of tissue samples from the liver, spleen, brain, and kidneys. The findings of the analysis suggest that there is no metallic contamination in the distant organs due to the implants.
Using NiTi paravertebral implants in 4 rabbits, Matsumoto et al. (1993) found that the blood Ni concentration after implantation reached a level twice the normal in 6-9 hours (28 ± 11 vs. 13 ± 5 ppb). After 4 weeks, the Ni concentration was 4-fold in the kidneys (140 ± 43 ppb), 2-fold in the liver (40 ± 18 ppb), and 10-fold in urine (90 ± 35 ppb). The authors concluded that Ni elution from NiTi alloy should be limited by, for example, using some coatings.
Most of the recent commercial NiTi applications are meant for cardiovascular solutions. The idea behind this is to provide minimally invasive treatment instead of major surgery. Since the first experiments by Cragg et al. (1983), several studies have provided further information on the biocompatibility of NiTi as vascular stent material.
In the experimental studies of Rabkin et al. (1986), altogether 66 endovascular NiTi prostheses were implanted in 36 dogs. Long-term results obtained over a period of 14 months demonstrated good and prolonged permeability of the NiTi prostheses. Morphological investigations showed that the endovascular prosthesis was separated in a ring-like fashion by a thin layer of connective tissue, while inside it was lined with a layer of endothelial cells.
The long-term effects of twelve intravascular NiTi endoprostheses implanted in the iliac and femoral arteries of six normal dogs were evaluated by Sutton et al. (1988). No migration, erosion, inflammation, surface thrombus, or stenosis of the side branches was seen. Nor were any histopathologic effects detected. The authors conclude that the good biocompatibility manifested as a completely endothelialized, thin and stable neointima, satisfactory delivery and long-term patency at 2 years.
Another study was carried out by Cragg et al. (1993) to test an expandable NiTi intraluminal stent for biocompatibility, corrosion resistance, and patency. Forty-four stents were implanted in the iliac arteries of 22 sheep. Follow-up was performed with angiography and histologic examination for up to 6 months. All but one stent remained widely patent during the follow-up period. Minimal corrosion was seen at 6 months, and the stent appeared to be biocompatible. The authors conclude that a stent can be reliably and safely deployed in the vascular system.
Wakhloo et al. (1994) assessed the efficacy of tantalum or porous, tubular self-expanding NiTi stents for the treatment of carotid aneurysms. A total of 14 experimentally constructed aneurysms in dogs were treated. No incompletely occluded aneurysms were visible after the implantation of NiTi stents. After nine months, significantly more abundant intimal fibrocellular tissue growth surrounded the tantalum filaments than the NiTi filaments, which were covered with a smooth, thin neointimal layer. It was concluded that NiTi stents may become the treatment of choice for broad-based and fusiform aneurysms of the internal carotid artery. Improvements in the introducing system, stent material, and stent shape are required for simple implantation and reduction of intimal hyperplasia.
Cwikiel et al. (1997) used 6 pigs to evaluate the early proliferative reaction of smooth muscle cells in the media of the iliac artery following percutaneous transluminal angioplasty (PTA) compared with the reaction on the insertion of NiTi stents. The cell reaction appeared to be more pronounced after PTA than after the insertion of a self-expanding stent.
NiTi stents were implanted into the vertebral arteries in six dogs to evaluate the response associated with stent placement in low flow velocity arteries. Throughout the observation period up to 9 months, five arteries remained patent without significant narrowing. The total mean thickness of the intima covering the stents showed no significant differences over time. The histologic findings on the stented vessels showed atrophic compression of the media, but intact endothelial cell linings without necrosis or perforation were observed. Thus, no significant risk of thromboembolic events exists after the implantation of NiTi stents in the vertebral arteries in dogs (Wakhloo et al. 1995).
Despite the improvements afforded by intracoronary stenting, restenosis remains a significant problem. In the present study by Carter et al. (1998), the vascular response of a NiTi stent was compared to a balloon-expandable stent in porcine coronary arteries. Eleven NiTi and eleven stainless steel stents were implanted. On histology at 3 days, the stainless steel stents had more inflammatory cells adjacent to the stent wires than their NiTi counterparts. After 28 days, the vessel response was similar for the NiTi and stainless steel designs. The mean neointimal area and the percentage of stenosis were significantly lower in the NiTi than in the stainless steel group. The authors concluded that a NiTi stent exerts a more favorable effect on vascular remodeling with less neointimal formation, than a balloon-expandable design. Progressive intrinsic stent expansion after the implantation does not appear to stimulate neointimal formation and may therefore prevent in-stent restenosis. The results were in accordance with an earlier study by Sheth et al. (1996).
Grenadier et al. (1994) investigated the acute and long-term patency rates and the histologic responses of coronary arteries to a self-expandable NiTi coil stent. Twenty-two stents were implanted in sixteen dogs. The animals were monitored for 1 to 2 weeks, 1 month, 3 months, 6 months, and 1 year and underwent subsequent angiography and histopathologic examination. Angiographic artery dimensions measured immediately after stent implantation did not differ from those noted at follow-up. A histologic examination showed outward stent pressure compressing the internal elastic membrane and the media in most cases. Intimal hyperplasia started at 2 weeks and was most apparent at 3 and 6 months. Therefore, the NiTi self-expandable stent provokes a moderate cellular proliferative response that reaches its maximum in 3 to 6 months without further progression.
Based on the above studies, the histopathological changes caused by vascular NiTi stents are associated with a mild inflammatory response, some atrophy of vessel media, acceptable fibrocellular tissue growth and endothelization. The biocompatibility of NiTi stents seems to be equal or better compared to stainless steel stents.
Nonspecific inflammatory reactions characterized by local tenderness, fever, and flu-like discomfort have been seen in patients undergoing endoluminal graft placement in the abdominal aorta or the femoral arteries.
In a study by Kellner et al. (1997), magnetic resonance imaging demonstrated perivascular inflammation in 79% of patients with polyester-covered NiTi stents. Clinical symptoms were seen in 57% of these patients. No reaction was evident among the controls with uncovered NiTi stents and the subjects who underwent peripheral percutaneous transluminal angioplasty. The polyester-covered NiTi stent may induce systemic and severe local reactions. These reactions seem to be specific to this type of stent. No definite cause has been established, although the phenomenon appears to be self-limiting.
Hayoz et al. (1997) undertook a study to assess the clinical and laboratory parameters of this inflammation. Ten patients with femoropopliteal artery or aortic lesions were treated with polyester-covered NiTi (Dacron) fabric and compared with eleven patients implanted with a bare NiTi stent. In the stent-graft group, four patients showed clinical signs of acute inflammation manifested as fever and local tenderness. The authors also did an in vitro analysis, which showed that individual components of the stent-graft did not activate human neutrophils, whereas the intact stent-graft itself induced a marked neutrophil activation. The component of the self-expanding stent-graft that caused the nonspecific inflammatory reaction was not identified.
To improve hemocompatibility, heparin-coated Dacron-covered NiTi stent-grafts have been used. These were also found to cause severe inflammatory perigraft responses in sheep during up to 6 months of follow-up. MR images demonstrated contrast enhancement and edema. Macroscopic examination showed marked vascular wall thickening and adhesions around the Dacron fabric; microscopic examination showed a pronounced inflammatory foreign-body response. There was almost no response to noncovered NiTi stents. The authors concluded, on the basis of their two studies, that the use of noncovered stents should thus be preferred to the use of Dacron-covered stent-grafts (Schurmann et al. 1997).
The polyurethane coating has also been associated with perivascular inflammation. Six polyurethane-coated and six bare NiTi stents were implanted and compared in rabbit carotid arteries. At 4 weeks, all stent struts were endothelialized. Mild proliferative responses with some neovascularization around both stent types were seen. No differences in the degree of neointimal proliferation between the stents were found, but the polyurethane coating was associated with an inflammatory tissue response consisting of lymphocytic infiltration and foreign-body reaction and the appearance of multinucleated giant cells. This may indicate a low biocompatibility of polyurethane, which may thus not be an ideal material for coating intravascular devices (Rechavia et al. 1998).
To determine the biocompatibility and thrombogenicity of NiTi blood clot filters, Prince et al. (1988) inserted 27 NiTi wire devices into the venae cavae of 16 dogs and one sheep. The results were analyzed after periods of one week to four years. All the 18 cleaned NiTi wire filters remained patent, but some showed venographic filling defects caused by adherent organized thrombi. The filters in larger veins tended to have less thrombus formation. Surface polishing and filter shape had no observable effect on thrombogenicity. Histologic study revealed patchy chronic inflammation on the surface of uncleaned filters, but only a benign fibrous tissue reaction on cleaned filters. Neointimal tissue overgrowth was observed in the contact area of the vena cava. Platelet adhesion and plasma coagulation effects of NiTi wire were tested in vitro in human blood and found to be similar to those of stainless steel. The authors suggest that NiTi may be a promising material for human intravascular prosthetic applications.
Das et al. (1993) designed a superelastic NiTi-Dacron atrial septal defect closure device and studied its efficacy in a canine model. The defects were created surgically in 20 adult dogs. Percutaneous transcatheter closures were attempted using the new device. The closures were successful in 19 studies and unsuccessful in one. Light microscopy at 8 weeks in 3 dogs showed the devices to be covered by smooth endocardium enmeshed in mature collagen tissue, with minimal mononuclear cell infiltration. The authors concluded that this new device permits effective and safe atrial septal defect closure in a canine model.
Urethral stents have been used for the treatment of urethral strictures. Very few studies have been available to date on the compatibility of NiTi urethral stents.
To study the long-term effects of urethral NiTi stents, 18 dogs were implanted by Latal et al. (1994). The reactions of the mucosa, muscles and periurethral tissue were evaluated. The follow-up examinations performed after 1 week and 1, 3, 6, 12 and 18 months included urine, macroscopic, radiological, histologic and scanning electron microscopic analyses. The authors conclude that, despite the excellent biocompatibility of the material with no evidence of foreign body reactions or corrosion, there were no complete incorporations of the stent by epithelialization. Clinical application therefore appears to be problematic. On the contrary, one study has been published where 39 patients with benign prostatic hyperplasia had NiTi urethral stents implanted with a clinical success rate of 89%. Follow-up for 26 months showed no incrustation or migration of the spiral (Qiu 1993).