Multinucleated Foreign Body Giant Cells Research Articles

The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation

A spontaneous mutation in Bruton's tyrosine kinase (Btk) induces a defect in B-cell development that results in the immunodeficiency diseases X-linked agammaglobulinemia in humans and X-linked immunodeficiency (Xid) in mice. Here we show an unexpected role of Btk in osteoclast formation. When bone marrow cells derived from Xid mice were stimulated with receptor activator of NF-kappaB ligand, an osteoclast differentiation factor, they did not completely differentiate into mature multinucleated osteoclasts. Moreover, we found that the defects appeared to occur at the stage in which mononuclear preosteoclasts fuse to generate multinucleated cells. Supporting this notion, macrophages from Xid mice also failed to form multinucleated foreign body giant cells. The fusion defect of the Xid mutant osteoclasts was caused by decreased expression of nuclear factor of activated T cells c1 (NFATc1), a master regulator of osteoclast differentiation, as well as reduced expression of various osteoclast fusion-related molecules, such as the d2 isoform of vacuolar H(+)-ATPase V0 domain and the dendritic cell-specific transmembrane protein. This deficiency was completely rescued by the introduction of a constitutively active form of NFATc1 into bone marrow-derived macrophages. Our data provide strong evidence that Btk plays a critical role in osteoclast multinucleation by modulating the activity of NFATc1.

Influence of biodegradable and non-biodegradable material surfaces on the differentiation of human monocyte-derived macrophages

Monocyte-derived macrophages (MDM) and multinucleated foreign body giant cells (FBGC) are the primary cell types that remain at the cell–material interface of polyurethane (PU)-based medical devices as a result of chronic inflammatory responses. In vitro studies have demonstrated that MDM possess degradative potential toward PU, which can result in device failure. Because most studies have followed the degradation potential, morphology, and function of these cells only once fully differentiated, the current study investigated the influence of a non-degradable control tissue culture-grade polystyrene (TCPS) surface relative to two degradable model polycarbonate-urethanes (PCNU), of different chemistry, on various parameters of MDM morphology and function during a 14-day differentiation time course. The differentiation of human monocytes isolated from whole blood on PCNU materials resulted in increased cell attachment, decreased multinucleation, and significant decreases in cell spreading when compared with cells differentiated on TCPS. Actin-stained podosome-like cell adhesion structures were increased in PCNU-adherent cells, accompanied by an alteration in β-actin and vinculin protein expression. The expression of the CD68 macrophage marker was reduced when cells were adherent to the PCNU materials and compared with TCPS, suggesting altered cell activation by the degradable relative to non-degradable materials. The degradative potential of these cells was altered by the material surface they were exposed to as measured by esterase activity and protein expression of monocyte-specific esterase. This was also supported by physical material breakdown evident in scanning electron microscopy images that illustrated holes in the PCNU films generated by the presence of differentiating MDM. It was concluded from these studies that PCNU materials significantly alter the function and morphology of differentiating MDM. This must be taken into consideration when studying cell–material interactions because these cells will receive cues from their immediate environment (including the biomaterial) upon differentiation, thereby affecting their resulting phenotype.

Complications of AlphaCor Keratoprosthesis

To describe the clinical and histopathologic features of intractable secondary glaucoma induced by AlphaCor keratoprosthesis. An elderly woman with pseudoexfoliation glaucoma and pseudophakic bullous keratopathy in the right eye had graft failures after penetrating keratoplasty. Her best-corrected visual acuity at presentation was counting fingers in the right eye and 20/30 in the left eye. Examination showed severe corneal neovascularization. Chirila keratoprosthesis type II was implanted in 2 stages. Ten months later, the patient developed dense retrocorneal membrane, 360 degrees occlusion of angles, intractable glaucoma, no light perception, and nasal stromal melting associated with partial extrusion of the keratoprosthesis. Histopathology revealed invasion of the porous material of the keratoprosthesis by reactive fibroblasts and multinucleated foreign-body giant cells. In the area of dehiscence, we noted thinning and lysis of the collagen fibers, infiltration of lymphocytes, and plasma cells with a sheet of fibroinflammatory tissue extending into the anterior chamber. Corneal stromal melting and retrocorneal prosthetic membrane formation after AlphaCor keratoprosthesis implantation led to intractable glaucoma and extrusion of the implant.

Not Your Typical Pneumonia: A Case of Exogenous Lipoid Pneumonia

The constellation of chronic cough, dyspnea, and hemoptysis can include a broad range of differential diagnoses. Although uncommon, exogenous lipoid pneumonia (ELP) should be considered when patients present with this symptom complex. We report a case of a 72-year-old female who presented with hemoptysis, cough, and dyspnea. The admission computed tomography scan of the chest revealed progressive interstitial infiltrates. Bronchoscopy revealed diffuse erythema without bleeding. Culture and cytology of lavage fluid were negative. Open-lung biopsy revealed numerous lipid-laden macrophages and multinucleated foreign-body giant cells. On further questioning, the patient admitted to the daily use of mineral oil for constipation. The diagnosis of ELP was made. The literature review revealed that many cases typically present with chronic cough with or without dyspnea. Our case illustrates an unusual presenting symptom of hemoptysis and the need to identify patients who can be at risk of developing this rare condition.

Retrieval analyses of highly cross-linked polyethylene acetabular liners four and five years after implantation

Two Durasul highly crosslinked polyethylene liners were exchanged during revision surgery four and five years after implantation, respectively. The retrieved liners were evaluated macroscopically and surface analysis was performed using optical and electron microscopy. A sample of each liner was used to determine the oxidation of the material by Fourier transform infrared spectroscopy. Samples of the capsule were examined histologically. The annual wear rate was found to be 0.010 and 0.015 mm/year, respectively. Surface analysis showed very little loss of material caused by wear. Histological evaluation revealed a continuous neosynovial lining with single multinucleated foreign-body giant cells. Our findings showed no unexpected patterns of wear on the articulating surfaces up to five years after implantation and no obvious failure of material.

Histologically verified bone wax (beeswax) granuloma after median sternotomy in 17 of 18 autopsy cases

To evaluate the sternum from ordinary or forensic autopsy cases with a midline sternal cutaneous scar macro- and microscopically and using computed tomography (CT) to detect if the haemostatic bone sealant bone wax (beeswax) had been applied after median sternotomy and if the bone wax had elicited inflammation. During a 3-year period, the sterna of 18 consecutive cadavers (15 ordinary autopsies, 3 forensic) who prior to death had undergone surgery with median sternotomy were examined macro- and microscopically and with CT. In addition, one virgin sternum was smeared with bone wax at the upper half after bench sternotomy, sutured and examined with CT. Unused bone wax was examined with CT for attenuation measurements. Macroscopically, bone wax was seen in 17 of 18 sterna. Acute inflammation was found in one, chronic inflammation and foreign body multinucleated giant cells were seen around the bone wax in 17 sterna. No inflammation was found in one. CT could only detect foci in the operated sterna with attenuation values from -45 to +20 Hounsfield units (HU) and values about -80 HU were found in the virgin sternum. Unused bone wax measured about -100 HU. Bone wax is non-resorbable and induces chronic inflammation in the operated sternum up to 10 years after application. Measurement of Hounsfield units with CT of the operated sterna could not verify bone wax granuloma.

Xanthogranuloma of the sellar region

The incidence of diagnosed xanthogranuloma of the sellar region is very low [1, 2, 5, 6]. We report about two cases 1) in a 57-year-old female and 2) in a 5-year-old boy. In both cases radiographic findings revealed an inhomogeneous, contrast enhancing sellar lesion. Histopathology showed the typical features of a xanthogranuloma of the sellar region with cholesterol clefts, lympho-plasmacellular infiltrates, marked hemosiderin deposits, multinucleated foreign body giant cells around cholesterol clefts, accumulation of macrophages and only small epithelial cell clusters [6]. As xanthogranuloma of the sellar region are rarely diagnosed we want to draw attention to this rather unusual diagnosis.

Conjunctival Granulomas Caused by Synthetic Fibers: Report of Two Cases and Review of Literature

We sought to demonstrate the histopathologic and ultrastructural features of conjunctival foreign body granulomas because of synthetic fibers and to compare them to other cases published in the literature. A 2- and a 7-year-old girl were referred for the surgical removal of slow-growing unilateral inferior conjunctival masses with a lack of primary trauma or surgery. In this report, we describe the light and electron microscopic findings of the 2 cases and review the literature of similar cases using the Medline database. Histopathologic and ultrastructural examination of both specimens revealed a granulomatous inflammatory cell response, including histiocytes and multinucleated foreign body giant cells around acellular, uniform sized, oval to round birefringent fibers with manufacturing artifacts. Thirteen other patients with conjunctival synthetic fiber granulomas were identified from the literature. On the basis of the findings in our cases and the review of literature, it appears that conjunctival synthetic fiber granulomas are not a rare entity but are not recognized frequently by ophthalmologists. The most reliable clinical sign to suggest this diagnosis is the presence of a unilateral inferior conjunctival mass in a child or adolescent. Histopathologic and ultrastructural evaluation appears to be the only way to specifically diagnose this condition with certainty.

Multinucleated Foreign Body Giant Cells in Placental Membrane

We report the pathologic finding of a multinucleated foreign body giant cell reaction to squames and fetal hair in the placental membranes in a 37-week 1-day intrauterine gestation. This reaction appeared to have developed in association with repeated intrauterine procedures performed in the third trimester, including cordocentesis for fetal blood sampling, intrauterine blood transfusion, and amnioreduction for polyhydramnios. This type of reaction most likely was directed to prolonged amniotic fluid leakage that occurred spontaneously or after intrauterine procedures in the second half of the second trimester and the third trimester. Careful examination of the placental membranes and recognition of the foreign body giant cell reaction may provide etiologic insight in cases of unexplained oligohydramnios.

Hyaluronic Acid–Poly-D-Lysine-Based Three-Dimensional Hydrogel for Traumatic Brain Injury

Brain tissue engineering in the postinjury brain represents a promising option for cellular replacement and rescue, providing a cell scaffold for either transplanted or resident cells. In this article, a hyaluronic acid (HA)-poly-D-lysine (PDL) copolymer hydrogel with an open porous structure and viscoelastic properties similar to neural tissue has been developed for brain tissue engineering. The chemicophysical properties of the hydrogel with HA:PDL ratios of 10:1, 5:1, and 4:1 were investigated by scanning electron microscopy (SEM) and X-ray photoelectron spectrometry. Neural cells cultured in the hydrogel were studied by phase-contrast microscope and SEM. The incorporation of PDL peptides into the HA-PDL hydrogel allowed for the modulation of neuronal cell adhesion and neural network formation. Macrophages and multinucleated foreign body giant cells found at the site of implantation of the hydrogel in the rat brain within the first weeks postimplantation decreased in numbers after 6 weeks, consistent with the host response to inert implants in numerous tissues. Of importance was the infiltration of the hydrogel by glial fibrillary acidic protein-positive cells-reactive astrocytes-by immunohistochemistry and the contiguity between the hydrogel and the surrounding tissue demonstrated by SEM. These findings indicated the compatibility of this hydrogel with brain tissue. Collectively, the results demonstrate the promise of an HA-PDL hydrogel as a scaffold material for the repair of defects in the brain.

Immunohistochemical detection of fungal elements in the tissues of goslings with pulmonary and systemic aspergillosis.

Nineteen goslings with pulmonary and systemic aspergillosis were the subject of the study. The lungs and air sacs were the main sites affected by the disease, and were generally characterised by diffuse yellowish-white granulomas. In 7 cases with pulmonary and air-sac involvement the granulomas were scattered to the serosal linings of the gastrointestinal and upper respiratory tracts, to the liver, spleen and kidneys, and in two cases also to the bursa of Fabricius, musculus (m.) longus colli and adventitia of aorta. The granulomas were often characterised by a necrotic centre surrounded by heterophils, macrophages, lymphocyte and plasma cells, and in late granulomas by multinucleated foreign-body giant cells, and again by an outer thin fibrous capsule. Numerous fungal hyphae were found within the necrotic debris of the granulomas by Gridley and PAS staining techniques. Immunohistochemistry reliably confirmed aspergillosis in all of the cases. Fungal elements in the lungs of goslings severely affected by the disease stained heavily within the centre of the granulomas, whereas few antigens reacted in the chronic cases. Fungal fragments, which were not discernible using routine fungal stains, reacted clearly in the cytoplasm of macrophages and giant cells. Thus, although fungal elements within the granulomas were histologically indicative of aspergillosis, immunohistochemistry also had to be applied to obtain a definitive diagnosis of the disease and to differentiate it from many of the filamentous fungi.

Foreign Body-Type Multinucleated Giant Cell Formation Is Potently Induced by α-Tocopherol and Prevented by the Diacylglycerol Kinase Inhibitor R59022

Multinucleated foreign body giant cells (FBGCs) form by monocyte-derived macrophage fusion on implanted biomedical devices and are believed to mediate oxidative damage to biomaterial surfaces. Our in vitro system of human macrophage culture and interleukin (IL)-4-induced FBGC formation was developed to study the macrophage fusion mechanism and the physiological significance of FBGCs on implanted biomaterials and at other sites of chronic inflammation. Here, we demonstrate that the antioxidant vitamin E (90% alpha-tocopherol) moderately induces macrophage fusion and increases IL-4-induced FBGC formation. Moreover, purified alpha-tocopherol, but not beta-, gamma-, or delta-tocopherol, most remarkably induces macrophage fusion, leading to cultures of confluent FBGCs below normal plasma concentrations. This is not observed with the similar antioxidants probucol or Trolox, suggesting that the alpha-tocopherol effects on FBGC formation are independent of its antioxidant activity. Consistent with the reported activation of diacylglycerol kinase by alpha-tocopherol, the diacylglycerol kinase inhibitor R59022 completely abrogates FBGC formation. R59022 inhibition of IL-4-induced FBGC formation is reversed by alpha-tocopherol, suggesting that FBGC formation involves diacylglycerol kinase activation. This study suggests a novel role for diacylglycerol kinase in the mechanism of macrophage fusion/FBGC formation at sites of chronic inflammation and reveals that the pleiotropic lipophilic compound, alpha-tocopherol, is a highly potent macrophage fusion factor.

Preparation of bupivacaine-loaded poly(ɛ-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

Poly(ε-caprolactone) microspheres containining bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3 μm in diameter, and the percentage of entrapment efficiency was 91±3%. In vitro drug release kinetic in phosphate buffer at 37°C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237±58 ng/ml at 105 h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(ε-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.

Preparation of bupivacaine-loaded poly(ε-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

Poly(ε-caprolactone) microspheres containining bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3 μm in diameter, and the percentage of entrapment efficiency was 91±3%. In vitro drug release kinetic in phosphate buffer at 37°C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237±58 ng/ml at 105 h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(ε-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.

Successful Treatment of Cutaneous Sarcoidosis Using Topical Photodynamic Therapy

A 67-year-old woman had a 17-year history of increasing numbers of asymptomatic but disfiguring red-brown, flat papules on the extremities. She was otherwise well and had no pulmonary or systemic symptoms. Seven years ago, the patient was referred to our department, and the diagnosis of cutaneous sarcoidosis (small nodular type) was repeatedly confirmed by skin biopsy results. The physical examination revealed numerous painless, red-brown, slightly elevated papules and plaques up to 1 cm in diameter, disseminated and partially confluent at the extensor aspects of the legs and to a lesser extent on the upper arms (Figure 1). On results of diascopy, the lesions appeared gray yellowish. Other body areas were not affected. Results of the histological evaluation of formalinfixed, paraffin-embedded biopsy specimens repeatedly obtained from the lesional skin revealed noncaseous epithelioid-cell granulomas with several multinucleated foreign body giant cells and a sparse perifocal lymphohistiocytic infiltrate in the dermis. Results of examination of sections stained with periodic acid–Schiff and Ziehl-Neelsen failed to detect fungi or acid-fast bacilli, respectively. Special cultures repeatedly yielded negative findings for mycobacteria. Results of internal examinations showed no lung involvement, and pulmonary function test findings were normal. Findings on chest x-ray examination, electrocardiography, abdominal ultrasonography, and neurologic and ophthalmologic examinations revealed no abnormalities. No enlarged peripheral lymph nodes or parotid glands were seen. Laboratory investigations, including complete blood cell count, liver and renal function tests, serum electrophoresis, and measurement of electrolyte (including calcium), angiotensin-converting enzyme, 2-microglobulin, and -globulin concentrations, were within reference limits. The erythrocyte sedimentation rate and antinuclear antibody concentration were slightly raised. Results of the tine tuberculin reaction test were positive ( 3), whereas acute tuberculosis and former bacille Calmette-Guerin vaccination were excluded.

Fibronectin modulates macrophage adhesion and FBGC formation: The role of RGD, PHSRN, and PRRARV domains

To probe the role of human plasma fibronectin in modulating human blood-derived macrophage adhesion and fusion to form multinucleated foreign-body giant cells (FBGC), a series of biomimetic oligopeptides based on the functional structure of fibronectin was designed and synthesized. Peptides incorporated the RGD and PHSRN integrin-binding sequences from FIII-10 and FIII-9 modules, respectively, and the PRRARV sequence from the C-terminal heparin-binding domain, either alone or in combination. Peptides were immobilized onto a polyethyleneglycol-based polymer substrate. The following conclusions were reached. Fibronectin modulated macrophage adhesion and the extent (i.e., size) of FBGC formation on control surfaces in the presence of serum proteins. Macrophages adhered to all substrates with relatively subtle differences between adhesion mediated by RGD, PHSRN, PRRARV, or combinations thereof. β1-integrin subunit was essential in macrophage adhesion to peptide-grafted networks in a receptor-peptide specific manner, whereas β3-integrin subunit was less important. Macrophage adhesion to PRRARV was mediated primarily by the direct interaction with integrins. RGD or PHSRN alone did not provide an adequate substrate for macrophage fusion to form FBGCs. However, the PHSRN synergistic site and the RGD site in a single oligopeptide provided a substrate for FBGC formation that was statistically comparable to that on the positive control material in the presence of serum proteins. This response was highly dependent upon the relative orientation between RGD and PHSRN. PRRARV did not support FBGC formation. These results demonstrate the importance of fibronectin and, specifically, the synergy between RGD and PHSRN domains, in supporting macrophage fusion to form FBGCs. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res 55: 79–88, 2001

A case of localized persistent interstitial pulmonary emphysema

Interstitial pulmonary emphysema is a well-documented complication of assisted mechanical ventilation in premature infants with respiratory distress syndrome. Localized persistent interstitial pulmonary emphysema (LPIPE) confined to a single lobe was incidentally presented in a 4-day-old female infant. This patient was a normal full-term baby with no respiratory distress symptom and no experience of assisted mechanical ventilation. Chest radiograph showed radiolucent area in right lower lobe zone, which needed differential diagnosis from other congenital lesions such as congenital cystic adenomatoid malformation and congenital lobar emphysema. CT scan showed irregular-shaped air cystic spaces and pathologically, cystic walls primarily consisted of compressed lung parenchyma and loose connective tissue intermittently lined by multinucleated foreign body giant cells.

Fibronectin modulates macrophage adhesion and FBGC formation: the role of RGD, PHSRN, and PRRARV domains.

To probe the role of human plasma fibronectin in modulating human blood-derived macrophage adhesion and fusion to form multinucleated foreign-body giant cells (FBGC), a series of biomimetic oligopeptides based on the functional structure of fibronectin was designed and synthesized. Peptides incorporated the RGD and PHSRN integrin-binding sequences from FIII-10 and FIII-9 modules, respectively, and the PRRARV sequence from the C-terminal heparin-binding domain, either alone or in combination. Peptides were immobilized onto a polyethyleneglycol-based polymer substrate. The following conclusions were reached. Fibronectin modulated macrophage adhesion and the extent (i.e., size) of FBGC formation on control surfaces in the presence of serum proteins. Macrophages adhered to all substrates with relatively subtle differences between adhesion mediated by RGD, PHSRN, PRRARV, or combinations thereof. beta1-integrin subunit was essential in macrophage adhesion to peptide-grafted networks in a receptor-peptide specific manner, whereas beta3-integrin subunit was less important. Macrophage adhesion to PRRARV was mediated primarily by the direct interaction with integrins. RGD or PHSRN alone did not provide an adequate substrate for macrophage fusion to form FBGCs. However, the PHSRN synergistic site and the RGD site in a single oligopeptide provided a substrate for FBGC formation that was statistically comparable to that on the positive control material in the presence of serum proteins. This response was highly dependent upon the relative orientation between RGD and PHSRN. PRRARV did not support FBGC formation. These results demonstrate the importance of fibronectin and, specifically, the synergy between RGD and PHSRN domains, in supporting macrophage fusion to form FBGCs.

Inflammatory cytokine production by immunological and foreign body multinucleated giant cells.

Multinucleated giant cells (MGC) are a common feature of granulomas. The mechanism of their formation has been studied extensively, but their function has not been completely characterized. A new method for the in vivo production of MGC was developed involving subcutaneous injection of microscopic nitrocellulose particles with adsorbed mycobacterial antigens into the footpads of sensitized BALB/c mice (immune [I]-MGC), or by nitrocellulose administration to non-sensitized mice (foreign body [FB]-MGC). The development of granulomas with a highly enriched MGC population was observed 2 weeks after the nitrocellulose injection. MGC were larger with a greater number of nuclei in I-MGC than in FB-MGC. From days 7-28 after nitrocellulose administration, the production of interleukin-1alpha (IL-1alpha) and tumour necrosis factor-alpha (TNF-alpha) was demonstrated in both MGC types by in situ reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. After 2 months, the MGC had ceased production of IL-1alpha and TNF-alpha, but the expression of transforming growth factor-beta (TGF-beta) was very high, occurring together with extensive fibrosis. These results suggest that MGC are an active source of inflammatory cytokines, which can contribute to the initiation, maintenance and down-regulation of granulomatous inflammation induced by immunological and inert substances.

Histologic Evidence of Foreign Body Granulation Tissue and de novo Lesions in Patients with Coronary Stent Restenosis

Objectives: We examined the relative contributions of foreign body granulation and de novo lesions to neointimal hyperplasia in atherectomized specimens of restenosis after coronary stenting. Background: Clinicopathological studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of restenosis after coronary stenting. It is not yet fully understood how SMC hyperplasia occurs or how SMCs stimulation can lead to intimal hyperplasia. Although inflammation has been postulated to be a major contributor to restenosis after coronary stenting, there is a paucity of data on the relationsip between inflammation and subsequent neointimal formation in humans. Only in a porcine experimental model of stent restenosis, foreign body granulation tissue as a cause of inflammation in stent restenosis was reported. Methods: Tissue specimens were retrieved by directional atherectomy from 11 patients in whom stent restenosis developed after percutaneous revascularization of coronary artery disease. For specimens preserved in 10% buffered formalin, analysis of cellular composition was performed quantitatively after cell-specific immunostaining, i.e. CD68, UCHL-1, HLA-DR, smooth muscle actin, vimentin, desmin, PCNA and TGF-β. Results: Five of the 11 patients showed granulation tissues 3–6 months after stent implantation, of whom 3 patients revealed foreign body multinucleated giant cells around the stent struts where PCNA- and vimentin-positive SMCs were demonstrated. Calcification and de novo lesions in medial and adventitial tissues were observed in 3 other patients, and fresh and/or organized thrombi were documented in 3 of the 11 patients. Conclusions: These findings support the notion that stent restenosis results from SMC hyperplasia and suggest that the foreign body granulation tissue against metals of the stents and de novo lesions could play an important role in chronic inflammation leading to intimal hyperplasia and subsequently to stent restenosis in some patients. Clinicians should thus consider whether a patient may be allergic to stent components with unknown reaction, e.g. haptens.