The Implant-Induced Foreign Body Response Is Limited by CD13-Dependent Regulation of Ubiquitination of Fusogenic Proteins.

Implanted medical devices, from artificial heart valves and arthroscopic joints to implantable sensors, often induce a foreign body response (FBR), a form of chronic inflammation resulting from the inflammatory reaction to a persistent foreign stimulus. The FBR is characterized by a subset of multinucleated giant cells (MGCs) formed by macrophage fusion, the foreign body giant cells (FBGCs), accompanied by inflammatory cytokines, matrix deposition, and eventually deleterious fibrotic implant encapsulation. Despite efforts to improve biocompatibility, implant-induced FBR persists, compromising the utility of devices and making efforts to control the FBR imperative for long-term function. Controlling macrophage fusion in FBGC formation presents a logical target to prevent implant failure, but the actual contribution of FBGCs to FBR-induced damage is controversial. CD13 is a molecular scaffold, and in vitro induction of CD13KO bone marrow progenitors generates many more MGCs than the wild type, suggesting that CD13 regulates macrophage fusion. In the mesh implant model of FBR, CD13KO mice produced significantly more peri-implant FBGCs with enhanced TGF-ß expression and increased collagen deposition versus the wild type. Prior to fusion, increased protrusion and microprotrusion formation accompanies hyperfusion in the absence of CD13. Expression of fusogenic proteins driving cell-cell fusion was aberrantly sustained at high levels in CD13KO MGCs, which we show is due to a novel CD13 function, to our knowledge, regulating ubiquitin/proteasomal protein degradation. We propose CD13 as a physiologic brake limiting aberrant macrophage fusion and the FBR, and it may be a novel therapeutic target to improve the success of implanted medical devices. Furthermore, our data directly implicate FBGCs in the detrimental fibrosis that characterizes the FBR.

Monocyte-Macrophage Lineage Cell Fusion.

Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte-macrophage lineage are highly fusogenic. They create syncytial multinucleated giant cells (MGCs) such as osteoclasts (OCs), MGCs associated with the areas of infection/inflammation, and foreign body-induced giant cells (FBGCs). The fusion of monocytes/macrophages with tumor cells may promote cancer metastasis. We describe types and examples of monocyte-macrophage lineage cell fusion and the role of actin-based structures in cell fusion.

Foreign body reaction toward hydrophilic polymer at the site of endovascular procedure: A report of two cases.

Hydrophilic polymer-coated devices have been increasingly utilized for various endovascular procedures, however not been without adverse effects. We report two cases of subacute cutaneous lesions on the neck encountered in our dermatology clinic. Histopathologic findings were significant for a nodular aggregate of epithelioid histiocytes and lymphocytes with numerous foreign body giant cells in the dermis. The granulomatous infiltrate was associated with an amorphous basophilic non-polarizable material. Further chart review reveals both patients receiving a central venous procedure in the past, thus attributing the hydrophilic polymers as the likely source of the foreign material found at the insertion site. Our cases contrast to the more commonly reported distal embolization by these hydrophilic polymer layers. We suspect the incidence of retained hydrophilic polymer at the site of prior endovascular procedures may be underreported in the literature with the more inconspicuous presentations. Therefore, retained foreign material should be considered by both treating physicians and dermatopathologists in presenting cases of lesions that occur at common sites of endovascular procedures.

Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation.

Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage and/or rejection of implants. However, while these features of FBGCs are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGCs may permit the development of novel implants that eliminate or reduce the FBR. Our previous study showed that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel/receptor, is required for FBGC formation and FBR to biomaterials. Here, we have determined that (a) TRPV4 is directly involved in fusogenic cytokine (interleukin-4 plus granulocyte macrophage-colony stimulating factor)-induced activation of Rac1, in bone marrow-derived macrophages; (b) TRPV4 directly interacts with Rac1, and their interaction is further augmented in the presence of fusogenic cytokines; (c) TRPV4-dependent activation of Rac1 is essential for the augmentation of intracellular stiffness and regulation of cytoskeletal remodeling; and (d) TRPV4-Rac1 signaling axis is critical in fusogenic cytokine-induced FBGC formation. Together, these data suggest a novel mechanism whereby a functional interaction between TRPV4 and Rac1 leads to cytoskeletal remodeling and intracellular stiffness generation to modulate FBGC formation.

Tuning the immune reaction to manipulate the cell-mediated degradation of a collagen barrier membrane.

In order to elicit a desired barrier function in guided bone regeneration (GBR) or guided tissue regeneration (GTR), a barrier membrane has to maintain its integrity for a certain period of time to guarantee the regeneration of target tissue. Due to the complexity and variety of clinical conditions, the healing time required for tissue regeneration varies from one case to another, which implies the need for tailoring the barrier membranes to diverse conditions via manipulating their degradation property. As a "non-self" biomaterial, a barrier membrane will inevitably trigger host-membrane immune response after implantation, which entails the activation of phagocytic cells. In the degradation process of a barrier membrane, the cell-mediated degradation may play a more vital role than enzymatic and physicochemical dissolution; however, limited studies have been carried out on this topic. In this context, we investigated the cell-mediated degradation and illustrated the possible key cells and mediators for immunomodulation via in vivo and in vitro studies. We discovered that IL-13, a key cytokine mainly released by T helper 2 cells (Th2), induced the formation of foreign body giant cells (FBGCs), thus resulting in membrane degradation. Neutralizing IL-13 could suppress membrane degradation and formation of FBGC. The contributions of this study are (1) unveiling the immune mechanisms underlying the cell-mediated collagen membrane degradation; (2) allowing the formation of an "immunodegradation" strategy to develop an "immune-smart" barrier membrane to manipulate its degradation; (3) providing the key regulatory immune cells and cytokines for the immunomodulation target in collagen membrane degradation. STATEMENT OF SIGNIFICANCE: The significance of this research includes.

Giant cells lepromatous leprosy. Diffuse dermatitis with exuberant foreign body giant cells in treated lepromatous leprosy / Células gigantes en lepra lepromatosa. Dermatitis difusa con células gigantes tipo cuerpo extraño exuberantes en lepra lepromatosa tratada

Patients with lepromatous leprosy that have received treatment for many years usually get follow up biopsies for persistent skin lesions or positive bacilloscopy even if the values are lower than in the initial bacilloscopy. We report the case of a 48-year old woman with long-standing lepromatous leprosy of 15 years of evolution, with a bacterial index of 4 in the direct smear and the initial skin biopsy. The patient was treated with multidrug therapy for 32 months although the treatment recommended by the World Health Organization (WHO) is only for 12 months. A skin biopsy was taken to determine if there was an active disease. We observed a diffuse dermal inflammation with numerous foreign body giant cells and vacuolated macrophages (Virchow´s cells). These cells contained granular acid-fast material that was also positive with immunohistochemistry for BCG. There were fragmented bacilli and the BI was 2. These cells were also strongly positive for CD68. The biopsy was interpreted as a residual form of lepromatous leprosy that did not require further multidrug therapy. We have observed similar histological profiles in several cases. The lack of clinical data makes it a histological challenge. The accumulation of lipids in these giant cells is due to bacillary destruction and fusion of vacuolated macrophages. We discuss here the role of bacillary and host lipids in the pathogenesis of lepromatous leprosy. We concluded that there was no need to extend the 12-month multidrug therapy recommended by WHO.

Los pacientes con lepra lepromatosa (LL) que han recibido tratamiento durante años, usualmente tienen seguimiento con biopsias de piel para lesiones persistentes o con baciloscopia positiva, con valores menores a los iniciales. Presentamos una mujer de 48 años con LL de 15 años de evolución, con índice bacilar (IB) 4 en el extendido directo y en la biopsia, que recibió terapia multidroga durante 32 meses, aunque el tratamiento recomendado por la Organización mundial de la salud (OMS) es de 12 meses. Se tomó una biopsia de piel para determinar si la enfermedad estaba activa. Se observó inflamación dérmica difusa con numerosas células gigantes tipo cuerpo extraño y macrófagos vacuolados (células de Virchow). Estas células, CD68 positivas, contenían material granular ácido-alcohol resistente, positivo con inmunohistoquímica para BCG. Se encontraron bacilos fragmentados y el IB fue de 2. Se interpretó como una forma residual de LL y que la paciente no requería MDT adicional. Este perfil histológico lo hemos observado en casos similares. Sin datos clínicos estas biopsias son un reto diagnóstico. La acumulación de lípidos en estas células gigantes se debe a la destrucción bacilar y a la fusión de macrófagos vacuolados. Revisamos el papel de los lípidos del bacilo y del huésped en la patogénesis de la LL. En estos casos no es necesario extender los 12 meses de MDT recomendados por la OMS. En el seguimiento de los pacientes se recomienda contar con los hallazgos clínicos, la baciloscopia, la biopsia anual de piel y los títulos IgM anti-glicolípido fenólico.

Solochrome cyanine: A histological stain for cobalt-chromium wear particles in metal-on-metal periprosthetic tissues.

Metal-on-metal (MoM) hip arthroplasties produce abundant implant-derived wear debris composed mainly of cobalt (Co) and chromium (Cr). Cobalt-chromium (Co-Cr) wear particles are difficult to identify histologically and need to be distinguished from other wear particle types and endogenous components (e.g., haemosiderin, fibrin) which may be present in MoM periprosthetic tissues. In this study we sought to determine whether histological stains that have an affinity for metals are useful in identifying Co-Cr wear debris in MoM periprosthetic tissues. Histological sections of periprosthetic tissue from 30 failed MoM hip arthroplasties were stained with haematoxylin-eosin (HE), Solochrome Cyanine (SC), Solochrome Azurine (SA) and Perls' Prussian Blue (PB). Sections of periprosthetic tissue from 10 cases of non-MoM arthroplasties using other implant biomaterials, including titanium, ceramic, polymethylmethacrylate (PMMA) and ultra-high molecular weight polyethylene (UHMWP) were similarly analysed. Sections of 10 cases of haemosiderin-containing knee tenosynovial giant cell tumour (TSGCT) were also stained with HE, SC, SA and PB. In MoM periprosthetic tissues, SC stained metal debris in phagocytic macrophages and in the superficial necrotic zone which exhibited little or no trichrome staining for fibrin. In non-MoM periprosthetic tissues, UHMWP, PMMA, ceramic and titanium particles were not stained by SC. Prussian Blue, but not SC or SA, stained haemosiderin deposits in MoM periprosthetic tissues and TSGT. Our findings show that SC staining (most likely Cr-associated) is useful in distinguishing Co-Cr wear particles from other metal/non-metal wear particles types in histological preparations of periprosthetic tissue and that SC reliably distinguishes haemosiderin from Co-Cr wear debris.

Live imaging the foreign body response in zebrafish reveals how dampening inflammation reduces fibrosis.

Implanting biomaterials in tissues leads to inflammation and a foreign body response (FBR), which can result in rejection. Here, we live image the FBR triggered by surgical suture implantation in a translucent zebrafish model and compare with an acute wound response. We observe inflammation extending from the suture margins, correlating with subsequent avascular and fibrotic encapsulation zones: sutures that induce more inflammation result in increased zones of avascularity and fibrosis. Moreover, we capture macrophages as they fuse to become multinucleate foreign body giant cells (FBGCs) adjacent to the most pro-inflammatory sutures. Genetic and pharmacological dampening of the inflammatory response minimises the FBR (including FBGC generation) and normalises the status of the tissue surrounding these sutures. This model of FBR in adult zebrafish allows us to live image the process and to modulate it in ways that may lead us towards new strategies to ameliorate and circumvent FBR in humans.This article has an associated First Person interview with the first author of the paper.

Células gigantes en lepra lepromatosa: dermatitis difusa con células gigantes exuberantes de tipo cuerpo extraño en lepra lepromatosa tratada / Giant cells lepromatous leprosy: Diffuse dermatitis with exuberant foreign body giant cells in treated lepromatous leprosy

Resumen Los pacientes con lepra lepromatosa que han recibido tratamiento durante años, usualmente requieren seguimiento con biopsias de piel para detectar lesiones persistentes o si la baciloscopia es positiva, incluso si los valores son menores que los iniciales. Se presenta el caso de una mujer de 48 años de edad con lepra lepromatosa de 15 años de evolución, índice bacilar de 4 en el extendido directo y en la biopsia, que recibió tratamiento con múltiples medicamentos durante 32 meses, aunque lo recomendado por la Organización Mundial de la Salud (OMS) es una duración de 12 meses. Se tomó una biopsia de piel para determinar si la enfermedad estaba activa. Se observó inflamación dérmica difusa con numerosas células gigantes de tipo cuerpo extraño y macrófagos vacuolados (células de Virchow). Estas células, CD68 positivas, contenían material granular ácido-alcohol resistente positivo con inmunohistoquímica para BCG. Se encontraron bacilos fragmentados y el índice bacilar fue de 2. Se interpretó como una forma residual de lepra lepromatosa y se concluyó que la paciente no requería prolongar el tratamiento con múltiples medicamentos. Este perfil histológico se ha observado en casos similares, pero sin datos clínicos estas biopsias representan un reto diagnóstico. La acumulación de lípidos en estas células gigantes se debe a la destrucción bacilar y a la fusión de macrófagos vacuolados. Se revisó el papel de los lípidos del bacilo y del huésped en la patogenia de la lepra lepromatosa. En estos casos, no es necesario extender los 12 meses de tratamiento con múltiples medicamentos recomendados por la OMS. En el seguimiento de los pacientes, se recomienda contar con los hallazgos clínicos, la baciloscopia, la biopsia anual de piel y los títulos IgM antiglucolípido fenólico.

Abstract Patients with lepromatous leprosy that have received treatment for many years usually get follow up biopsies for persistent skin lesions or positive bacilloscopy even if the values are lower than in the initial bacilloscopy. We report the case of a 48-year old woman with long-standing lepromatous leprosy of 15 years of evolution, with a bacterial index of 4 in the direct smear and the initial skin biopsy. The patient was treated with multidrug therapy for 32 months although the treatment recommended by the World Health Organization (WHO) is only for 12 months. A skin biopsy was taken to determine if there was an active disease. We observed a diffuse dermal inflammation with numerous foreign body giant cells and vacuolated macrophages (Virchow´s cells). These cells contained granular acid-fast material that was also positive with immunohistochemistry for BCG. There were fragmented bacilli and the BI was 2. These cells were also strongly positive for CD68. The biopsy was interpreted as a residual form of lepromatous leprosy that did not require further multidrug therapy. We have observed similar histological profiles in several cases. The lack of clinical data makes it a histological challenge. The accumulation of lipids in these giant cells is due to bacillary destruction and fusion of vacuolated macrophages. We discuss here the role of bacillary and host lipids in the pathogenesis of lepromatous leprosy. We concluded that there was no need to extend the 12-month multidrug therapy recommended by WHO. Clinical findings, bacilloscopy, annual skin biopsy, and anti-phenolic glycolipid-I IgM titers are recommended procedures for the follow-up of these patients.

Transient Receptor Potential Vanilloid 4 Is Required for Foreign Body Response and Giant Cell Formation.

The presence of biomaterials and devices implanted into soft tissue is associated with development of a foreign body response (FBR), a chronic inflammatory condition that can ultimately lead to implant failure, which may cause harm to or death of the patient. Development of FBR includes activation of macrophages at the tissue-implant interface, generation of destructive foreign body giant cells (FBGCs), and generation of fibrous tissue that encapsulates the implant. However, the mechanisms underlying the FBR remain poorly understood, as neither the materials composing the implants nor their chemical properties can explain triggering of the FBR. Herein, we report that genetic ablation of transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable mechanosensitive cation channel in the transient receptor potential vanilloid family, protects TRPV4 knockout mice from FBR-related events. The mice showed diminished collagen deposition along with reduced macrophage accumulation and FBGC formation compared with wild-type mice in a s.c. implantation model. Analysis of macrophage markers in spleen tissues and peritoneal cavity showed that the TRPV4 deficiency did not impair basal macrophage maturation. Furthermore, genetic deficiency or pharmacologic antagonism of TRPV4 blocked cytokine-induced FBGC formation, which was restored by lentivirus-mediated TRPV4 reintroduction. Taken together, these results suggest an important, previously unknown, role for TRPV4 in FBR.

Granulomatosis with polyangiitis: potentially lethal gingival lesions presenting to the dentist.

Gingival pathology is a daily presentation, however a small number of systemic conditions can manifest similar to a common gingival condition and have fatal results. Dentist referred 56-year-old woman to Oral and Maxillofacial Surgery department with a 2-week medical history of gingival bleeding not responding to local measures. Biopsy showed eosinophilic infiltrate and vasculitis, and blood tests showed positive markers including cytoplasmic antineutrophil cytoplasmatic antibodies. Granulomatosis with polyangiitis is a rare disease affecting the respiratory tract, blood vessels and kidneys. Oral lesions are rarely the primary presenting feature. When left untreated, most cases are fatal within a year of diagnosis. The diagnosis can only be made when certain criteria are found, including granular oral lesions exhibiting an eosinophilic inflammatory infiltrate on biopsy. With 5% of cases showing intraoral lesions as the primary feature, it is essential that dentists have the knowledge of this rare disease to refer and not to treat as a common gingival condition.

Biomaterial-induced multinucleated giant cells express proinflammatory signaling molecules: A histological study in humans.

The biomaterials physicochemical characteristics influence their cellular reaction, degradation and regenerative capacities. Macrophages and multinucleated giant cells (MNGCs) are observed in the augmentation area of biomaterials. This study, for the first time, evaluated the polarization pattern of macrophages and MNGCs in response to two different bone substitute materials (synthetic bone substitute material [SBSM] = NanoBone vs. xenogeneic bone substitute material [XBSM] = Bio-Oss) in human bone biopsies compared to non-augmented bone (control). Histomorphometrical analysis of the polarization in proinflammatory (M1) and anti-inflammatory (M2) cells was performed using different immunohistochemical markers: CD-68 = macrophages; CCR-7 and Cox-2 (M1) and CD-206 and CD-163 (M2) and tartrate-resistant acid phosphatase (TRAP). The macrophage polarization pattern in SBSM showed a significantly higher number of M1 cells than did XBSM and non-augmented bone. XBSM induced a significantly higher number of CD-206-positive macrophages than SBSM did. No significant difference was found between XBSM and the non-augmented bone. MNGCs expressed CD-68 and TRAP. In both test-groups, MNGCs showed a high proinflammatory character (CCR-7 and Cox-2-positive) and their number in the SBSM group was significantly higher than that of XBSM. The tissue distribution showed a significantly low percentage of the remaining biomaterial in SBSM compared to XBSM. Within the limitations of this study, these findings show that MNGCs exhibit a rather proinflammatory character and lead to biomaterial degradation, once they are induced in a high number. The premature degradation of bone substitute materials is compensated with a high percentage of connective tissue and not new bone formation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 780-790, 2019.

Application of low-crystalline carbonate apatite granules in 2-stage sinus floor augmentation: a prospective clinical trial and histomorphometric evaluation

PURPOSE: The purpose of this study was to elucidate the efficacy and safety of carbonate apatite (CO₃Ap) granules in 2-stage sinus floor augmentation through the radiographic and histomorphometric assessment of bone biopsy specimens.METHODS: Two-stage sinus floor augmentation was performed on 13 patients with a total of 17 implants. Radiographic assessment using panoramic radiographs was performed immediately after augmentation and was also performed 2 additional times, at 7±2 months and 18±2 months post-augmentation, respectively. Bone biopsy specimens taken from planned implant placement sites underwent micro-computed tomography, after which histological sections were prepared.RESULTS: Postoperative healing of the sinus floor augmentation was uneventful in all cases. The mean preoperative residual bone height was 3.5±1.3 mm, and this was increased to 13.3±1.7 mm by augmentation with the CO₃Ap granules. The mean height of the augmented site had decreased to 10.7±1.9 mm by 7±2 months after augmentation; however, implants with lengths in the range of 6.5 to 11.5 mm could still be placed. The mean height of the augmented site had decreased to 9.6±1.4 mm by 18±2 months post-augmentation. No implant failure or complications were observed. Few inflammatory cells or foreign body giant cells were observed in the bone biopsy specimens. Although there were individual differences in the amount of new bone detected, new bone was observed to be in direct contact with the CO₃Ap granules in all cases, without an intermediate layer of fibrous tissue. The amounts of bone and residual CO₃Ap were 33.8%±15.1% and 15.3%±11.9%, respectively.CONCLUSIONS: In this first demonstration, low-crystalline CO₃Ap granules showed excellent biocompatibility, and bone biopsy showed them to be replaced with bone in humans. CO₃Ap granules are a useful and safe bone substitute for two-stage sinus floor augmentation.

The in vivo inflammatory and foreign body giant cell response against different poly(l-lactide-co-d/l-lactide) implants is primarily determined by material morphology rather than surface chemistry.

Biomaterials can cause a chronic local inflammation called foreign body reaction, with formation of foreign body giant cells (FBGC) by monocyte/macrophage fusion. However, FBGC appearance and role for biomaterials with different physicochemical properties are not yet fully understood. This study aimed at examining FBGC and inflammatory cells after intramuscular implantation of poly(l-lactide-co-d/l-lactide) (PLA) as membranes and uncoated electro-spun fiber meshes or meshes with a positively charged plasma-polymer coating into rats. After 7, 14 and 56 days, CD68+ and CD163+ macrophages, T lymphocytes, MHC-II+ cells, FBGC, and nestin-stained tissue area as regeneration marker were morphometrically analyzed. FBGC occurrence was primarily determined by material morphology, as their numbers for meshes were 10-fold higher during acute and 50-fold higher during chronic inflammation than for membranes but comparable between uncoated and coated meshes. CD68+ macrophages decreased around and within meshes, while CD163+ macrophages and MHC-II+ cells increased within meshes. T lymphocytes within meshes were higher for coated meshes, suggesting that the peri-implant tissue immunological response is also influenced by surface chemistry. FBGC were predominantly CD68+ and CD163- , and nestin-stained tissue area was negatively correlated with CD68+ monocytes/macrophages numbers and positively correlated with CD163+ macrophages numbers, highlighting differing roles in FBGC formation and tissue regeneration. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2726-2734, 2018.

Granuloma formation associated with patellar tendon necrosis in response to Ethibond confirmed by histopathological examination.

The aim of this study is to describe a case of delayed granuloma formation associated with tendon necrosis in response to Ethibond confirmed by histopathological examination and to review and discuss the related literature. A 40-year-old woman underwent a patellar tendon repair with Krakow-like #5 Ethibond sutures. Four years after the repair, she noticed progressive soreness with knee extension and swelling. An ultrasound examination revealed a proximal partial patellar tendon rupture. Based on these findings, the patient was advised to undergo surgical intervention due to a diagnosis of re-rupture. Tendinosis, fibrosis and necrosis scar tissue surrounding the previous suture were observed and excised, and samples were sent for histopathological and microbiological examination. Stripping of the patellar paratenon was performed. Surprisingly, a giant cell foreign body reaction surrounding the synthetic refringent material, as well as polymorphonuclear cells surrounding the necrotic tendon, was reported.

Foreign Body Giant Cell Reaction to a Proplast/Teflon Interpositional Implant: A Case Report and Literature Review.

After discectomy, interpositional implants (IPIs) are believed to provide temporomandibular joint stability and protect against degenerative joint space remodeling. Alloplastic IPIs gained popularity in the late 1970s because the practice showed early success without donor site morbidity. Unfortunately, these implants were subject to substantial fragmentation resulting in an exuberant foreign body giant cell response that progressively eroded adjacent structures. Most of these alloplastic implants were removed in the years following their recall by the US Food and Drug Administration in 1991, however some remained in circulation. This report describes a case of a failed Proplast/Teflon IPI 27 years after its placement. This case highlights the considerations for managing a patient with a Proplast/Teflon IPI and serves to remind providers that, although increasingly rare, these implants are still present and subject to delayed failure.