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.

Amitriptyline efficacy in decreasing implant-induced foreign body reaction.

Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant-induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin-1ß (IL-1ß) or fibrogenic parameters (collagen, TGF-ß, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7-day-old implants. However, AM was able to downregulate angiogenesis and FBR in 14-day-old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices.

Polymethylmethacrylate-induced foreign body reaction presenting as bilateral parotid lesions: A case report of dermal filler adverse reaction diagnosed on fine needle aspiration.

BACKGROUND: Dermal filler injections are being increasingly used as a non-surgical option for facial cosmetic procedures. However, their use has been implicated in multiple adverse events including immediate, early onset, and late onset complications. AIM: We present a case of dermal filler-induced foreign body reaction presenting as bilateral parotid lesions and diagnosed using fine needle aspiration. CONCLUSION: This case elucidate the risk of delayed adverse events in patients with dermal filler injections and stresses the importance of awareness by patients and providers for such events.

Carbol fuchsin stain enhances detection of poly-(d, l-lactide-co-glycolide) microspheres in exenatide extended-release cutaneous injection-site foreign body reaction.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

Fortuitous Eradication of an Aggressive Basal Cell Carcinoma Via Foreign Body Reaction to a Polyurethane Vacuum-Assisted Closure Sponge.

ABSTRACT: The foreign body reaction (FBR) is a well-documented immune reaction. Much of the literature on FBRs has focused on minimizing this immune response to mitigate the impact on medical implants. Here, we present a case that illustrates a serendipitous oncologic outcome from an FBR. A 54-year-old man presented with an aggressive basal cell carcinoma (BCC). At the first resection, he had broadly positive surgical margins. The surgical wound was temporized with a polyurethane wound vacuum assisted closure (VAC) device. He was lost to follow-up having retained a VAC sponge for a total of 12 weeks. A wide re-resection was performed 7 months after the initial resection. Exhaustive examination of the resected specimen was performed. There was an absence of any BCC, replaced by a widespread chronic FBR to polyurethane VAC sponge particles. This suggests that the foreign body immune response was sufficiently intense to eradicate any remaining BCC. This case illustrates the concept of an FBR as a novel method of local immunotherapy.

Injection of oral medication into the skin confirmed by infrared spectroscopy.

"Skin popping" refers to the practice of injecting drugs, most commonly heroin, subcutaneously or into granulation tissue. Pharmaceutical tablets meant for oral consumption are modified into solutions for injection. Excipients-inactive substances that serve as vehicles for medication-are often not filtered out before injection and result in abscess formation, granulomatous inflammation, and scarring. Common excipients used in the production of pharmaceutical tablets include starch, microcrystalline cellulose, magnesium stearate, silica, and polyvinylpyrrolidone (PVP). Identification of these exogenous materials is valuable in confirming the diagnosis of skin popping, especially when patients may not be forthcoming about their drug use. We present a case of subcutaneous oral medication injection in which PVP and cellulose were identified by Fourier transform infrared spectroscopy. Considering the variable cutaneous manifestations of injection drug abuse, recognition of histopathologic and chemical characteristics of exogenous material from oral medications is helpful for diagnosis and intervention.

Rosai-Dorfman Disease-Like Reaction to Tattoo.

A 47-year-old white man presented with a 14-month history of an asymptomatic 2-cm, slow-growing nodular lesion on his left shin that arose in the background of a black tattoo. An excisional biopsy followed by histological examination revealed a prominent lymphohistiocytic infiltrate, with many large, foamy histiocytic cells containing intact inflammatory cells within their cytoplasm, findings consistent with emperipolesis, a feature typical of Rosai-Dorfman disease (RDD). By immunohistochemistry, S-100 (a marker that is positive in almost all cases of RDD) was negative, arguing against the diagnosis of RDD. In addition, prominent black tattoo pigment was seen in many areas, expanding the differential diagnosis to include an unusual reactive lymphohistiocytic response to the tattoo mimicking RDD. Histologically, RDD shows many plasma cells, neutrophils, lymphocytes, and histiocytes with abundant foamy cytoplasm that contains intact lymphocytes and other cells, a phenomenon described as emperipolesis. A wide variety of cutaneous reactions to tattoos have been described, including tenderness, burning pain, inflammation, and pruritus. However, histologic features suggestive of RDD as a reaction to tattoo pigment have not been previously described and should therefore also be considered as a potential rare reaction pattern to tattoos.

Human Histology and Persistence of Various Injectable Filler Substances for Soft Tissue Augmentation.

An increasing number of soft tissue filler substances have been introduced to the beauty market outside the U.S. which lackexperimental and clinical data in support of their claim. Ten commercially available filler substances were examined for biocompatibility and durability: 0.1 cc of each substance was injected deep intradermally into the volar forearm of one of the authors and observed for clinical reaction and permanence. At 1, 3, 6, and 9 months the test sites were excised, histologically examined, and graded according to foreign body reactions classification. Collagen (Zyplast) was phagocytosed at 6 months and hyaluronic acid (Restylane) at 9 months. PMMA microspheres (Artecoll) had encapsulated with connective tissue, macrophages, and sporadic giant cells. Silicone oil (PMS 350) was clinically inconspicuous but dissipated into the tissue, causing a chronic foreign body reaction. Polylactic acid microspheres (New-Fill) induced a mild inflammatory response and had disappeared clinically at 4 months. Dextran microspheres (Reviderm intra) induced a pronounced foreign body reaction and had disappeared at 6 months. Polymethylacrylate particles (Dermalive) induced the lowest cellular reaction but had disappeared clinically at 6 months. Polyacrylamide (Aquamid) was well tolerated and remained palpable to a lessening degree over the entire testing period. Histologically, it dissipated more slowly and was kept in place through fine fibrous capsules. Polyvinylhydroxide microspheres suspended in acrylamide (Evolution) were well tolerated, slowly diminishing over 9 months. Calcium hydroxylapatite microspheres (Radiance FN) induced almost no foreign body reaction but were absorbed by the skin at 12 months.Host defense mechanisms react differently to the various filler materials, but all substances- resorbable or nonresorbable-appeared to be clinically and histologically safe, although all exhibit undesirable side effects. Since the mechanism of late inflammation or granuloma formation is still unknown, early histological findings are not useful in predicting possible late reactions to filler substances.

Biocompatibility of alumina-based biomaterials-A review.

In today's medicine world, alumina-based biomaterials owing to their excellent biomechanical, and biocompatibility properties play a key role in biomedical engineering. However, the literature still suffers from not having a valid database regarding the protein adsorption and subsequently cell responses to these surfaces. Proteins by adsorption on biomaterials surfaces start interpreting the construction and also arranging the biomaterials surfaces into a biological language. Hence, the main concentration of this review is on the protein adsorption and subsequently cell responses to alumina's surface, which has a wide range biomedical applications, especially in dentistry and orthopedic applications. In the presented review article, the general principles of foreign body response mechanisms, and also the role of adsorbed proteins as key players in starting interactions between cells and alumina-based biomaterials will be discussed in detail. In addition, the essential physicochemical, and mechanical properties of alumina surfaces which significantly impact on proteins and cells responses as well as the recent studies that have focused on the biocompatibility of alumina will be given. An in depth understanding of how the immune system interacts with the surface of alumina could prove the pivotal importance of the biocompatibility of alumina on its success in tissue engineering after implantation in body.

Clinical Features and Management of "Phlebitis-like Abnormal Reaction" After Cyanoacrylate Closure for the Treatment of Incompetent Saphenous Veins.

BACKGROUND: Cyanoacrylate closure for the treatment of incompetent saphenous veins does not cause thermal damage and demonstrates satisfactory outcomes with rapid recovery. However, the characteristics of phlebitis-like abnormal reaction (PLAR), the most common adverse event after cyanoacrylate closure, have not been clarified. Moreover, it differs from typical phlebitis after thermal ablation. The objective of our study is to investigate the clinical features of PLAR after cyanoacrylate closure and to report its management. METHODS: A total of 160 patients with 271 incompetent saphenous veins (great saphenous veins, 201; small saphenous veins, 70) underwent cyanoacrylate closure with the VenaSeal™ system. We defined PLAR as any unusual skin condition that develops suddenly, such as erythema, itching, swelling, and pain/tenderness, over the treated veins several days after cyanoacrylate closure. Oral antihistamines and intravenous dexamethasone were administered to manage PLAR. RESULTS: Of the 271 treated veins, 69 experienced PLAR (25.4%). The mean time of occurrence was 13.6 ± 4.6 days after treatment. The rate of occurrence of erythema, itching, swelling, and pain/tenderness were 92.2%, 91.2%, 66.2%, and 48.5%, respectively. The occurrence of PLAR was significantly higher for great saphenous veins than for small saphenous veins (P < 0.001). Occurrences were more frequent in cases with a suprafascial great saphenous vein of length >10 cm than in cases with a subfascial great saphenous vein (P = 0.001). The proportion of patients who reported swelling decreased by more than half after the administration of oral antihistamine. The pain score on the 10th day also decreased significantly after the administration of antihistamine (P = 0.006). CONCLUSIONS: PLAR must be distinguished from classic phlebitis. We believe that PLAR is a type IV hypersensitivity reaction due to a foreign body, and in our experience, antihistamines or steroids are effective for the prevention and management of PLAR.

Host-specific factors affect the pathogenesis of adverse reaction to metal debris.

BACKGROUND: Adverse Reaction to Metal Debris (ARMD) is a major reason for revision surgeries in patients with metal-on-metal (MoM) hip replacements. Most failures are related to excessively wearing implant producing harmful metal debris (extrinsic factor). As ARMD may also occur in patients with low-wearing implants, it has been suggested that there are differences in host-specific intrinsic factors contributing to the development of ARMD. However, there are no studies that have directly assessed whether the development of ARMD is actually affected by these intrinsic factors. METHODS: We included all 29 patients (out of 33 patients) with sufficient data who had undergone bilateral revision of ASR MoM hips (58 hips) at our institution. Samples of the inflamed synovia and/or pseudotumour were obtained perioperatively and sent to histopathological analysis. Total wear volumes of the implants were assessed. Patients underwent MARS-MRI imaging of the hips preoperatively. Histological findings, imaging findings and total wear volumes between the hips of each patient were compared. RESULTS: The difference in wear volume between the hips was clinically and statistically significant (median difference 15.35 mm3, range 1 to 39 mm3, IQR 6 to 23 mm3) (p < 0.001). The median ratio of total wear volume between the hips was 2.0 (range 1.09 to 10.0, IQR 1.67 to 3.72). In majority of the histological features and in presence of pseudotumour, there were no differences between the left and right hip of each patient (p > 0.05 for all comparisons). These features included macrophage sheet thickness, perivascular lymphocyte cuff thickness, presence of plasma cells, presence of diffuse lymphocytic infiltration and presence of germinal centers. CONCLUSIONS: Despite the significantly differing amounts of wear (extrinsic factor) seen between the sides, majority of the histological findings were similar in both hips and the presence of pseudotumour was symmetrical in most hips. As a direct consequence, it follows that there must be intrinsic factors which contribute to the symmetry of the findings, ie. the pathogenesis of ARMD, on individual level. This has been hypothesized in the literature but no studies have been conducted to confirm the hypothesis. Further, as the threshold of metal debris needed to develop ARMD appears to be largely variable based on the previous literature, it is likely that there are between-patient differences in these intrinsic factors, ie. the host response to metal debris is individual.

Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates.

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

Current Approaches Including Novel Nano/Microtechniques to Reduce Silicone Implant-Induced Contracture with Adverse Immune Responses.

Capsular contracture, which is the pathologic development of fibrous capsules around implants, is a major complication of reconstructive and aesthetic breast surgeries. Capsular contracture can cause implant failure with breast hardening, deformity, and severe pain. The exact mechanisms underlying this complication remain unclear. In addition, anaplastic large cell lymphoma is now widely recognized as a very rare disease associated with breast implants. Foreign body reactions are an inevitable common denominator of capsular contracture. A number of studies have focused on the associated immune responses and their regulation. The present article provides an overview of the currently available techniques, including novel nano/microtechniques, to reduce silicone implant-induced contracture and associated foreign body responses.

Idiosyncratic reaction after injection of polyacrylate - polyalcohol copolymer.

CONTEXT: Polyacrylate-polyalcohol copolymer is a synthetic product, non-biodegradable, with low rate of therapeutic failure and lower incidence of reactions at the site of injection, when compared to biodegradable agents. We report an unprecedent, exuberant and persistent inflammatory reaction following injection of that substance. PATIENT: A 17 years-old patient with vesico-ureteral reflux and complete pyelocaliceal right duplication was submitted to treatment with polyacrylate-polyalcohol copolymer (STING technique). In the seventh day of post-operatory, she presented intense dysuria and hypogastric pain, without laboratory exams alterations; a symptomatic treatment was started. After two months, the symptoms persisted and an ultrasound detected thickening of bladder wall close to the uretero-vesical junction. After that exam, a cystostopic biopsy showed epithelial hyperplasia with increased edema of lamina propria, suggesting an adverse reaction to the polymer. After four months, there was complete remission, but the reflux persisted with the same grade. HYPOTHESIS: This is an unprecedent reaction following injection of this copolymer. The presence of characteristics such as absence of infection, temporal relation between treatment and beginning of symptoms, and detection of epithelial hyperplasia at the local of injection reinforce the hypothesis of association of the substance and adverse reaction. In that patient, important complains motivated early investigation of urinary tract, that confirmed those aspects. Maybe if that reaction had occurred in patients with lower capacity of expression (such as in infants) it would be unnoticed.

Pro - inflammatory cytokines and metalloproteinase activation in polypropylene mesh implant in rat subcutaneous tissue.

AIMS AND OBJECTIVES: Polypropylene meshes have been increasingly adopted for correction of pelvic organ prolapse due to its lower recurrence rate when compared to surgeries without meshes. The study of the interaction of these materials with the host tissue may contribute to the development of materials with best biocompatibility and, consequently, less complication rates. MATERIALS AND METHODS: The present study compares the inflammatory reaction of standard-weight (SW) and lightweight (LW) meshes (72 g/m216g/m2 respectively), implanted in the abdomen of 20 adult rats, which were euthanized in four or 30 days. Quantification of pro-inflammatory markers, IL-1 and TNF-α, and of metalloproteinases, MMP2 and MMP3, were carried out through immunohistochemistry with AxioVision ® software. RESULTS: There were no significant differences in the quantification of IL-1 and TNF-α in LW versus SW meshes. However, IL-1 quantification increased along time (30 days >4 days, p=0.0269). Also, MMP-2 quantification was similar to SW and LW and both presented a significant increase along time (30 days >4 days, p < 0.0001). MMP-3 quantification also showed no difference between the SW and LW groups, but increased along time (30 days >4 days, p=0.02). CONCLUSIONS: Mesh's density did not influence the quantification of pro-inflammatory cytokines IL-1 and TNF-α and metalloproteinases 2 and 3. The increased expression of IL-1, MMP-2 and MMP-3 over time could represent a longstanding inflammatory response after PP mesh implantation. Possibly, the occurrence of adverse events following PP prosthetic implants can be influenced by other factors, not solely related to the amount of implanted material.

Reconstruction of Penile Shaft Defects Following Silicone Injection by Bipedicled Anterior Scrotal Flap.

PURPOSE: Numerous causalities, including attempts at penile augmentation with silicone or paraffin, can lead to extensive circular penile shaft defects. Reconstruction is challenging and skin grafting is a suboptimal option despite its widespread use. We present a surgical technique for penile shaft reconstruction with a bipedicled anterior scrotal flap. MATERIALS AND METHODS: A retrospective data analysis was performed of patients treated for symptomatic penile siliconomas who underwent subsequent penile reconstruction with a bipedicled anterior scrotal flap between 2010 and 2015. The surgical technique is described and depicted in detail. RESULTS: A total of 43 men were treated with radical circular excision of penile siliconomas and extensive shaft defects were reconstructed with a bipedicled anterior scrotal flap. Mean ± SD age was 36.95 ± 11.27 years, mean followup duration was 10.69 ± 9.54 months and mean operative time was 2.53 ± 0.46 hours. The operation proved uneventful in all cases. Only minor complications were observed, such as partial necrosis in 9% of patients, hematoma of the donor site in 12% and partial wound disruption in 19%. The mean patient satisfaction score was 4.37 on a scale of 1 to 5. All patients reported postoperative erection ability and the ability to achieve sexual intercourse. CONCLUSIONS: We present a surgical technique to reconstruct extensive penile shaft defects with an axial scrotal flap, which provides well vascularized coverage with comparable donor skin quality and thickness. The results are associated with minor donor site morbidity, good functional and aesthetic outcomes, and high patient satisfaction.

Dermal fillers: pathophysiology, prevention and treatment of complications.

Dermal fillers are increasingly used for soft tissue augmentation of the face and hands. The widespread use of dermal fillers for rejuvenation has led to a rise in reports of associated complications. Although the majority of complications are mild and transient, serious and long-lasting complications have been observed. This article discusses the key complications including pigmentary changes, hypersensitivity reactions, infections, nodule formation, granulomatous reactions, vascular occlusion and migration of filler material. A thorough literature review was performed in addition to the combined extensive authors' (GP and FA) experience. Complications from fillers are increasingly being recognized and highlighted in the literature partly reflecting the growth in the market. This article provides a comprehensive overview of the filler complications with mechanisms of prevention and treatment per complication. A thorough understanding of the preventative and management strategies for the associated dermal filler complications will help the physician to prepare the patient well, and deal with complications that may arise effectively.

A Nodular Foreign Body Reaction in a Dialysis Patient Receiving Long-term Treatment With Lanthanum Carbonate.

A 63-year-old man with HIV (human immunodeficiency virus) infection and end-stage renal disease, treated with lanthanum carbonate phosphate binder for 4 years, presented with anemia and an upper gastrointestinal bleed. Upper endoscopy revealed a nodular hyperplastic epithelium, with an endoscopic ultrasound confirming hyperechoic material within the nodules. Light microscopy showed collections of histiocytes and multinucleated giant cells containing brown granular cytoplasmic material and extracellular crystalline material, a finding confirmed by electron microscopy. Similar pathologic findings associated with lanthanum exposure have been described recently. In our patient, lanthanum carbonate treatment was withdrawn and gastrointestinal bleeding has since ceased. The patient was exposed to a high amount of lanthanum over a long period, which may explain his adverse reaction. However, other contributing factors, such as competing medications or comorbid conditions, also may have increased his sensitivity to the drug.

Foreign body reaction triggered by cytotoxic T lymphocyte-associated protein 4 blockade 25 years after dermal filler injection.

Foreign body reactions are regularly seen as a late complication of cosmetic treatment with synthetic dermal fillers. Often this foreign body reaction is triggered by a systemic infection, but other systemic triggers are also reported. In this case report, we present a woman in her 60s who was treated with ipilimumab for metastatic melanoma. After two courses of treatment she developed painless facial nodules. A foreign body reaction to dermal fillers was suspected because the patient had received cosmetic treatment with dermal fillers 25 years previously. This reaction was confirmed by excision and histological examination. In the absence of other known triggers, this case revealed immunotherapy (ipilimumab) and subsequent activation of the adaptive immune system as potential triggers of foreign body reactions to dermal fillers. Immunotherapy is increasingly used as anticancer treatment for an increasing number of tumour types. Furthermore, synthetic dermal fillers have frequently been used in the past. Therefore, physicians should be aware of this late-occurring complication of synthetic filler treatment in patients who develop skin lesions during immunotherapy.