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.

Adverse Reactions Associated with Dermal Fillers in the Oral and Maxillofacial Region: A Venezuelan Experience.

BACKGROUND: Dermal facial fillers are increasingly popular. Published reports on the clinical and histopathologic characteristics related to adverse reactions to dermal fillers in the facial region have been relatively well documented. This study adds to the literature on adverse reactions to injected filler in the oral and maxillofacial region in a South American population. METHODS: A retrospective, descriptive cross-sectional study (2019-2020) was performed. The study population was a dermatology service in Venezuela. Clinical and histopathologic features of patients with adverse effects were documented. RESULTS: A total of 35 cases of adverse reactions associated with cosmetic filler procedures were diagnosed during the analyzed period; of these, six cases (17.1%) involved the oral and maxillofacial region. All cases occurred in women. The mean age at diagnosis was 59.3 years (58-73). In three cases, dermal fillers were used in different locations on the face, while three involved the lips. Five patients exhibited adverse reactions to lip filler. All six cases were histopathologically diagnosed as foreign body reactions to injected material. Four and two cases revealed microscopic features compatible with hyaluronic acid and polymethylmethacrylate, respectively. CONCLUSION: Reflecting the dramatic increase in cosmetic procedures with soft tissue fillers, this study contributed by reporting six cases of foreign body reaction involving the oral and maxillofacial region, confirmed with biopsy and histopathology.

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.

An in vitro model that mimics the foreign body response in the peritoneum: Study of the bioadhesive properties of HA-based materials.

A cascade of reactions known as the foreign body response (FBR) follows the implantation of biomaterials leading to the formation of a fibrotic capsule around the implant and subsequent health complications. The severity of the FBR is driven mostly by the physicochemical characteristics of implanted material, the method and place of implantation, and the degree of immune system activation. Here we present an in vitro model for assessing new materials with respect to their potential to induce a FBR in the peritoneum. The model is based on evaluating protein sorption and cell adhesion on the implanted material. We tested our model on the free-standing films prepared from hyaluronan derivatives with different hydrophobicity, swelling ratio, and rate of solubilization. The proteomic analysis of films incubated in the mouse peritoneum showed that the presence of fibrinogen was driving the cell adhesion. Neither the film surface hydrophobicity/hydrophilicity nor the quantity of adsorbed proteins were decisive for the induction of the long-term cell adhesion leading to the FBR, while the dissolution rate of the material proved to be a crucial factor. Our model thus helps determine the probability of a FBR to materials implanted in the peritoneum while limiting the need for in vivo animal testing.

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.

Root cause determination of intraperitoneal catheter obstructions: Insulin amyloid aggregates vs foreign body reaction.

Continuous intraperitoneal insulin infusion, from an implanted insulin pump connected to a catheter that delivers insulin directly to the peritoneal cavity has many clinical advantages for patients with Type 1 diabetes. However, the ongoing incidence of catheter obstructions remains a barrier to the widespread use of this therapy. To date, the root cause of these obstructions remains unknown. Here, a two-year clinical investigation was conducted, along with the development of an animal model to enable a mechanistic investigation into this issue. This novel animal model was able to mimic the catheter obstructions that occur in patients and, fortuitously, at an accelerated rate. This model allowed for independent assessment of each potential cause associated with catheter obstructions to help identify the root cause. Both macroscopic and microscopic analysis were conducted with regards to the onset and progression of catheter obstructions, along with monitoring of insulin delivery. Interestingly, although insulin aggregation occurs in insulin pumps and insulin aggregates were found in some catheter obstructions, insulin is unlikely to be the root cause, since obstructions also occurred in the control groups where only diluent (no insulin) was administered to the animals. Inflammatory cells, different phenotypes of fibroblasts, as well as collagen were observed in all obstructed catheters explanted from the patients and the animals. The presence of these cells and collagen is indicative of a typical foreign body reaction. In addition, the dynamic change in the fibroblasts with respect to morphology, phenotype, and spatial distribution suggests that tissue irritation-mediated epithelial to mesenchymal transition plays a role in catheter obstructions.

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.

Comparison of bone wax and chitosan usage on post-sternotomy bone healing.

BACKGROUND: Sternotomy is a standard approach performed in almost every surgical procedure on the heart and mediastinum. Effective hemostasis of the sternum is required to keep the operative field dry, avoid excessive blood transfusions during surgery, and prevent reoperation due to massive postoperative bleeding, which can further increase morbidity and mortality in patients. Bone wax is a mechanical hemostat commonly used after sternotomy and has been known to affect bone healing, trigger chronic inflammatory reactions, and increase the rate of infection. The application of chitosan, which has intrinsic hemostat ability, as hemostatic material is believed to improve bone healing following sternotomy. This study aimed to compare the effectiveness of bone wax and chitosan on bone healing after sternotomy. METHODS: Median sternotomies were performed on 2 groups of New Zealand White rabbits. Each group of 16 animals received either bone wax or chitosan powder as hemostatic material. The degree of bone healing, the number of foreign-body giant cells, and the number of osteoblasts were evaluated after 6 weeks. RESULTS: Radiographs showed that significantly more animals in the chitosan group had total sternal healing (p = 0.033). Histopathology revealed that the number of foreign-body giant cells was significantly less (p = 0.036) and the number of osteoblasts was significantly greater (p < 0.0001) in the group of animals that received chitosan. CONCLUSION: The use of chitosan as hemostatic material can promote better bone healing compared to bone wax.

Breast reconstruction after complications following breast augmentation with massive filler injections.

INTRODUCTION: Breast filler injections are less commonly used due to their associated complications, such as pain and foreign body reactions. Yet, these fillers are often administered illegally, resulting in aesthetic or life-threatening complications. These are treated by removing the foreign material, and the breasts are reconstructed using silicone implants or autologous tissue/fat injection. PATIENT CONCERNS: Case 1. A 45-year-old woman with polyacrylamide gel injections in both breasts visited our clinic for breast pain and tenderness. Grade I ptosis was observed in each breast, without skin necrosis and discoloration. Case 2. A 51-year-old woman, with unknown breast filler injections, visited our clinic for painful masses. Intraoperatively, massive amounts of foreign material had severely infiltrated the nearby tissues; thus, an immediate breast reconstruction could not be performed. Three months later, severe deformities including shrinkage and irregular breast skin surfaces were observed. DIAGNOSIS: Case 1. Multiple cystic lesions, fluid collection in the retromammary spaces, and diffuse infiltration were observed on mammography, computed tomography, and ultrasonography. Case 2. Multiple cystic lesions, calcified areas, and diffuse infiltrations in the axillae and retromammary spaces were observed on mammography, computed tomography, and ultrasonography. INTERVENTIONS: Case 1. The foreign material was removed and the breasts were reconstructed using silicone implants into subpectoral pocket with acellular dermal matrices (Alloderm, Lipocell Corporation). Case 2. A delayed reconstruction was undertaken using silicone implants covered by latissimus dorsi muscle flaps, 3 months after the foreign material removal. OUTCOMES: Case 1. The foreign material was removed and there were no complications such as foreign body reaction, capsular contracture. Ptosis was corrected and both breasts were symmetric with proper projection. Case 2. Residual foreign material was removed and there were no complications such capsular contracture, implant malposition. CONCLUSION: Massive injections of foreign materials into the breast can cause severe infiltration and associated foreign body reactions. By a near-complete removal of the foreign materials and breast reconstruction using silicone implants, we achieved satisfactory results, without complications such as wound disruption, capsular contracture, and implant malposition.

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.

Complete zwitterionic double network hydrogels with great toughness and resistance against foreign body reaction and thrombus.

Conventional tough hydrogels offer enhanced mechanical properties for load-bearing implants; however, their application is still hindered by a lack of biocompatibility. In this study, we demonstrate a new methodology for developing biocompatible double network (DN) hydrogels by using a responsive amphoteric polymer as a first framework. Tough DN hydrogels were formed by penetrating zwitterionic poly(sulfobetaine acrylamide) (PSBAA) into a swollen poly(lysine acrylamide) (PLysAA) network in an acidic or alkaline solution, and polymerizing under UV irradiation. The DN hydrogels were able to become zwitterionic entirely under physiological conditions, and possess excellent mechanical strength, comparable to conventional DN hydrogels with permanently charged polyelectrolyte frameworks. Additionally, in vitro studies including biofouling, cytotoxicity and hemolysis were conducted to show the superior biocompatibility of the complete zwitterionic DN hydrogels. After the circulation of human blood in tubular DN hydrogels, the zwitterionic DN gels displayed negligible thrombus formation. Furthermore, PLysAA/PSBAA hydrogels were implanted subcutaneously, showing excellent resistance against inflammatory response and long-term capsule formation. This work has presented a new strategy for synthesizing a biocompatible tough DN hydrogel to effectively mitigate the foreign body reaction to render great benefit for the development of biomedical implants.

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.

Glial cell responses on tetrapod-shaped graphene oxide and reduced graphene oxide 3D scaffolds in brain in vitro and ex vivo models of indirect contact.

Brain implants are promising instruments for a broad variety of nervous tissue diseases with a wide range of applications, e.g. for stimulation, signal recording or local drug delivery. Recently, graphene-based scaffold materials have emerged as attractive candidates as neural interfaces, 3D scaffolds, or drug delivery systems due to their excellent properties like flexibility, high surface area, conductivity, and lightweight. To date, however, there is a lack of appropriate studies of the foreign body response, especially by glial cells, towards graphene-based materials. In this work, we investigated the effects of macroscopic, highly porous (>99.9%) graphene oxide (GO) and reduced graphene oxide (rGO) (conductivity ∼1 S m-1) scaffolds with tailorable macro- and microstructure on human astrocyte and microglial cell viability and proliferation as well as expression of neuroinflammation and astrogliosis associated genes in an indirect contact approach. In this in vitro model, as well as ex vivo in organotypic murine brain slices, we could demonstrate that both GO and rGO based 3D scaffolds exert slight effects on the glial cell populations which are the key players of glial scar formation. These effects were in most cases completely abolished by curcumin, a known anti-inflammatory and anti-fibrotic drug that could in perspective be applied to brain implants as a protectant.

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.

Be Aware of a Potential Pitfall in Oral and Dental Specimens: Alvogyl Fibers.

Alvogyl dressing is used to help control hemostasis, foster healing, and prevent complications after certain oral procedures. It is a paste composed of different antiseptic and analgesic substances, and fern-derived Penghawar djambi fibers that have styptic properties. It is claimed to be a resorbable and self-eliminating paste with little complications. However, some studies have demonstrated detrimental effects. We report 3 cases of postextraction nonhealing sockets after Alvogyl dressing. Histologically, they demonstrated residual Alvogyl fibers with foreign body giant cell stromal reaction and complications that were clinically confused with abscess, cysts, infections, and neoplastic lesions. Being unaware of their histopathologic appearances, the foreign bodies in 2 cases were initially confused with fungal hyphae, parasitic ova, vegetable material, and other surgical and nonsurgical materials. To add to our confusion, they were periodic acid-Schiff (PAS) and Grocott methenamine silver (GMS) positive, septated, spiked, and calcified. A history of Alvogyl dressing was retrospectively found. Learning from our mistakes and being aware of the histologic manifestations of Alvogyl fibers, the third case was correctly spotted. Because Alvogyl fibers are undissolvable and are not spontaneously eliminated, they may, if left for a long period, elicit tumefactive foreign body giant cell stromal and epithelial reactions that can be confused with inflammatory, infectious, and neoplastic lesions. Histologically, they can mimic infectious agents and noninfectious materials. Because history of dressing is not always provided, pathologists should be familiar with their histomorphologic features to avoid pitfalls and guide clinicians to correct diagnosis and management. In absence of history, certain histologic features are helpful hints.

Modulation of Foreign Body Reaction against PDMS Implant by Grafting Topographically Different Poly(acrylic acid) Micropatterns.

The surface of poly(dimethylsiloxane) (PDMS) is grafted with poly(acrylic acid) (PAA) layers via surface-initiated photopolymerization to suppress the capsular contracture resulting from a foreign body reaction. Owing to the nature of photo-induced polymerization, various PAA micropatterns can be fabricated using photolithography. Hole and stripe micropatterns ≈100-µm wide and 3-µm thick are grafted onto the PDMS surface without delamination. The incorporation of PAA micropatterns provides not only chemical cues by hydrophilic PAA microdomains but also topographical cues by hole or stripe micropatterns. In vitro studies reveal that a PAA-grafted PDMS surface has a lower proliferation of both macrophages (Raw 264.7) and fibroblasts (NIH 3T3) regardless of the pattern presence. However, PDMS with PAA micropatterns, especially stripe micropatterns, minimizes the aggregation of fibroblasts and their subsequent differentiation into myofibroblasts. An in vivo study also shows that PDMS samples with stripe micropatterns polarized macrophages into anti-inflammatory M2 macrophages and most effectively inhibits capsular contracture, which is demonstrated by investigation of inflammation score, transforming-growth-factor-ß expression, number of macrophages, and myofibroblasts as well as the collagen density and capsule thickness.

Inflammation via myeloid differentiation primary response gene 88 signaling mediates the fibrotic response to implantable synthetic poly(ethylene glycol) hydrogels.

Synthetic hydrogels, such as poly(ethylene glycol) (PEG), are promising for a range of in vivo applications. However, like all non-biological biomaterials, synthetic hydrogels including PEG elicit a foreign body response (FBR). The FBR is thought to be initiated by adsorbed protein that is recognized by and subsequently activates inflammatory cells, notably macrophages, and culminates with fibrotic encapsulation. However, the molecular mechanisms that drive the FBR are not well understood. Toll-like receptors (TLRs) are key receptors that recognize pathogens, but also recognize altered host proteins that display damage-associated molecular patterns (DAMPs). Thus TLRs may play a role in the FBR. Here, we investigated myeloid differentiation primary response gene 88 (MyD88), a signaling adaptor protein that mediates inflammatory cytokine production induced by most TLRs. An in vitro model was used consisting of macrophages cultured on the surface of synthetic hydrogels, specifically PEG, with pre-adsorbed serum proteins. Our in vitro findings demonstrate that MyD88-dependent signaling is the predominant inflammatory pathway in macrophage activation to synthetic hydrogels. When stimulated with TLR agonists to mimic additional DAMPs present in vivo, MyD88-dependent signaling was also the predominant pathway in macrophage activation. An in vivo model of PEG hydrogels implanted subcutaneously in wild-type and MyD88-/- mice also demonstrated that MyD88 is the key contributor to the recruitment of inflammatory cells and formation of the fibrous capsule surrounding the implanted hydrogel. Taken together, findings from this study identify MyD88-mediated inflammation as being a critical pathway involved not only in the inflammatory response, but in formation of the fibrous capsule to PEG hydrogels. STATEMENT OF SIGNIFICANCE: Synthetic hydrogels are promising for in vivo applications but, like all non-biological biomaterials, synthetic hydrogels elicit a foreign body response (FBR). The molecular mechanisms that drive the FBR are not well understood. This work identifies the myeloid differentiation primary response gene 88 (MyD88) as a central mediator to macrophage activation in response to a poly(ethylene glycol) hydrogel with pre-adsorbed proteins in vitro. Moreover, MyD88 was also central to the recruitment of inflammatory cells, which included neutrophils, monocytes, and macrophages, to implanted PEG hydrogels and to fibrous encapsulation. These findings demonstrate that MyD88-mediated inflammation is responsible in part for the formation of the fibrous capsule of the FBR.