Altered Foreign Body Response at the Posterior Surface Compared to the Anterior Surface of Human Silicone Breast Implants.

Soft implantable devices are crucial to optimizing form and function for many patients. However, periprosthetic capsule fibrosis is one of the major challenges limiting the use of implants. Currently, little is understood about how spatial and temporal factors influence capsule physiology and how the local capsule environment affects the implant structure. In this work, we analyzed breast implant capsule specimens with staining, immunohistochemistry, and real-time polymerase chain reaction to investigate spatiotemporal differences in inflammation and fibrosis. We demonstrated that in comparison to the anterior capsule against the convex surface of breast implants, the posterior capsule against the flat surface of the breast implant displays several features of a dysregulated foreign body reaction including increased capsule thickness, abnormal extracellular remodeling, and infiltration of macrophages. Furthermore, the expression of pro-inflammatory cytokines increased in the posterior capsule across the lifespan of the device, but not in the anterior capsule. We also analyzed the surface oxidation of breast explant samples with XPS analysis. No significant differences in surface oxidation were identified either spatially or temporally. Collectively, our results support spatiotemporal heterogeneity in inflammation and fibrosis within the breast implant capsule. These findings presented here provide a more detailed picture of the complexity of the foreign body reaction surrounding implants destined for human use and could lead to key research avenues and clinical applications to treat periprosthetic fibrosis and improve device longevity.

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.

Oral formulation of Wnt inhibitor complex reduces inflammation and fibrosis in intraperitoneal implants in vivo.

The use of implantable biomaterials to replace physiological and anatomical functions has been widely investigated in the clinic. However, the selection of biomaterials is crucial for long-term function, and the implantation of certain biomaterials can cause inflammatory and fibrotic processes, triggering a foreign body reaction that leads to loss of function and consequent need for removal. Specifically, the Wnt signaling pathway controls the healing process of the human body, and its dysregulation can result in inflammation and fibrosis, such as in peritoneal fibrosis. Here, we assessed the effects of daily oral administration of a Wnt pathway inhibitor complex (CD:LGK974) to reduce the inflammatory, fibrotic, and angiogenic processes caused by intraperitoneal implants. CD:LGK974 significantly reduced the infiltration of immune cells and release of inflammatory cytokines in the implant region compared to the control groups. Furthermore, CD:LGK974 inhibited collagen deposition and reduced the expression of pro-fibrotic α-SMA and TGF-ß1, confirming fibrosis reduction. Finally, the CD:LGK974 complex decreased VEGF levels and both the number and area of blood vessels formed, suggesting decreased angiogenesis. This work introduces a potential new application of the Wnt inhibitor complex to reduce peritoneal fibrosis and the rejection of implants at the intraperitoneal site, possibly allowing for longer-term functionality of existing clinical biomaterials.

Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation.

Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.

ST2 deletion accelerates inflammatory-angiogenesis and remodeling in subcutaneous implants in mice.

Implantation of biomedical/synthetic devices to replace and/or repair biological tissues very often induces an adverse healing response (scarce angiogenesis, excessive collagen deposition) which is detrimental to implant functionality and integration to host tissue. Interleukin-33/ST2 axis (IL-33/ST2) has been shown to modulate angiogenic and remodeling processes in several types of injuries. However, its effects on these processes after implantation of synthetic matrix have not been reported. Using synthetic matrix of polyether-polyurethane implanted subcutaneously in mice lacking ST2 receptor (ST2/KO), we characterized neovascularization and matrix remodeling in the fibrovascular tissue induced by the implants. Tissue accumulation was increased inside and around the implants in KO implants relative to the wild type (WT). More intense proliferative activity, using CDC 47 marker, was observed in KO implants compared with that of WT implants. Angiogenesis, using two endothelial cell markers, Von Willebrand Factor (VWF) and vascular endothelial cell VE cadherin and hemoglobin content, increased in implants of KO mice relative to control WT. Remodeling of the newly formed fibrovascular tissue (soluble collagen and PicroSirius Red-stained histological sections) showed predominance of type 1 collagen in ST2-KO implants versus type 3 in control implants. The number of positive cells for caspase-3, apoptotic marker, decreased in ST2 group. Our findings evidenced a role of IL-33/ST2 axis in restraining blood vessel formation and regulating the pattern of matrix remodeling in the fibrovascular tissue induced by synthetic implants. Intervention in this cytokine complex holds potential to accelerate integration of biomaterial and host tissue by improving blood supply and matrix remodeling.

Implant Fibrosis and the Underappreciated Role of Myofibroblasts in the Foreign Body Reaction.

Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell? We will here take the position of a fibrosis researcher (which, coincidentally, we are) to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses.

Profiles of inflammation factors and inflammatory pathways around the peri-miniscrew implant.

BACKGROUND: Peri-miniscrew implant is a temporary assistant armamentarium for the treatment of severe malocclusion and complex tooth movement, the inflammation around it is the main reason for the failure of orthodontic treatment due to the implant loosening and falling out. Inflammation around the peri-miniscrew implant is associated with the release of pro-inflammatory cytokines. These pro-inflammatory cytokines, in turn, recruit immune cells (such as macrophages, dendritic cells, T cells, and B cells), which can produce and release inflammatory biomarkers, regulate the interaction between immune cells, periodontal ligament cells, osteoblasts, and so on. However, there is currently no effective clinical treatment plan to prevent inflammation around implants. PURPOSE: To investigate the potentially essential factors in the inflammatory response around the peri-miniscrew implant and explore the signaling pathways involved. METHODS: Here, we review the studies focused on inflammatory biomarkers (Interleukins, tumor necrosis factor-α (TNF-α), receptor activator of NF-κB ligand (RANKL), matrix metalloproteinases (MMPs), and cellular adhesion molecules (CAMs)) in peri-miniscrew implant crevicular fluid (PMICF), as well as inflammatory signaling pathways (Wnt5a, JNK, Erk1/2, NF-κBp65 and TAB/TAK) in periodontal cells from 1998 to 2020. RESULTS: A literature search revealed TLR-2, TLR-4, LOX-1, and BMPs are involved in regulating ILs (IL-1ß, IL-6, IL-8, and IL-17), TNF-α, RANKL, MMP-2, MMP-9 expression via JNK, Erk1/2, Wnt5a, NF-κBp65, OPN, and TAB/TAK signaling pathways. Among them, IL-1ß and IL-6 are the critical inflammation factors in the signaling pathways inducing the inflammatory reaction surrounding implants. Besides, CAM-1 was also regulated by MMP-9 and IL-17. CONCLUSION: There are considerable potential factors involving regulating inflammatory biomarkers on downstream signaling pathways in peri-minisrew implant crevicular fluid. CLINICAL SIGNIFICANCE: This review provides the substantiation of these cell factors and signaling pathways around peri-miniscrew implants, proposes more practical clinical therapeutic ideas and schemes for improving the stability and clinical efficacy of peri-miniscrew implants.

A peritoneal defect covered by intraperitoneal mesh prosthesis effects an increased and distinctive foreign body reaction in a minipig model.

BACKGROUND: The incidence of incisional hernia is with up to 30% one of the frequent long-term complication after laparotomy. After establishing minimal invasive operations, the laparoscopic intraperitoneal onlay mesh technique (lap. IPOM) was first described in 1993. Little is known about the foreign body reaction of IPOM-meshes, which covered a defect of the parietal peritoneum. This is becoming more important, since IPOM procedure with peritoneal-sac resection and hernia port closing (IPOM plus) is more frequently used. METHODS: In 18 female minipigs, two out of three Polyvinylidene-fluoride (PVDF) -meshes (I: standard IPOM; II: IPOM with modified structure [bigger pores]; III: IPOM with the same structure as IPOM II + degradable hydrogel-coating) were placed in a laparoscopic IPOM procedure. Before mesh placement, a 2x2cm peritoneal defect was created. After 30 days, animals were euthanized, adhesions were evaluated by re-laparoscopy and mesh samples were explanted for histological and immunohistochemichal investigations. RESULTS: All animals recovered after implantation and had no complications during the follow-up period. Analysing foreign body reaction, the IPOM II mesh had a significant smaller inner granuloma, compared to the other meshes (IPOM II: 8.4 µm ± 1.3 vs. IPOM I 9.1 µm ± 1.3, p < 0.001). The degradable hydrogel coating does not prevent adhesions measured by Diamond score (p = 0.46). A peritoneal defect covered by a standard or modified IPOM mesh was a significant factor for increasing foreign body granuloma, the amount of CD3+ lymphocytes, CD68+ macrophages and decrease of pore size. CONCLUSION: A peritoneal defect covered by IPOM prostheses leads to an increased foreign body reaction compared to intact peritoneum. Whenever feasible, a peritoneal defect should be closed accurately before placing an IPOM-mesh to avoid an excessive foreign body reaction and therefore inferior biomaterial properties of the prosthesis.

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.

Implant-induced inflammatory angiogenesis is up-regulated in obese mice.

The damaging effects of obesity extend to multiple pre-existing tissue/organs. However, the influence of this condition on key components (inflammation and angiogenesis) of fibrovascular connective proliferating tissue, essential in repair processes, has been neglected. Our objective in this study was to investigate whether obesity would influence inflammatory-angiogenesis induced by synthetic matrix of polyether-polyurethane implanted subcutaneously in high-fat-fed obese C57/BL6 mice. Fourteen days after implantation, the inflammatory and angiogenic components of the newly formed tissue intra-implant were evaluated. The pro-inflammatory enzyme activities, myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAG), the levels of TNF-α, CXCL1/KC and CCL2 and NF-κB transcription factor were examined. Angiogenesis was determined by morphometric analysis of implant blood vessels, intra-implant levels of hemoglobin content, VEGF levels, and western blot for VEGFR2. All inflammatory and angiogenic markers were increased in the implants of obese mice compared with their non-obese counterparts. Similarly, activation of the NF-κB pathway and phosphorylation of VEGFR2 were higher in implants of obese mice (1.60 ± 0.28 Np65/Cp65; 0.96 ± 0.08 p-VEGFR2/VEGFR2-T) compared with implants of non-obese animals (1.40 ± 0.14; 0.49 ± 0.08). These observations suggest that obesity exerts critical role in sponge-induced inflammatory-angiogenesis, possibly by activating fibrovascular components in the inflamed microenvironment. Thus, this pathological condition causes damage not only to pre-existing tissues/organs but also to newly formed proliferating fibrovascular tissue. This is relevant to the development of therapeutic approaches to improve healing processes in patients with obesity.

Hyaluronic acid induced foreign body reaction mimicking neoplastic parotid cytology.

Masses near the angle of the mandible containing extracellular matrix or mucin on cytology raise concern for various benign and malignant parotid gland neoplasms. Here a 76-year-old female with a history of cosmetic hyaluronic acid (HA) filler injections presented with a painless 6 mm left sided facial mass. Injection of hyaluronidase into the mass had failed to cause regression, raising concern for a neoplastic process. Fine-needle aspiration (FNA) showed amorphous, mucinous/extracellular matrix-like material in a background of numerous histiocytes and occasional multinucleated giant cells, consistent with a foreign body giant cell reaction to HA. This uncommon reaction to HA filler creates previously unrecognized diagnostic pitfalls because of its resemblance on FNA to the extracellular matrix or mucin found in many salivary neoplasms.

Role of dendritic cells in the host response to biomaterials and their signaling pathways.

Strategies to enhance, inhibit, or qualitatively modulate immune responses are important for diverse biomedical applications such as vaccine adjuvant, drug delivery, immunotherapy, cell transplant, tissue engineering, and regenerative medicine. However, the clinical efficiency of these biomaterial systems is affected by the limited understanding of their interaction with complex host microenvironments, for example, excessive foreign body reaction and immunotoxicity. Biomaterials and biomedical devices implanted in the body may induce a highly complicated and orchestrated series of host responses. As macrophages are among the first cells to infiltrate and respond to implanted biomaterials, the macrophage-mediated host response to biomaterials has been well studied. Dendritic cells (DCs) are the most potent antigen-presenting cells that activate naive T cells and bridge innate and adaptive immunity. The potential interaction of DCs with biomaterials appears to be critical for exerting the function of biomaterials and has become an important, developing area of investigation. Herein, we summarize the effects of the physicochemical properties of biomaterials on the immune function of DCs together with their receptors and signaling pathways. This review might provide a complete understanding of the interaction of DCs with biomaterials and serve as a reference for the design and selection of biomaterials with particular effects on targeted cells. STATEMENT OF SIGNIFICANCE: Biomaterials implanted in the body are increasingly applied in clinical practice. The performance of these implanted biomaterials is largely dependent on their interaction with the host immune system. As antigen-presenting cells, dendritic cells (DCs) directly interact with biomaterials through pattern recognition receptors (PRRs) recognizing "biomaterial-associated molecular patterns" and generate a battery of immune responses. In this review, the physicochemical properties of biomaterials that regulate the immune function of DCs together with their receptors and signaling pathways of biomaterial-DC interactions are summarized and discussed. We believe that knowledge of the interplay of DC and biomaterials may spur clinical translation by guiding the design and selection of biomaterials with particular effects on targeted cell for tissue engineering, vaccine delivery, and cancer therapy.

An in vitro model mimics the contact of biomaterials to blood components and the reaction of surrounding soft tissue.

The therapeutic efficacy of a medical product after implantation depends strongly on the host-initiated fibrotic response (foreign body reaction). For novel biomaterials, it is of high relevance to understand this fibrotic process. As an alternative to in vivo studies, in vitro models mimic parts of the whole foreign body reaction. Aim of this study was to develop a wound model with key cells and matrix proteins in coculture. This approach combined blood components such as primary macrophages in a plasma-derived fibrin hydrogel, directly exposed to reference biomaterials (PTFE, glass, titanium). The soft tissue reaction is resembled by integrating fibroblasts in a collagen or a fibrin matrix. Those two experimental setups were conducted to show whether a long-term in vitro culture of 13 days is feasible. The response to reference biomaterials was assessed by multi-parametric analyses, comprising molecular profiling (cytokines, collagen I and ß-actin) and tissue remodeling (cell adherence, histological structure, tissue deposition). Polytetrafluorethylene (PTFE) and titanium were tested as references to correlate the in vitro evaluation to previous in vivo studies. Most striking, both model setups evaluated references' fibrotic characteristics as previously reported by in vivo studies. STATEMENT OF SIGNIFICANCE: We present a test platform applied for assessments on the foreign body reaction to biomaterials. This test system consists of blood components - macrophages and plasma-derived fibrin - as well as fibroblasts and collagen, generating a three-dimensional wound microenvironment. By this modular approach, we achieved a suitable test for long-term studies and overcame the limited short-term stability of whole blood tests. In contrast to previous models, macrophages' viability is maintained during the extended culture period and excels the quality of the model. The potential to evaluate a foreign body reaction in vitro was demonstrated with defined reference materials. This model system might be of high potential as a screening platform to identify novel biomaterial candidates.

The Protective Effect of a Topical Mucin Secretagogue on Ocular Surface Damage Induced by Airborne Carbon Black Exposure.

Purpose: Exposure to airborne particulate matter can induce ocular surface damage and inflammation. We evaluated the effects of a topical mucin secretagogue on the mitigation of ocular surface damage induced by exposure to airborne carbon black (CB). Methods: Sprague-Dawley rats were exposed to ambient CB for 2 hours twice daily for 5 days. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage. Serum immunoglobulin (Ig) G and IgE levels and the sizes of cervical lymph nodes were also measured. The expressions of interleukin (IL)-4, IL-17, and interferon (IFN)-γ were measured by Western blot analysis. Diquafosol tetrasodium was instilled six times a day for 5 days, and the extent of ocular surface damage was evaluated. Results: After exposure to airborne CB, the median corneal staining score and LDH activity were significantly increased. Serum IgG and IgE levels and the sizes of cervical lymph nodes were also significantly increased. Additionally, the expression of IL-4 and IFN-γ was elevated in the anterior segment of the eyeball. Furthermore, the expression of IL-4, IL-17, and IFN-γ was elevated in the cervical lymph nodes. When exposed to airborne black carbon, topical diquafosol tetrasodium significantly increased tear MUC5AC concentration and decreased tear LDH activity. Conclusions: Exposure to airborne CB induced ocular surface damage and increased proinflammatory cytokines in the eyes and cervical lymph nodes. Topical mucin secretagogues seem to have a protective effect on the ocular surface against exposure to airborne particulate matters.

Tissue reaction after subcutaneous implants of a new material composed of ethylene-vinyl acetate and starch for future use as a biomaterial.

This study aimed to evaluate the tissue reaction of ethylene-vinyl acetate (EVA) in 4 different compositions and processing: EVA foamed at high pressure with ultrasound (EVACU); EVA with 15% starch foamed at high pressure with ultrasound (EVAMCU); EVA with 15% starch foamed at high pressure without ultrasound and EVA foamed at high pressure without ultrasound as future use as a porous scaffold. Scanning electron microscopy images showed the influence of starch, reducing the diameter of pores. The number of open pores was also reduced with the addition of starch. The ultrasound applied during the manufacturing of composites does not affect these characteristics. Eighteen rats were used to test the tissue reaction of materials and PTFE (polytetrafluoroethylene), proven biocompatible material. After 7, 15, and 60 days of surgery, the materials were removed and processed for microscopic evaluation and counting of the inflammatory infiltrate. The data shows inflammatory reaction similar to PTFE. However, in the quantitative analysis at 60 days, the EVACU and EVAMCU showed less quantity of mononuclear cells (p < 0.05). Thus, the results suggest that the use of ultrasound in the production method (EVA) seems to have improved cell behavior regarding the reduction of infiltration over the period, with tissue response equivalent to the PTFE. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 400-407, 2019.

Improved biocompatibility of profiled sutures through lower macrophages adhesion.

The biocompatibility of a textile implant is determined by various parameters, such as material composition and surface chemistry. However, little is known about the influence of geometry of sutures on biocompatibility. To elucidate this factor we focused on geometry-modification resulting in ultrafine polyethylene terephthalate (UFPET) suture and a snowflake like shaped polyvenylidenfluorid (PVDF) suture. Forty-eight rats were divided into two observation periods. In each rat 3 out of 4 sutures (profiled UFPET, snowflake-like profiled PVDF, reference Prolene and Mersilene suture) were randomly placed into the subcutaneous tissue. Rats were euthanized after 7 and 21 days and samples were explanted. Foreign body granuloma was measured and expression of CD68, TUNEL, Ki-67 and Collagen I/III ratio were determined. The profiled (snowflake) suture showed a significantly smaller FBG in comparison to standard sutures (p < 0.001). Both modified sutures showed a significant lower tissue remodeling by Ki-67 and TUNEL expression (p < 0.03). Furthermore, profiled sutures caused a lower inflammatory reaction expressed in a significant lower amount of CD68 positive macrophages after 21 days (p < 0.001). Modifications of suture geometry alter the foreign body granuloma and the inflammatory reaction. Therefore, profiled sutures might be a promising approach to improve biocompatibility of textile mesh prosthesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1772-1778, 2019.

Molecular pathology of adverse local tissue reaction caused by metal-on-metal implants defined by RNA-seq.

Total hip arthroplasty (THA) alleviates hip pain and improves joint function. Current implant design permits long-term survivorship of THAs, but certain metal-on-metal (MoM) articulations can portend catastrophic failure due to adverse local tissue reactions (ALTR). Here, we identified biological and molecular differences between periacetabular synovial tissues of patients with MoM THA failure undergoing revision THA compared to patients undergoing primary THA for routine osteoarthritis (OA). Analysis of tissue biopsies by RNA-sequencing (RNA-seq) revealed that MoM patient samples exhibit significantly increased expression of immune response genes but decreased expression of genes related to extracellular matrix (ECM) remodeling. Thus, interplay between local tissue inflammation and ECM degradation may account for the pathology and compromised clinical outcomes in select patients with MoM implants. We conclude that adverse responses of host tissues to implant materials result in transcriptomic modifications in patients with MoM implants that permit consideration of strategies that could mitigate ECM damage.

Characterization of the T-cell response to polypropylene mesh in women with complications.

BACKGROUND: Polypropylene mesh is used widely for surgical treatment of pelvic organ prolapse and stress urinary incontinence. Although these surgeries demonstrate favorable functional and anatomic outcomes, their use has been limited by complications, the 2 most common being exposure and pain. Growing evidence suggests that T lymphocytes play a critical role in the regulation of the host response to biomaterials. OBJECTIVE: The purpose of this study was to define and characterize the T-cell response and to correlate the response to collagen deposition in fibrotic capsules in mesh tissue complexes that are removed for the complications of pain vs exposure. STUDY DESIGN: Patients who were scheduled to undergo a surgical excision of mesh for pain or exposure at Magee-Women's Hospital were offered enrollment. Forty-two mesh-vagina tissue complexes were removed for the primary complaint of exposure (n=24) vs pain (n=18). Twenty-one patients agreed to have an additional vaginal biopsy away from the site of mesh that served as control tissue. T cells were examined via immunofluorescent labeling for cell surface markers CD4+ (Th), CD8+ (cytotoxic) and foxp3 (T-regulatory cell). Frozen sections were stained with hematoxylin-eosin for gross morphologic condition and picrosirius red for collagen fiber analysis. Interrupted sodium-dodecyl sulfate gel electrophoresis was used to quantify the content of collagens type I and III, and the collagen III/I ratio. Transforming growth factor-ß and connective tissue growth factor, which are implicated in the development of fibrosis, were measured via enzyme-linked immunosorbent assays. Data were analyzed with the Student's t tests, mixed effects linear regression, and Spearman's correlation coefficients. RESULTS: Demographic data were not different between groups, except for body mass index, which was 31.7 kg/m2 for the exposure group and 28.2 kg/m2 for pain (P=.04). Tissue complexes demonstrated a marked, but highly localized, foreign body response. We consistently observed a teardrop-shaped fibroma that encapsulated mesh fibers in both pain and exposure groups, with the T cells localized within the tip of this configuration away from the mesh-tissue interface. All 3 T-cell populations were significantly increased relative to control: CD4+ T helper (P<.001), foxp3+ T regulatory (P<.001), and CD8+ cytotoxic T cell (P=.034) in the exposure group. In the pain group, only T-helper (P<.001) and T-regulatory cells (P<.001) were increased, with cytotoxic T cells (P=.520) not different from control. Picrosirius red staining showed a greater area of green (thin) fibers in the exposure group (P=.025) and red (thick) fibers in the pain group (P<.001). The ratio of area green/(yellow + orange + red) that represented thin vs thick fibers was significantly greater in the exposure group (P=.005). Analysis of collagen showed that collagen type I was increased by 35% in samples with mesh complications (exposure and pain) when compared with control samples (P=.043). Strong correlations between the profibrosis cytokine transforming growth factor-ß and collagen type I and III were found in patients with pain (r≥0.833; P=.01) but not exposure (P>.7). CONCLUSION: T cells appear to play a critical role in the long-term host response to mesh and may be a central pathway that leads to complications. The complexity of this response warrants further investigation and has the potential to broaden our understanding of mesh biology and clinical outcomes.

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.

On the use of Parylene C polymer as substrate for peripheral nerve electrodes.

Parylene C is a highly flexible polymer used in several biomedical implants. Since previous studies have reported valuable biocompatible and manufacturing characteristics for brain and intraneural implants, we tested its suitability as a substrate for peripheral nerve electrodes. We evaluated 1-year-aged in vitro samples, where no chemical differences were observed and only a slight deviation on Young's modulus was found. The foreign body reaction (FBR) to longitudinal Parylene C devices implanted in the rat sciatic nerve for 8 months was characterized. After 2 weeks, a capsule was formed around the device, which continued increasing up to 16 and 32 weeks. Histological analyses revealed two cell types implicated in the FBR: macrophages, in contact with the device, and fibroblasts, localized in the outermost zone after 8 weeks. Molecular analysis of implanted nerves comparing Parylene C and polyimide devices revealed a peak of inflammatory cytokines after 1 day of implant, returning to low levels thereafter. Only an increase of CCL2 and CCL3 was found at chronic time-points for both materials. Although no molecular differences in the FBR to both polymers were found, the thick tissue capsule formed around Parylene C puts some concern on its use as a scaffold for intraneural electrodes.