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.

Bio-inspired poly-DL-serine materials resist the foreign-body response.

Implantation-caused foreign-body response (FBR) is a commonly encountered issue and can result in failure of implants. The high L-serine content in low immunogenic silk sericin, and the high D-serine content as a neurotransmitter together inspire us to prepare poly-DL-serine (PSer) materials in mitigating the FBR. Here we report highly water soluble, biocompatible and easily accessible PSer hydrogels that cause negligible inflammatory response after subcutaneous implantation in mice for 1 week and 2 weeks. No obvious collagen capsulation is found surrounding the PSer hydrogels after 4 weeks, 3 months and 7 months post implantation. Histological analysis on inflammatory cytokines and RNA-seq assay both indicate that PSer hydrogels show low FBR, comparable to the Mock group. The anti-FBR performance of PSer hydrogels at all time points surpass the poly(ethyleneglycol) hydrogels that is widely utilized as bio-inert materials, implying the potent and wide application of PSer materials in implantable biomaterials and biomedical devices.

Host-biomaterial interactions in mesh complications after pelvic floor reconstructive surgery.

Polypropylene (PPL) mesh is widely used in pelvic floor reconstructive surgery for prolapse and stress urinary incontinence. However, some women, particularly those treated using transvaginal PPL mesh placement for prolapse, experience intractable pain and mesh exposure or extrusion. Explanted tissue from patients with complications following transvaginal implantation of mesh is typified by a dense fibrous capsule with an immune cell-rich infiltrate, suggesting that the host immune response has a role in transvaginal PPL mesh complications through the separate contributions of the host (patient), the biological niche within which the material is implanted and biomaterial properties of the mesh. This immune response might be strongly influenced by both the baseline inflammatory status of the patient, surgical technique and experience, and the unique hormonal, immune and microbial tissue niche of the vagina. Mesh porosity, surface area and stiffness also might have an effect on the immune and tissue response to transvaginal mesh placement. Thus, a regulatory pathway is needed for mesh development that recognizes the roles of host and biological factors in driving the immune response to mesh, as well as mandatory mesh registries and the longitudinal surveillance of patients.

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.

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing.

Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.

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.

Modulating the foreign body response of implants for diabetes treatment.

Diabetes Mellitus is a group of diseases characterized by high blood glucose levels due to patients' inability to produce sufficient insulin. Current interventions often require implants that can detect and correct high blood glucose levels with minimal patient intervention. However, these implantable technologies have not reached their full potential in vivo due to the foreign body response and subsequent development of fibrosis. Therefore, for long-term function of implants, modulating the initial immune response is crucial in preventing the activation and progression of the immune cascade. This review discusses the different molecular mechanisms and cellular interactions involved in the activation and progression of foreign body response (FBR) and fibrosis, specifically for implants used in diabetes. We also highlight the various strategies and techniques that have been used for immunomodulation and prevention of fibrosis. We investigate how these general strategies have been applied to implants used for the treatment of diabetes, offering insights on how these devices can be further modified to circumvent FBR and fibrosis.

Uniform 40-µm-pore diameter precision templated scaffolds promote a pro-healing host response by extracellular vesicle immune communication.

Implanted porous precision templated scaffolds (PTS) with 40-µm spherical pores reduce inflammation and foreign body reaction (FBR) while increasing vascular density upon implantation. Larger or smaller pores, however, promote chronic inflammation and FBR. While macrophage (MØ) recruitment and polarization participates in perpetuating this pore-size-mediated phenomenon, the driving mechanism of this unique pro-healing response is poorly characterized. We hypothesized that the primarily myeloid PTS resident cells release small extracellular vesicles (sEVs) that induce pore-size-dependent pro-healing effects in surrounding T cells. Upon profiling resident immune cells and their sEVs from explanted 40-µm- (pro-healing) and 100-µm-pore diameter (inflammatory) PTS, we found that PTS pore size did not affect PTS resident immune cell population ratios or the proportion of myeloid sEVs generated from explanted PTS. However, quantitative transcriptomic assessment indicated cell and sEV phenotype were pore size dependent. In vitro experiments demonstrated the ability of PTS cell-derived sEVs to stimulate T cells transcriptionally and proliferatively. Specifically, sEVs isolated from cells inhabiting explanted 100 µm PTS significantly upregulated Th1 inflammatory gene expression in immortalized T cells. sEVs isolated from cell inhabiting both 40- and 100-µm PTS upregulated essential Treg transcriptional markers in both primary and immortalized T cells. Finally, we investigated the effects of Treg depletion on explanted PTS resident cells. FoxP3+ cell depletion suggests Tregs play a unique role in balancing T cell subset ratios, thus driving host response in 40-µm PTS. These results indicate that predominantly 40-µm PTS myeloid cell-derived sEVs affect T cells through a distinct, pore-size-mediated modality.

Cyclophosphamide modulated the foreign body inflammatory reaction in tilapia (Oreochromis niloticus).

In order to understand events and mechanisms present in the pathophysiology of tilapia's chronic inflammation and based on the immunomodulatory activity attributed to cyclophosphamide which is widely used to suppress immune responses in human medicine, the present study investigated the effects of cyclophosphamide (CYP) treatment on the modulation of foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus) with round glass coverslip implanted in the subcutaneous tissue (9 mm of diameter). Forty tilapia (151 ± 10,2 g) were randomly distributed in 5 aquariums (n = 8) with a capacity of 250 L of water each, to compose two treatments (sampled 3 and 6 days post-implantation): implanted/untreated (control) and implanted/treated with 200 mg of CYP kg-1 of b.w., through i.p. route. A fifth group (n = 8) was sampled without any stimulus (naive) to obtain reference values. CYP-treated tilapia showed decrease in macrophage accumulation, giant cell formation and Langhans cells on the glass coverslip when compared to control fish. The treatment with CYP resulted in decrease of leukocyte and thrombocyte counts. Decrease in alpha-2-macroglobulin, ceruloplasmin, albumin and transferrin levels, as well as increase in haptoglobin, complement C3 and apolipoprotein A1 were observed in tilapias during foreign body inflammation. Blood levels of complement C3, alpha-2-macroglobulin, ceruloplasmin and transferrin were modulated by treatment with CYP. Therefore, the treatment with 200 mg of CYP kg-1 of b.w. in tilapia resulted in an anti-inflammatory effect by suppressing the dynamics between leukocytes in the bloodstream and macrophage accumulation with giant cell formation in the inflamed focus, as well as by modulating APPs during foreign body reaction.

Rotator cuff repair with biological graft augmentation causes adverse tissue outcomes.

Background and purpose - Biological patches can be used to augment rotator cuff tendon repair in an attempt to improve healing and reduce rates of re-rupture. However, little is known about the in vivo tissue response to these patches. We assessed native rotator cuff tissue response after surgical repair and augmentation with 2 commercially available extracellular matrix (ECM) patches. Patients and methods - Patients underwent a rotator cuff repair augmented with either GraftJacket (Wright Medical), Permacol (Zimmer Biomet), or no patch (Control), applied using an onlay technique. A sample of supraspinatus tendon was collected intraoperatively and 4 weeks post-surgery, using ultrasound-guided biopsy. Histology and immunohistochemistry were performed on all samples. Results - The Permacol group (n = 3) and GraftJacket group (n = 4) demonstrated some changes in native tendon ECM compared with the control group (n = 3). Significant disruption of the extracellular matrix of the repaired native supraspinatus, underlying both patches, was observed. The patches did not generally increase cellularity, foreign body giant cell count, or vascularity compared to the control group. 1 patient in the Permacol group had an adverse tissue immune response characterized by extensive infiltration of IRF5+, CD68+, and CD206+ cells, suggesting involvement of macrophages with a pro-inflammatory phenotype. No significant differences in protein expression of CD4, CD45, CD68, CD206, BMP7, IRF5, TGFß, and PDPN were observed among the groups. Interpretation - Histological and immunohistochemical analysis of native tendon tissue after patch augmentation in rotator cuff repair raises some concerns about a lack of benefit and potential for harm from these materials.

Switch of macrophage fusion competency by 3D matrices.

Foreign body reaction reflects the integration between biomaterials and host cells. At the implantation microenvironment, macrophages usually fuse into multinuclear cells, also known as foreign body giant cells, to respond to the biomaterial implants. To understand the biomaterial-induced macrophage fusion, we examined whether biomaterial alone can initiate and control the fusion rate without exogenous cytokines and chemicals. We introduced a collagen-based 3D matrix to embed Raw264.7 cell line and primary rat bone marrow-derived macrophages. We found the biomaterial-stimuli interacted regional macrophages and altered the overall fusogenic protein expressions to regulate the macrophage fusion rate. The fusion rate could be altered by modulating the cell-matrix and cell-cell adhesions. The fused macrophage morphologies, the nuclei number in the fused macrophage, and the fusion rates were matrix dependent. The phenomena were also observed in the in vivo models. These results suggest that the biomaterial-derived stimuli exert similar functions as cytokines to alter the competency of macrophage fusion as well as their drug sensitivity in the biomaterial implanted tissue environment. Furthermore, this in vitro 3D-matrix model has the potential to serve as a toolbox to predict the host tissue response on implanted biomaterials.

A new method for three-dimensional immunofluorescence study of the cochlea.

Visualisation of cochlear histopathology in three-dimensions has been long desired in the field of hearing research. This paper outlines a technique that has made this possible and shows a research application in the field of hearing protection after cochlear implantation. The technique utilises robust immunofluorescent labelling followed by effective tissue clearing and fast image acquisition using Light Sheet Microscopy. We can access the health of individual components by immunofluorescent detection of proteins such as myosin VIIa to look at cochlear hair cells, NaKATPase alpha 3 to look at spiral ganglion neurons, and IBA1 to look at macrophages within a single cochlea, whilst maintaining the integrity of fine membranous structures and keeping the cochlear implant in place. This allows the tissue response to cochlear implantation to be studied in detail, including the immune reaction to the implant and the impact on the structure and health of neural components such as hair cells. This technique reduces time and labour required for sectioning of cochleae and can allow visualisation of cellular detail. Use of image analysis software allows conversion of high-resolution image stacks into three-dimensional interactive data sets so volumes and numbers of surfaces can be measured. Immunofluorescent whole cochlea labelling and Light Sheet Microscopy have the capacity to be applied to many questions in hearing research of both the cochlea and vestibular system.

Innate sensing of mechanical properties of brain tissue by microglia.

External organic or inorganic objects (foreign bodies) that are inadvertently or purposefully placed in the human or animal tissues can trigger local tissue responses that aim at the elimination and/or segregation of foreign bodies from the tissue. The foreign body response (FBR) may have major implications for neurodegeneration associated with the formation of aberrant protein-based aggregates or plaques. The distinct physical features of the plaques, including high rigidity and varying surface properties, may trigger microglial mechanosensing of the plaque as a foreign body. The microglial FBR may have a dual function by promoting and/or suppressing the plaque driven neurodegeneration. Microglial contact with the plaque may trigger inflammatory activation of microglia and support microglia-driven neuronal damage. Conversely, persistent microglial activation may trigger the formation of a microglia-supported cell barrier that segregates and compacts the plaques thus preventing further plaque-induced damage to healthy neurons.

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.

Harnessing the Properties of Biomaterial to Enhance the Immunomodulation of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have great therapeutic potential for tissue engineering and regenerative medicine due to their multipotency and paracrine functions. However, shortly after in vivo implantation, MSCs tend to migrate to the lungs and undergo apoptosis, which impairs their clinical efficacy. In addition, the ex vivo two-dimensional expansion of MSCs results in changes in their immunophenotype and functional activities compared to those in vivo. The use of biomaterials to culture and deliver MSCs has the potential to overcome these limitations. MSC-biomaterial constructs retain MSCs in situ and prolong their survival, while the MSCs ameliorate the foreign body reaction and fibrosis caused by the biomaterial. Biomaterial scaffolds can both preserve the tissue architecture and provide a three-dimensional biomimetic milieu for embedded MSCs, which enhance their paracrine functions, including their immunomodulatory potential. The dimensionality, physical characteristics, topographical cues, biochemistry, and microstructure can enhance the immunomodulatory potential of MSCs. Here, we review the link between the properties of biomaterial and the immunomodulatory potential of MSCs. Impact Statement Regeneration of cells, tissues, and whole organs is challenging. Mesenchymal stem cells (MSCs) have therapeutic potential in tissue engineering and regenerative medicine due to their paracrine functions, including immunomodulatory activity. The dimensionality, physical characteristics, topographical cues, biochemistry, and microstructure of biomaterial can be harnessed to enhance the immunomodulatory potential of MSCs for tissue engineering, which will increase their clinical efficacy, particularly for immune-related diseases.

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.

Biomaterials: Foreign Bodies or Tuners for the Immune Response?

The perspectives of regenerative medicine are still severely hampered by the host response to biomaterial implantation, despite the robustness of technologies that hold the promise to recover the functionality of damaged organs and tissues. In this scenario, the cellular and molecular events that decide on implant success and tissue regeneration are played at the interface between the foreign body and the host inflammation, determined by innate and adaptive immune responses. To avoid adverse events, rather than the use of inert scaffolds, current state of the art points to the use of immunomodulatory biomaterials and their knowledge-based use to reduce neutrophil activation, and optimize M1 to M2 macrophage polarization, Th1 to Th2 lymphocyte switch, and Treg induction. Despite the fact that the field is still evolving and much remains to be accomplished, recent research breakthroughs have provided a broader insight on the correct choice of biomaterial physicochemical modifications to tune the reaction of the host immune system to implanted biomaterial and to favor integration and healing.

A Foreign Body Response-on-a-Chip Platform.

Understanding the foreign body response (FBR) and desiging strategies to modulate such a response represent a grand challenge for implant devices and biomaterials. Here, the development of a microfluidic platform is reported, i.e., the FBR-on-a-chip (FBROC) for modeling the cascade of events during immune cell response to implants. The platform models the native implant microenvironment where the implants are interfaced directly with surrounding tissues, as well as vasculature with circulating immune cells. The study demonstrates that the release of cytokines such as monocyte chemoattractant protein 1 (MCP-1) from the extracellular matrix (ECM)-like hydrogels in the bottom tissue chamber induces trans-endothelial migration of circulating monocytes in the vascular channel toward the hydrogels, thus mimicking implant-induced inflammation. Data using patient-derived peripheral blood mononuclear cells further reveal inter-patient differences in FBR, highlighting the potential of this platform for monitoring FBR in a personalized manner. The prototype FBROC platform provides an enabling strategy to interrogate FBR on various implants, including biomaterials and engineered tissue constructs, in a physiologically relevant and individual-specific manner.