Cellular and microenvironmental cues that promote macrophage fusion and foreign body response.

During the foreign body response (FBR), macrophages fuse to form foreign body giant cells (FBGCs). Modulation of FBGC formation can prevent biomaterial degradation and loss of therapeutic efficacy. However, the microenvironmental cues that dictate FBGC formation are poorly understood with conflicting reports. Here, we identified molecular and cellular factors involved in driving FBGC formation in vitro. Macrophages demonstrated distinct fusion competencies dependent on monocyte differentiation. The transition from a proinflammatory to a reparative microenvironment, characterised by specific cytokine and growth factor programmes, accompanied FBGC formation. Toll-like receptor signalling licensed the formation of FBGCs containing more than 10 nuclei but was not essential for cell-cell fusion to occur. Moreover, the fibroblast-macrophage crosstalk influenced FBGC development, with the fibroblast secretome inducing macrophages to secrete more PDGF, which enhanced large FBGC formation. These findings advance our understanding as to how a specific and timely combination of cellular and microenvironmental factors is required for an effective FBR, with monocyte differentiation and fibroblasts being key players.

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation.

Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes.

Osteointegration of Ti Bone Implants: A Study on How Surface Parameters Control the Foreign Body Response.

The integration of titanium (Ti)-based implants with bone is limited, resulting in implant failure. This lack of osteointegration is due to the foreign body response (FBR) that occurs after the implantation of biodevices. The process begins with protein adsorption, which is governed by implant surface properties, e.g., chemistry, charge, wettability, and/or topography. The distribution and composition of the protein layer in turn influence the recruitment, differentiation, and modulation of immune and bone cells. The subsequent events that occur at the bone-material interface will ultimately determine whether the implant is encapsulated or will integrate with bone. Despite the numerous studies evaluating the influence of surface properties in the various stages of the FBR, the factors that affect tissue-material interactions are often studied in isolation or in small correlations due to the technical challenges involved in assessing them in vitro or in vivo. Consequently, the influence of protein conformation on the Ti bone implant surface design remains an unresolved research question. The objective of this review is to comprehensively evaluate the existing literature on the effect of surface parameters of Ti and its alloys in the stages of FBR, with a particular focus on protein adsorption and osteoimmunomodulation. This evaluation aims to systematically describe these effects on bone formation.

Dapansutrile OLT1177 suppresses foreign body response inflammation while preserving vascularisation of implanted materials.

Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices.

Biomechanical and Histological Study of Retrieved LARS Synthetic Ligaments.

BACKGROUND: Synthetic grafts have been used for a number of years in anterior cruciate ligament (ACL) reconstruction surgery. One of the more recent additions to the stable of synthetic ligaments is the Ligament Augmentation and Reconstruction System (LARS) ligament. PURPOSE: To analyze the biomechanics and histology of LARS grafts retrieved due to failure of the device. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 22 LARS ligament grafts that were explanted from patients were sent for analysis. Five new, unused samples of the standard LARS ACL graft were also analyzed. Biomechanical testing was performed: ultimate tensile force, force versus displacement, and stress versus strain were recorded. Histopathological examination was performed looking for degree of fibrous tissue ingrowth as well as the presence of a foreign body reaction. RESULTS: Of the 22 grafts retrieved, 14 were used for ACL grafts, 1 for a lateral collateral ligament graft, 2 for medial collateral ligament grafts, 4 for gluteal tendon augmentation, and 1 for a supraspinatus augmentation. A severe foreign body reaction was found in 86% of the grafts (18/22) and a mild foreign body reaction in the remaining 14% (4/22). Tissue ingrowth was minimal in the majority of ACL grafts; the other grafts showed moderate tissue ingrowth. Maximal tensile force was significantly higher for the new ACL grafts (mean ± SD, 1667 ± 845 N) compared with the retrieved grafts (897 ± 395 N; P < .05). CONCLUSION: This study demonstrated that the vast majority of retrieved LARS artificial ligaments had a florid foreign body reaction. There was minimal tissue ingrowth in ACL grafts and moderate ingrowth in other grafts. Retrieved grafts had a decreased ultimate tensile force, which increased their risk of rupture. CLINICAL RELEVANCE: Surgeons should be cautious in choosing to use these grafts in reconstructive surgery for patients.

Long-Term Evaluation of Inserted Nanocomposite Hydrogel-Based Phosphorescent Oxygen Biosensors: Evolution of Local Tissue Oxygen Levels and Foreign Body Response.

Phosphorescence-based oxygen-sensing hydrogels are a promising platform technology for an upcoming generation of insertable biosensors that are smaller, softer, and potentially more biocompatible than earlier designs. However, much remains unknown about their long-term performance and biocompatibility in vivo. In this paper, we design and evaluate a range of hydrogel sensors that contain oxygen-sensitive phosphors stabilized by micro- and nanocarrier systems. These devices demonstrated consistently good performance and biocompatibility in young adult rats for over three months. This study thoroughly establishes the biocompatibility and long-term suitability of phosphorescence lifetime sensors in vivo, providing the groundwork for expansion of this platform technology into a family of small, unobtrusive biosensors for a range of clinically relevant metabolites.

Neuronal functional connectivity is impaired in a layer dependent manner near chronically implanted intracortical microelectrodes in C57BL6 wildtype mice.

Objective.This study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near chronically implanted microelectrodes. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how the FBR affects the functional stability of neural circuits near implanted brain-computer interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders.Approach.This study utilized single-shank, 16-channel,100µm site-spacing Michigan-style microelectrodes (3 mm length, 703µm2 site area) that span all cortical layers and the hippocampal CA1 region. Sex balanced C57BL6 wildtype mice (11-13 weeks old) received perpendicularly implanted microelectrode in left primary visual cortex. Electrophysiological recordings were performed during both spontaneous activity and visual sensory stimulation. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of local field potential (LFP) and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation.Main results. The study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations.Significance. This study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our study's understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

Adhesive anti-fibrotic interfaces on diverse organs.

Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant-tissue interfaces1-4. Here we demonstrate that an adhesive implant-tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant-tissue interface compared to the non-adhesive implant-tissue interface. Histological analysis shows that the adhesive implant-tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo. In vitro protein adsorption, multiplex Luminex assays, quantitative PCR, immunofluorescence analysis and RNA sequencing are additionally carried out to validate the hypothesis. We further demonstrate long-term bidirectional electrical communication enabled by implantable electrodes with an adhesive interface over 12 weeks in a rat model in vivo. These findings may offer a promising strategy for long-term anti-fibrotic implant-tissue interfaces.

Exploring therapy transport from implantable medical devices using experimentally informed computational methods.

Implantable medical devices that can facilitate therapy transport to localized sites are being developed for a number of diverse applications, including the treatment of diseases such as diabetes and cancer, and tissue regeneration after myocardial infraction. These implants can take the form of an encapsulation device which encases therapy in the form of drugs, proteins, cells, and bioactive agents, in semi-permeable membranes. Such implants have shown some success but the nature of these devices pose a barrier to the diffusion of vital factors, which is further exacerbated upon implantation due to the foreign body response (FBR). The FBR results in the formation of a dense hypo-permeable fibrous capsule around devices and is a leading cause of failure in many implantable technologies. One potential method for overcoming this diffusion barrier and enhancing therapy transport from the device is to incorporate local fluid flow. In this work, we used experimentally informed inputs to characterize the change in the fibrous capsule over time and quantified how this impacts therapy release from a device using computational methods. Insulin was used as a representative therapy as encapsulation devices for Type 1 diabetes are among the most-well characterised. We then explored how local fluid flow may be used to counteract these diffusion barriers, as well as how a more practical pulsatile flow regimen could be implemented to achieve similar results to continuous fluid flow. The generated model is a versatile tool toward informing future device design through its ability to capture the expected decrease in insulin release over time resulting from the FBR and investigate potential methods to overcome these effects.

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.

Materials Strategies to Overcome the Foreign Body Response.

The foreign body response (FBR) is an immune-mediated reaction that can occur with most biomaterials and biomedical devices. The FBR initiates a deterioration in the performance of implantable devices, representing a longstanding challenge that consistently hampers their optimal utilization. Over the last decade, significant strides are achieved based on either hydrogel design or surface modifications to mitigate the FBR. This review delves into recent material strategies aimed at mitigating the FBR. Further, the authors look forward to future novel anti-FBR materials from the perspective of clinical translation needs. Such prospective materials hold the potential to attenuate local immune responses, thereby significantly enhancing the overall performance of implantable devices.

Medical textile implants: hybrid fibrous constructions towards improved performances.

OBJECTIVES: One main challenge for textile implants is to limit the foreign body reaction (FBR) and in particular the fibrosis development once the device is implanted. Fibrotic tissue in-growth depends on the fiber size, the pore size, and the organization of the fibrous construction. Basically, non-woven fibrous assemblies present a more favorable interface to biological tissues than do woven structures. However, they are mechanically less strong. In order to combine both strength and appropriate topography properties, the design of a hybrid fibrous construct was considered and discussed in this work. METHODS: Two polyethylene terephthalate (PET) weaves (satin and plain) were assembled with a non-woven PET mat, using an ultrasound welding process. RESULTS: The physical and mechanical properties of the construction as well as its ability to interact with the biological environment were then evaluated. In particular, the wettability of the obtained substrate as well as its ability to interact with mesenchymal stem cells (MSC) at 24 h (adhesion) and 72 h (proliferation) in vitro were studied. CONCLUSIONS: The results show that the non-woven layer helps limiting cell proliferation in the plain weave construction and promotes conversely proliferation in the satin construction.

Poly(Glutamic Acid-Lysine) Hydrogels with Alternating Sequence Resist the Foreign Body Response in Rodents and Non-Human Primates.

The foreign body response (FBR) to implanted biomaterials and biomedical devices can severely impede their functionality and even lead to failure. The discovery of effective anti-FBR materials remains a formidable challenge. Inspire by the enrichment of glutamic acid (E) and lysine (K) residues on human protein surfaces, a class of zwitterionic polypeptide (ZIP) hydrogels with alternating E and K sequences to mitigate the FBR is prepared. When subcutaneously implanted, the ZIP hydrogels caused minimal inflammation after 2 weeks and no obvious collagen capsulation after 6 months in mice. Importantly, these hydrogels effectively resisted the FBR in non-human primate models for at least 2 months. In addition, the enzymatic degradability of the gel can be controlled by adjusting the crosslinking degree or the optical isomerism of amino acid monomers. The long-term FBR resistance and controlled degradability of ZIP hydrogels open up new possibilities for a broad range of biomedical applications.

[Silver Ion Decreases Foreign Body Reaction and Venous Neointimal Hyperplasia through the Inhibition of Interleukin-33 Expression].

INTRODUCTION: Vascular prosthetic grafts are widely used in vascular surgery; however, graft infection remains a major concern. Silver-coated vascular grafts have demonstrated anti-infection properties in clinical settings; however, whether the silver irons influence foreign body reaction or neointimal hyperplasia remains unclear. METHODS: Sodium alginate and hyaluronic acid (SA/HA) hydrogel patches loaded with rhodamine, with or without silver, were fabricated. Patches were implanted in the subcutaneous or abdominal cavity and inferior vena cava of rats. Samples were harvested on day 14 and examined via immunohistochemical and immunofluorescence analyses. RESULTS: Silver hydrogel was found to decrease the foreign body reaction; after subcutaneous and abdominal cavity implantation in rats, the capsule was found to be thinner in the silver hydrogel group than in the control hydrogel group. The silver hydrogel group had fewer CD68-positive cells and proliferating cell nuclear antigen and interleukin-33 (IL-33) dual-positive cells than the control hydrogel group. Additionally, the silver hydrogel patch reduced the neointimal thickness after patch venoplasty in rats, and the number of IL-33- and IL-1ß-positive cells was lower than that in the control patch. CONCLUSION: Silver-loaded SA/HA hydrogel patches decreased the foreign body reaction and venous neointimal hyperplasia in rats by the inhibition of IL-33 expression.

Spatially Resolved Molecular Analysis of Host Response to Medical Device Implantation Using the 3D OrbiSIMS Highlights a Critical Role for Lipids.

A key goal for implanted medical devices is that they do not elicit a detrimental immune response. Macrophages play critical roles in the modulation of the host immune response and are the cells responsible for persistent inflammatory reactions to implanted biomaterials. Two novel immune-instructive polymers that stimulate pro- or anti-inflammatory responses from macrophages in vitro are investigated. These also modulate in vivo foreign body responses (FBR) when implanted subcutaneously in mice. Immunofluorescent staining of tissue abutting the polymer reveals responses consistent with pro- or anti-inflammatory responses previously described for these polymers. Three Dimensional OrbiTrap Secondary Ion Mass Spectrometry (3D OrbiSIMS) analysis to spatially characterize the metabolites in the tissue surrounding the implant, providing molecular histology insight into the metabolite response in the host is applied. For the pro-inflammatory polymer, monoacylglycerols (MG) and diacylglycerols (DG) are observed at increased intensity, while for the anti-inflammatory coating, the number of phospholipid species detected decreased, and pyridine and pyrimidine levels are elevated. Small molecule signatures from single-cell studies of M2 macrophages in vitro correlate with the in vivo observations, suggesting potential for prediction. Metabolite characterization by the 3D OrbiSIMS is shown to provide insight into the mechanism of bio-instructive materials as medical devices and to inform on the FBR to biomaterials.

Cell- and Serum-Derived Proteins Act as DAMPs to Activate RAW 264.7 Macrophage-like Cells on Silicone Implants.

Protein adsorption after biomaterial implantation is the first stage of the foreign body response (FBR). However, the source(s) of the adsorbed proteins that lead to damaged associated molecular patterns (DAMPs) and induce inflammation have not been fully elucidated. This study examined the effects of different protein sources, cell-derived (from a NIH/3T3 fibroblast cell lysate) and serum-derived (from fetal bovine serum), which were compared to implant-derived proteins (after a 30 min subcutaneous implantation in mice) on activation of RAW 264.7 cells cultured in minimal (serum-free) medium. Both cell-derived and serum-derived protein sources when preadsorbed to either tissue culture polystyrene or medical-grade silicone induced RAW 264.7 cell activation. The combination led to an even higher expression of pro-inflammatory cytokine genes and proteins. Implant-derived proteins on silicone explants induced a rapid inflammatory response that then subsided more quickly and to a greater extent than the studies with in vitro cell-derived or serum-derived protein sources. Proteomic analysis of the implant-derived proteins identified proteins that included cell-derived and serum-derived, but also other proteinaceous sources (e.g., extracellular matrix), suggesting that the latter or nonproteinaceous sources may help to temper the inflammatory response in vivo. These findings indicate that both serum-derived and cell-derived proteins adsorbed to implants can act as DAMPs to drive inflammation in the FBR, but other protein sources may play an important role in controlling inflammation.

Porous Precision-Templated 40 µm Pore Scaffolds Promote Healing through Synergy in Macrophage Receptor with Collagenous Structure and Toll-Like Receptor Signaling.

Porous precision-templated scaffolds (PTS) with uniform, interconnected, 40 µm pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR). Macrophage receptor with collagenous structure (MARCO) and toll-like receptors (TLRs) have been identified as key surface receptors in the initial inflammatory phase of wound healing. However, the role of MARCO and TLRs in modulating monocyte and macrophage phenotypes within PTS remains uncharacterized. In this study, we demonstrate a synergetic relationship between MARCO and TLR signaling in cells inhabiting PTS, where induction with TLR3 or TLR4 agonists to 40 µm scaffold-resident cells upregulates the transcription of MARCO. Upon deletion of MARCO, the prohealing phenotype within 40 µm PTS polarizes to a proinflammatory and profibrotic phenotype. Analysis of downstream TLR signaling shows that MARCO is required to attenuate nuclear factor kappa B (NF-κB) inflammation in 40 µm PTS by regulating the transcription of inhibitory NFKB inhibitor alpha (NFKBIA) and interleukin-1 receptor-associated kinase 3 (IRAK-M), primarily through a MyD88-dependent signaling pathway. Investigation of implant outcome in the absence of MARCO demonstrates an increase in collagen deposition within the scaffold and the development of tissue fibrosis. Overall, these results further our understanding of the molecular mechanisms underlying MARCO and TLR signaling within PTS. Impact statement Monocyte and macrophage phenotypes in the foreign body reaction (FBR) are essential for the development of a proinflammatory, prohealing, or profibrotic response to implanted biomaterials. Identification of key surface receptors and signaling mechanisms that give rise to these phenotypes remain to be elucidated. In this study, we report a synergistic relationship between macrophage receptor with collagenous structure (MARCO) and toll-like receptor (TLR) signaling in scaffold-resident cells inhabiting porous precision-templated 40 µm pore scaffolds through a MyD88-dependent pathway that promotes healing. These findings advance our understanding of the FBR and provide further evidence that suggests MARCO, TLRs, and fibrosis may be interconnected.

Decoding the "Fingerprint" of Implant Materials: Insights into the Foreign Body Reaction.

Foreign body reaction (FBR) is a prevalent yet often overlooked pathological phenomenon, particularly within the field of biomedical implantation. The presence of FBR poses a heavy burden on both the medical and socioeconomic systems. This review seeks to elucidate the protein "fingerprint" of implant materials, which is generated by the physiochemical properties of the implant materials themselves. In this review, the activity of macrophages, the formation of foreign body giant cells (FBGCs), and the development of fibrosis capsules in the context of FBR are introduced. Additionally, the relationship between various implant materials and FBR is elucidated in detail, as is an overview of the existing approaches and technologies employed to alleviate FBR. Finally, the significance of implant components (metallic materials and non-metallic materials), surface CHEMISTRY (charge and wettability), and physical characteristics (topography, roughness, and stiffness) in establishing the protein "fingerprint" of implant materials is also well documented. In conclusion, this review aims to emphasize the importance of FBR on implant materials and provides the current perspectives and approaches in developing implant materials with anti-FBR properties.