Search Results (14)

Silicone mammary implants (SMIs) frequently result in capsular fibrosis, which is marked by the overproduction of fibrous tissue surrounding the implant. This review provides a detailed examination of the molecular and immunological mechanisms driving capsular fibrosis, focusing on the role of foreign body responses (FBRs) and microbial biofilm formation. We investigate how microbial adhesion to implant surfaces and biofilm development contribute to persistent inflammation and fibrotic responses. The review critically evaluates antimicrobial strategies, including preoperative antiseptic protocols and antimicrobial-impregnated materials, designed to mitigate infection and biofilm-related complications. Additionally, advancements in material science, such as surface modifications and antibiotic-impregnated meshes, are discussed for their potential to reduce capsular fibrosis and prevent contracture of the capsule. By integrating molecular insights with clinical applications, this review aims to elucidate the current understanding of SMI-related fibrotic responses and highlight knowledge gaps. The synthesis of these findings aims to guide future research directions of improved antimicrobial interventions and implant materials, ultimately advancing the management of capsular fibrosis and enhancing patient outcomes. Full article

Foreign body response (FBR) is a universal reaction to implanted biomaterial that can affect the function and longevity of the implant. A few studies have attempted to identify targets for treating FBR through the use of single-cell RNA sequencing (scRNA-seq), though the generalizability of these findings from an individual study may be limited. In our study, we perform a meta-analysis of scRNA-seq data from all available FBR mouse studies and integrate these data to identify gene signatures specific to FBR across different models and anatomic locations. We identify subclusters of fibroblasts and macrophages that emerge in response to foreign bodies and characterize their signaling pathways, gene ontology terms, and downstream mediators. The fibroblast subpopulations enriched in the setting of FBR demonstrated significant signaling interactions in the transforming growth factor-beta (TGF-β) signaling pathway, with known pro-fibrotic mediators identified as top expressed genes in these FBR-derived fibroblasts. In contrast, FBR-enriched macrophage subclusters highly expressed pro-fibrotic and pro-inflammatory mediators downstream of tumor necrosis factor (TNF) signaling. Cell–cell interactions were additionally interrogated using CellChat, with identification of key signaling interactions enriched between fibroblasts and macrophages in FBR. By combining multiple FBR datasets, our meta-analysis study identifies common cell-specific gene signatures enriched in foreign body reactions, providing potential therapeutic targets for patients requiring medical implants across a myriad of devices and indications. Full article

Breast cancer is the most common cancer in women globally, often necessitating mastectomy and subsequent breast reconstruction. Silicone mammary implants (SMIs) play a pivotal role in breast reconstruction, yet their interaction with the host immune system and microbiome remains poorly understood. This study investigates the impact of SMI surface topography on host antimicrobial responses, wound proteome dynamics, and microbial colonization. Biological samples were collected from ten human patients undergoing breast reconstruction with SMIs. Mass spectrometry profiles were analyzed for acute and chronic wound proteomes, revealing a nuanced interplay between topography and antimicrobial response proteins. 16S rRNA sequencing assessed microbiome dynamics, unveiling topography-specific variations in microbial composition. Surface topography alterations influenced wound proteome composition. Microbiome analysis revealed heightened diversity around rougher SMIs, emphasizing topography-dependent microbial invasion. In vitro experiments confirmed staphylococcal adhesion, growth, and biofilm formation on SMI surfaces, with increased texture correlating positively with bacterial colonization. This comprehensive investigation highlights the intricate interplay between SMI topography, wound proteome dynamics, and microbial transmission. The findings contribute to understanding host–microbe interactions on SMI surfaces, essential for optimizing clinical applications and minimizing complications in breast reconstruction. Full article

The etiology of exaggerated fibrous capsule formation around silicone mammary implants (SMI) is multifactorial but primarily induced by immune mechanisms towards the foreign material silicone. The aim of this work was to understand the disease progression from implant insertion and immediate tissue damage response reflected in (a) the acute wound proteome and (b) the adsorption of chronic inflammatory wound proteins at implant surfaces. An intraindividual relative quantitation TMT-liquid chromatography–tandem mass spectrometry approach was applied to the profile wound proteome formed around SMI in the first five days post-implantation. Compared to plasma, the acute wound profile resembled a more complex composition comprising plasma-derived and locally differentially expressed proteins (DEPs). DEPs were subjected to a functional enrichment analysis, which revealed the dysregulation of signaling pathways mainly involved in immediate inflammation response and ECM turnover. Moreover, we found time-course variations in protein enrichment immediately post-implantation, which were adsorbed to SMI surfaces after 6–8 months. Characterization of the expander-adhesive proteome by a label-free approach uncovered a long-term adsorbed acute wound and the fibrosis-associated proteome. Our findings propose a wound biomarker panel for the early detection and diagnosis of excessive fibrosis that could potentially broaden insights into the characteristics of fibrotic implant encapsulation. Full article

The extent and patterns of foreign body reaction (FBR) influence the function and feasibility of biomaterials. Polysaccharides, as an important biomaterial category, have received increasing attention in diverse biomaterials design and biomedical applications due to their excellent polymeric and biocompatible characteristics. Their biological effects are usually associated with their monosaccharide composition or functional groups, yet the contribution of their glycan structure is still unknown. Herein, two glucomannans, similar in composition and molecular weight with differences in glycan structure, linear-chain (Konjac glucomannan, KGM), and branched-chain (Bletilla striata polysaccharide, BSP), were adopted to explore the host–biomaterials interaction. After acetyl modification, these polysaccharides were fabricated into electrospun scaffolds to reduce the impacts derived from the physical properties and surface morphology. According to a systematic study of their biological effects on immune cells and host response in a subcutaneous implantation model in vivo, it was revealed that acetyl KGM (acKGM) scaffolds caused a stronger FBR than acetyl BSP materials. Additionally, acKGM could stimulate macrophages to release pro-inflammatory cytokines, suggesting the influence of sugar chain arrangement on FBR and providing clues for the fine regulation of immune response and novel biomaterials design. Full article

Increasing evidence shows that the physical properties of biomaterials play an important role in regulating cell behavior and function, especially the mechanical properties of biomaterials. Macrophages can also be multidirectionally regulated by mechanical factors in the microenvironment, which simultaneously mediate biomaterials response that triggered by foreign body reactions (FBR). However, how the stiffness of biomaterials regulates macrophages and the underlying mechanisms are still not well understood. Our study demonstrates that chitosan freeze-dried scaffolds with different elastic modulus can modulate the proliferative capacity, growth morphology and polarization behavior of macrophages. The compression tests and morphology observation confirmed that the prepared lyophilized chitosan scaffolds possessed varied stiffness. The fluorescence staining experiments showed that the RAW macrophage cell lines exhibited differences in proliferation and morphology on the freeze-dried scaffolds with different stiffness. Macrophages in the 5% group (elastic modulus of 106.7 kPa) had the largest number and mean cell area. Furthermore, ELISA and qPCR results illustrated that macrophage polarization towards the M1/M2 phenotype was strongly influenced by the stiffness of the lyophilized scaffolds. The study may provide new insights and references for designing the elastic moduli of biomaterials for regulating immune responsiveness. Full article

Analysing the composition and organisation of the fibrous capsule formed as a result of the Foreign Body Response (FBR) to medical devices, is imperative for medical device improvement and biocompatibility. Typically, analysis is performed using histological techniques which often involve random sampling strategies. This method is excellent for acquiring representative values but can miss the unique spatial distribution of features in 3D, especially when analysing devices used in large animal studies. To overcome this limitation, we demonstrate a non-destructive method for high-resolution large sample imaging of the fibrous capsule surrounding human-sized implanted devices using diffusion tensor imaging (DTI). In this study we analyse the fibrous capsule surrounding two unique macroencapsulation devices that have been implanted in a porcine model for 21 days. DTI is used for 3D visualisation of the microstructural organisation and validated using the standard means of fibrous capsule investigation; histological analysis and qualitative micro computed tomography (microCT) and scanning electron microscopy (SEM) imaging. DTI demonstrated the ability to distinguish microstructural differences in the fibrous capsules surrounding two macroencapsulation devices made from different materials and with different surface topographies. DTI-derived metrics yielded insight into the microstructural organisation of both capsules which was corroborated by microCT, SEM and histology. The non-invasive characterisation of the integration of implants in the body has the potential to positively influence analysis methods in pre-clinical studies and accelerate the clinical translation of novel implantable devices. Full article

Implantable glucose biosensors provide real-time information about blood glucose fluctuations, but their utility and accuracy are time-limited due to the foreign body response (FBR) following their insertion beneath the skin. The slow release of nitric oxide (NO), a gasotransmitter with inflammation regulatory properties, from a sensor surface has been shown to dramatically improve sensors’ analytical biocompatibility by reducing the overall FBR response. Indeed, work in a porcine model suggests that as long as the implants (sensors) continue to release NO, even at low levels, the inflammatory cell infiltration and resulting collagen density are lessened. While these studies strongly support the benefits of NO release in mitigating the FBR, the mechanisms through which exogenous NO acts on the surrounding tissue, especially under the condition of hyperglycemia, remain vague. Such knowledge would inform strategies to refine appropriate NO dosage and release kinetics for optimal therapeutic activity. In this study, we evaluated mediator, immune cell, and mRNA expression profiles in the local tissue microenvironment surrounding implanted sensors as a function of NO release, diabetes, and implantation duration. A custom porcine wound healing-centric multiplex gene array was developed for nanoString barcoding analysis. Tissues adjacent to sensors with sustained NO release abrogated the implant-induced acute and chronic FBR through modulation of the tissue-specific immune chemokine and cytokine microenvironment, resulting in decreased cellular recruitment, proliferation, and activation at both the acute (7-d) and chronic (14-d) phases of the FBR. Further, we found that sustained NO release abrogated the implant-induced acute and chronic foreign body response through modulation of mRNA encoding for key immunological signaling molecules and pathways, including STAT1 and multiple STAT1 targets including MAPK14, IRAK4, MMP2, and CXCL10. The condition of diabetes promoted a more robust FBR to the implants, which was also controlled by sustained NO release. Full article

Synthetic macroporous biomaterials are widely used in the field of skin tissue engineering to mimic membrane functions of the native dermis. Biomaterial designs can be subclassified with respect to their shape in fibrous designs, namely fibers, meshes or fleeces, respectively, and porous designs, such as sponges and foams. However, synthetic matrices often have limitations regarding unfavorable foreign body responses (FBRs). Severe FBRs can result in unfavorable disintegration and rejection of an implant, whereas mild FBRs can lead to an acceptable integration of a biomaterial. In this context, comparative in vivo studies of different three-dimensional (3D) matrix designs are rare. Especially, the differences regarding FBRs between synthetically derived filamentous fleeces and sponge-like constructs are unknown. In the present study, the FBRs on two 3D matrix designs were explored after 25 days of subcutaneous implantation in a porcine model. Cellular reactions were quantified histopathologically to investigate in which way the FBR is influenced by the biomaterial architecture. Our results show that FBR metrics (polymorph-nucleated cells and fibrotic reactions) were significantly affected according to the matrix designs. Our findings contribute to a better understanding of the 3D matrix tissue interactions and can be useful for future developments of synthetically derived skin substitute biomaterials. Full article

Invasive intraneural electrodes can control advanced neural-interfaced prostheses in human amputees. Nevertheless, in chronic implants, the progressive formation of a fibrotic capsule can gradually isolate the electrode surface from the surrounding tissue leading to loss of functionality. This is due to a nonspecific inflammatory response called foreign-body reaction (FBR). The commonly used poly(ethylene glycol) (PEG)-based low-fouling coatings of implantable devices can be easily encapsulated and are susceptible to oxidative damage in long-term in vivo applications. Recently, sulfobetaine-based zwitterionic hydrogels have emerged as an important class of robust ultra-low fouling biomaterials, holding great potential to mitigate FBR. The aim of this proof-of-principle in vitro work was to assess whether the organic zwitterionic—poly(sulfobetaine methacrylate) [poly(SBMA)]—hydrogel could be a suitable coating for Polyimide (PI)-based intraneural electrodes to reduce FBR. We first synthesized and analyzed the hydrogel through a mechanical characterization (i.e., Young’s modulus). Then, we demonstrated reduced adhesion and activation of fibrogenic and pro-inflammatory cells (i.e., human myofibroblasts and macrophages) on the hydrogel compared with PEG-coated and polystyrene surfaces using cell viability assays, confocal fluorescence microscopy and high-content analysis of oxidative stress production. Interestingly, we successfully coated PI surfaces with a thin film of the hydrogel through covalent bond and demonstrated its high hydrophilicity via water contact angle measurement. Importantly, we showed the long-term release of an anti-fibrotic drug (i.e., Everolimus) from the hydrogel. Because of the low stiffness, biocompatibility, high hydration and ultra-low fouling characteristics, our zwitterionic hydrogel could be envisioned as long-term diffusion-based delivery system for slow and controlled anti-inflammatory and anti-fibrotic drug release in vivo. Full article

Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. −VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR. Full article

The chemically cross-linking 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride/N-hydroxy-succinimide (EDC/NHS) collagen membrane endows such natural polymers with promising mechanical properties. Nevertheless, it is inadequate to advance the modulation of foreign body response (FBR) after implantation or guidance of tissue regeneration. In previous research, macrophages have a strong regulatory effect on regeneration, and such enhanced membranes underwent the modification with Epigallocatechin-3-gallate (EGCG) could adjust the recruitment and phenotypes of macrophages. Accordingly, we develop EGCG-EDC/NHS membranes, prepared with physical immersion, while focusing on the surface morphology through SEM, the biological activity of collagen was determined by FTIR, the activity and adhesion of cell culture in vitro, angiogenesis and monocyte/macrophage recruitment after subcutaneous implantation in vivo, are characterized. It could be concluded that it is hopeful EGCG-EDC/NHS collagen membrane can be used in implant dentistry for it not only retains the advantages of the collagen membrane itself, but also improves cell viability, adhesion, vascularization, and immunoregulation tendency. Full article

Brain–computer interfaces (BCI) are reliant on the interface between electrodes and neurons to function. The foreign body reaction (FBR) that occurs in response to electrodes in the brain alters this interface and may pollute detected signals, ultimately impeding BCI function. The size of the FBR is influenced by several key factors explored in this review; namely, (a) the size of the animal tested, (b) anatomical location of the BCI, (c) the electrode morphology and coating, (d) the mechanics of electrode insertion, and (e) pharmacological modification (e.g., drug eluting electrodes). Trialing methods to reduce FBR in vivo, particularly in large models, is important to enable further translation in humans, and we systematically reviewed the literature to this effect. The OVID, MEDLINE, EMBASE, SCOPUS and Scholar databases were searched. Compiled results were analysed qualitatively. Out of 8388 yielded articles, 13 were included for analysis, with most excluded studies experimenting on murine models. Cats, rabbits, and a variety of breeds of minipig/marmoset were trialed. On average, over 30% reduction in inflammatory cells of FBR on post mortem histology was noted across intervention groups. Similar strategies to those used in rodent models, including tip modification and flexible and sinusoidal electrode configurations, all produced good effects in histology; however, a notable absence of trials examining the effect on BCI end-function was noted. Future studies should assess whether the reduction in FBR correlates to an improvement in the functional effect of the intended BCI. Full article

Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks. Full article