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.

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.

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.

Foreign Body Reaction Mimicking Lymph Node Metastasis is Not Rare After Lung Cancer Resection.

BACKGROUND: Mediastinal lymphadenopathies with high 18-fluorodeoxyglucose uptake in patients previously operated on for lung cancer are alarming for recurrence and necessitate invasive diagnostic procedures. Peroperative placement of oxidized cellulose to control minor bleeding may lead to a metastasis-like image through a foreign body reaction within the dissected mediastinal lymph node field at postoperative examinations. In this study, we investigated clinicopathological features and the frequency of foreign body reaction mimicking mediastinal lymph node metastasis. METHODS: Patients who underwent surgery for lung cancer between January 2016 and August 2021 and who were subsequently evaluated for mediastinal recurrence with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were included. Patients were grouped according to the results of EBUS-TBNA as metastasis, foreign body, and reactive. Clinicopathological features of these patients were compared and characteristics of patients in the foreign body group were scrutinized. RESULTS: EBUS-TBNA was performed on a total of 34 patients during their postoperative follow-up due to suspicion of mediastinal recurrence. EBUS-TBNA pathological workup revealed metastasis in 18 (52.9%), foreign body reaction in 10 (29.4%) and reactive lymph nodes in 6 (17.6%) patients. Mean maximum standardized uptake value (SUVMax) for metastasis group and foreign body group were 9.39 ± 4.69 and 5.48 ± 2.54, respectively (p = 0.022). Time interval between the operation and EBUS-TBNA for the metastasis group was 23.72 ± 10.48 months, while it was 14.90 ± 12.51 months in the foreign body group (p = 0.015). CONCLUSION: Foreign body reaction mimicking mediastinal lymph node metastasis is not uncommon. Iatrogenic cause of mediastinal lymphadenopathy is related to earlier presentation and lower SUVMax compared with metastatic lymphadenopathy.

Releasable, Immune-Instructive, Bioinspired Multilayer Coating Resists Implant-Induced Fibrosis while Accelerating Tissue Repair.

Implantable biomaterials trigger foreign body reactions (FBRs), which reduces the functional life of medical devices and prevents effective tissue regeneration. Although existing therapeutic approaches can circumvent collagen-rich fibrotic encapsulation secondary to FBRs, they disrupt native tissue repair. Herein, a new surface engineering strategy in which an apoptotic-mimetic, immunomodulatory, phosphatidylserine liposome (PSL) is released from an implant coating to induce the formation of a macrophage phenotype that mitigates FBRs and improves tissue healing is described. PSL-multilayers constructed on implant surfaces via the layer-by-layer method release PSLs over a 1-month period. In rat muscles, poly(etheretherketone) (PEEK), a nondegradable polymer implant model, induces FBRs with dense fibrotic scarring under an aberrant cellular profile that recruits high levels of inflammatory infiltrates, foreign body giant cells (FBGCs), scar-forming myofibroblasts, and inflammatory M1-like macrophages but negligible amounts of anti-inflammatory M2-like phenotypes. However, the PSL-multilayer coating markedly diminishes these detrimental signatures by shifting the macrophage phenotype. Unlike other therapeutics, PSL-multilayered coatings also stimulate muscle regeneration. This study demonstrates that PSL-multilayered coatings are effective in eliminating FBRs and promoting regeneration, hence offering potent and broad applications for implantable biomaterials.

Intermittent actuation attenuates fibrotic behaviour of myofibroblasts.

The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical implants as it can isolate the implant from the host environment. Modulation of fibrotic capsule formation has been achieved using intermittent actuation of drug delivery implants, however the mechanisms underlying this response are not well understood. Here, we use analytical, computational, and in vitro models to understand the response of human myofibroblasts (WPMY-1 stromal cell line) to intermittent actuation using soft robotics and investigate how actuation can alter the secretion of collagen and pro/anti-inflammatory cytokines by these cells. Our findings suggest that there is a mechanical loading threshold that can modulate the fibrotic behaviour of myofibroblasts, by reducing the secretion of soluble collagen, transforming growth factor beta-1 and interleukin 1-beta, and upregulating the anti-inflammatory interleukin-10. By improving our understanding of how cells involved in the FBR respond to mechanical actuation, we can harness this technology to improve functional outcomes for a wide range of implanted medical device applications including drug delivery and cell encapsulation platforms. STATEMENT OF SIGNIFICANCE: A major barrier to the successful clinical translation of many implantable medical devices is the foreign body response (FBR) and resultant deposition of a hypo-permeable fibrotic capsule (FC) around the implant. Perturbation of the implant site using intermittent actuation (IA) of soft-robotic implants has previously been shown to modulate the FBR and reduce FC thickness. However, the mechanisms of action underlying this response were largely unknown. Here, we investigate how IA can alter the activity of myofibroblast cells, and ultimately suggest that there is a mechanical loading threshold within which their fibrotic behaviour can be modulated. These findings can be harnessed to improve functional outcomes for a wide range of medical implants, particularly drug delivery and cell encapsulation devices.

Biocompatibility of polyurethane-coated breast implants: A histological comparison of implant capsules.

BACKGROUND: Biocompatibility describes the influence of materials on their biological environment. Implant material in the human body can cause a foreign body reaction and the formation of a capsule around the foreign material. Since capsular formation is the most frequent issue after breast-implant insertion, knowledge and awareness of biocompatibility is crucial, especially since worldwide, breast augmentation continues to be the most popular plastic surgery, with over 1.6 million procedures performed in 2020, according to surveys by the International Society of Aesthetic Plastic Surgery (ISAPS). MATERIAL AND METHODS: This study includes 80 capsular samples of female patients who underwent revision surgery after breast-implant insertion at the University Hospital Regensburg. Capsules of breast implants with different surface structures (smooth, textured and polyurethane-coated) and shapes (round-shaped, anatomically-shaped) were analyzed histologically after hematoxylin-eosin-staining in respect to capsular thickness and layer formation. RESULTS: Capsular thickness and layering showed a statistically significant difference between polyurethane-coated and smooth as well as polyurethane-coated and textured implants. Capsules around polyurethane-coated implants presented greater thickness. However, the difference between smooth and textured implants was not statistically significant. Furthermore, the shape of the implants also indicated a statistically significant difference in capsular thickness. Implants of anatomical shape resulted in a thinner capsule than round-shaped breast-implants. CONCLUSION: In conclusion, this study demonstrated a thicker capsule around polyurethane-coated breast implants and no difference in capsular thickness between smooth and textured breast implants. Anatomically shaped breast-implants presented a thinner capsule than round shaped breast-implants.

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

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

Amitriptyline efficacy in decreasing implant-induced foreign body reaction.

Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant-induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin-1ß (IL-1ß) or fibrogenic parameters (collagen, TGF-ß, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7-day-old implants. However, AM was able to downregulate angiogenesis and FBR in 14-day-old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices.

Significantly reduced inflammatory foreign-body-response to neuroimplants and improved recording performance in young compared to adult rats.

The multicellular inflammatory encapsulation of implanted intracortical multielectrode arrays (MEA) is associated with severe deterioration of their field potentials' (FP) recording performance, which thus limits the use of brain implants in basic research and clinical applications. Therefore, extensive efforts have been made to identify the conditions in which the inflammatory foreign body response (FBR) is alleviated, or to develop methods to mitigate the formation of the inflammatory barrier. Here, for the first time, we show that (1) in young rats (74±8 gr, 4 weeks old at the onset of the experiments), cortical tissue recovery following MEA implantation proceeds with ameliorated inflammatory scar as compared to adult rats (242 ± 18 gr, 9 weeks old at the experimental onset); (2) in contrast to adult rats in which the Colony Stimulating factor 1 Receptor (CSF1R) antagonist chow eliminated ∼95% of the cortical microglia but not microglia adhering to the implant surfaces, in young rats the microglia adhering to the implant were eliminated along with the parenchymal microglia population. The removal of microglia adhering to the implant surfaces was correlated with improved recording performance by in-house fabricated Perforated Polyimide MEA Platforms (PPMP). These results support the hypothesis that microglia adhering to the surface of the electrodes, rather than the multicellular inflammatory scar, is the major underlying mechanism that deteriorates implant recording performance, and that young rats provide an advantageous model to study months-long, multisite electrophysiology in freely behaving rats. STATEMENT OF SIGNIFICANCE: Multisite electrophysiological recordings and stimulation devices play central roles in basic brain research and medical applications. The insertion of multielectrode-array platforms into the brain's parenchyma unavoidably injures the tissue, and initiates a multicellular inflammatory cascade culminating in the formation of an encapsulating scar tissue (the foreign body response-FBR). The dominant view, which directs most current research efforts to mitigate the FBR, holds that the FBR is the major hurdle to effective electrophysiological use of neuroprobes. By contrast, this report demonstrates that microglia adhering to the surface of a neuroimplants, rather than the multicellular FBR, underlie the performance deterioration of neuroimplants. These findings pave the way to the development of novel and focused strategies to overcome the functional deterioration of neuroimplants.

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.

Lesiones perirradiculares persistentes: revisión narrativa / Persistent periradicular lesions: a narrative review

La persistencia de lesiones perirradiculares luego del tra- tamiento endodóntico es un problema que requiere del clínico un conocimiento cabal de la histofisiología y de la histopato- logía del sistema de conductos radiculares del tejido pulpar y de los tejidos perirradiculares (periodonto y hueso); además de considerar siempre la posible existencia de enfermedades sistémicas que también pueden actuar como factores de in- fluencia. La presencia de bacterias remanentes a posteriori del tratamiento es considerada como una de las causas principales y más frecuentes para la perpetuación de las lesiones perirra- diculares. Sin embargo, existen otros factores causales, como la existencia de conductos laterales o accesorios infectados y no tratados, la reabsorción dentinaria interna, intercomunica- ciones, cul-de-sacs o istmos; que representan áreas de difícil acceso durante la instrumentación e irrigación. Cuando la cau- sa original se localiza en la zona perirradicular, como en los casos de actinomicosis, reacciones a cuerpo extraño, cristales de colesterol (CRCo) y granulomas o quistes con alto conte- nido de CRCo, la indicación más adecuada es el retratamiento y la cirugía periapical como complemento (AU)

The persistence of periradicular lesions after endodontic treatment is a problem that requires the doctor to have a thor- ough knowledge of the histophysiology and histopathology of the root canal system, the pulp tissue and periradicular tis- sues (periodontium and bone); as well as always considering the possible existence of systemic alterations that can also be influencing factors. Persisting bacteria within the root canal system after treatment is one of the major and most frequent causes for the perpetuation of periradicular lesions. Howev- er, there are other possible causal factors such as the exist- ence of untreated lateral or accessory canals, internal dentin resorption, intercommunications, cul-de-sacs or isthmuses; areas that represent a difficulty in access during instrumen- tation and irrigation. If the original cause is located in the periradicular area, in cases like actinomycosis, foreign-body reactions, cholesterol crystals (CRCo) and granulomas or cysts with high content of CRCo, retreatment coupled with periapical surgery is the best approach to treatment (AU)

Multilocular Myospherulosis of the Mandible: A Case Report.

Myospherulosis in the jaw is a rare, foreign body reaction that typically follows tooth extraction and the use of petrolatum-based medicaments. It appears as a radiolucency and can be mistaken for endodontic pathosis or other lesions without thorough clinical and radiographic evaluation as well as biopsy submission. Treatment is surgical removal and the recurrence is rare. This case report presents a unique finding of a posterior mandible multilocular radiolucency appearing as an apical lesion on 2-dimensional panoramic imaging until visualized with 3-dimensional imaging. Clinical testing and patient referral led to a biopsy and diagnosis of myospherulosis. This is the first case report of myospherulosis presented in the endodontic literature.

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.

A case of disintegrated Strattice™ 4 years after immediate breast reconstruction.

Acellular dermal matrices (ADMs) are used frequently in immediate breast reconstruction (IBR). In general, the porcine-derived ADM Strattice™ has been reported with good outcomes and low complication rates. Nonetheless, we report here a case of a 42-year-old, otherwise healthy woman with a history of uncomplicated bilateral prophylactic nipple-sparing mastectomies and subpectoral IBRs performed using Strattice™ and Mentor® CPG™, who was referred to the Department of Plastic Surgery 4 years after this surgery due to changed appearance of her breast implants. Both CPG implants were found intact and there were no signs of infection but, surprisingly, the Strattice™ had completely disintegrated on both sides. Examinations did not show any malignancies, and at 1-year clinical follow-up, the patient had no signs of relapse. Thus, we suggest that the Strattice™ had disintegrated as a late aseptic foreign body reaction and emphasise the importance of surgeons being aware of this late and rare complication.

Ahmed implant coated with poly(2-methacryloyloxyethyl phosphorylcholine) inhibits foreign body reactions in rabbit eyes.

PURPOSE: Wound healing after Ahmed glaucoma valve (AGV) implantation often entails fibrosis as a foreign body reaction to the silicone plate. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) forms an antifouling surface that inhibits fibrosis during wound healing. In this study, we aimed to compare the effects of the implantation of AGV coated with PMPC (wPMPC) versus AGV without PMPC (woPMPC) in rabbits. METHODS: Six New Zealand White rabbit does underwent AGV implantation in both eyes. For each rabbit, one eye was randomly selected for implantation of AGV wPMPC and a conventional AGV (woPMPC) was implanted in the contralateral eye. Gross conjunctival vascularity was compared between the two groups at the first, second, and fourth weeks after surgery. The eyes were enucleated in four weeks and subjected to staining with hematoxylin and eosin and Masson's trichrome stain. The fibrosis and inflammation status among the eye samples were compared by measuring the thickness of the fibrotic walls and counting the number of chronic inflammatory cells around the AGV. Counting of inflammatory cells and measuring fibrotic wall thickness were done in a blinded method to eliminate observer bias. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: Gross and histological examinations revealed no toxic effects of PMPC. There were no apparent differences in overall conjunctival vascularity between the two groups at weeks 1, 2, and 4 after surgery. The average inflammatory cell counts were 14.3 ± 5.8 per slide and 27.3 ± 8.6 per slide in the wPMPC and woPMPC groups, respectively (p = 0.037). The average thicknesses of the fibrotic wall were 57.9 ± 11.3 µm and 81.5 ± 21.3 µm in the wPMPC and woPMPC groups, respectively (p = 0.025). CONCLUSION: Compared to the woPMPC group, the number of inflammatory cells and fibrosis were significantly decreased in the wPMPC group.

SEM and TEM for identification of capsular fibrosis and cellular behavior around breast implants - a descriptive analysis.

BACKGROUND: Capsular fibrosis (CF) is the most common long-term complication in implant-based breast augmentation. It is well accepted that the foreign body response (FBR) instigates the development of fibrotic disease. Our study aims to compare murine and human samples of CF and describe the cellular and extracellular matrix (ECM) composition using scanning and transmission electron microscopy (SEM and TEM). RESULTS: Miniature microtextured silicone breast implants were implanted in mice and subsequently harvested at days 15, 30, and 90 post-operation. Isolated human capsules with the most aggravated form of CF (Baker IV) were harvested post-operation. Both were analyzed with SEM and TEM to assess cellular infiltration and ECM structure. An architectural shift of collagen fiber arrangement from unidirectional to multidirectional was observed at day 90 when compared to days 15 and 30. Fibrosis was observed with an increase of histiocytic infiltration. Moreover, bacterial accumulation was seen around silicone fragments. These findings were common in both murine and human capsules. CONCLUSIONS: This murine model accurately recapitulates CF found in humans and can be utilized for future research on cellular invasion in capsular fibrosis. This descriptive study helps to gain a better understanding of cellular mechanisms involved in the FBR. Increases of ECM and cellularity were observed over time with SEM and TEM analysis.

The relationship between crosslinking structure and silk fibroin scaffold performance for soft tissue engineering.

Biologically active scaffolds with tunable mechano- and bio-performance remain desirable for soft tissue engineering. Previously, highly elastic and robust silk fibroin (SF) scaffolds were prepared via cryogelation. In order to get more insight into the role of ethylene glycol diglycidyl ether (EGDE) on the structure and properties of SF scaffolds, we investigated the fate of SF scaffolds with different usages of the crosslinking agent in vitro and in vivo. Although SF scaffolds with varied EGDE contents showed similar micro-morphology, increasing EGDE from 1 mmol/g to 5 mmol/g resulted in firstly increased and later decreased content of ß-sheet conformation, and linearly increased tensile modulus and decreased elasticity. The dual-crosslinked SF scaffolds with EGDE up to 5 mmol/g did not show in vitro cytotoxicity for NIH3T3 fibroblasts. In vivo subcutaneous implantation of SF scaffolds with <3 mmol/g EGDE displayed excellent degradation behavior and tissue ingrowth after 28 days of implantation. However, with ≥3 mmol/g EGDE, SF scaffolds exhibited obvious post-implantation foreign body reactions, probably associated with slow degradation due to excess chemical crosslinks and less mechanical compatibility. These results suggest that an appropriate dosage of crosslinking agent was critical to achieve balanced mechanical properties, degradability in vivo and immuno-properties of the SF scaffold platform for soft tissue engineering.

Effect of tissue microenvironment on fibrous capsule formation to biomaterial-coated implants.

Within tissue exposed to the systemic immune system, lymphocytes and fibroblasts act against biomaterials via the development of a fibrous capsule, known as the foreign body reaction (FBR). Inspired by the natural tolerance that the uterine cavity has to foreign bodies, our study explores the role of microenvironment across classical (subcutaneous) and immune privileged (uterine) tissues in the development of the FBR. As a model biomaterial, we used electrospun fibers loaded with sclerosing agents to provoke scar tissue growth. Additionally, we integrated these materials onto an intrauterine device as a platform for intrauterine biomaterial studies. Polyester materials in vitro achieved drug release up to 10 days, greater pro-inflammatory and pro-healing cytokine expression, and the addition of gelatin enabled greater fibroblast attachment. We observed the materials that induced the greatest FBR in the mouse, had no effect when inserted at the utero-tubal junction of non-human primates. These results suggest that the FBR varies across different tissue microenvironments, and a dampened fibrotic response exists in the uterine cavity, possibly due to immune privilege. Further study of immune privileged tissue factors on biomaterials could broaden our understanding of the FBR and inform new methods for achieving biocompatibility in vivo.