Foreign Body Giant Cells Research Articles

Clinicopathological Features of 19 Eyelid Pilomatrixomas

Introduction: Pilomatrixoma is a relatively rare, benign tumor arising from the hair root matrix. It is found frequently on the head and neck, with most involving the eyebrow in the periocular region. In contrast, eyelid pilomatrixoma is less common, and often clinically misdiagnosed. Here, we present clinical and histological data from 19 pilomatrixomas arising in the eyelid. Methods: The study represents a retrospective study of eyelid pilomatrixoma diagnosed at our institution since 1981. All slides were reviewed, and demographic as well as clinical data were obtained. Results: Patient ages ranged from 2 to 63 years (mean 24 years), including 12 (63%) females and 7 (37%) males. Eight (42%) and 4 (21%) cases arose in the first and second decades of life, respectively. Upper eyelid involvement was found in 14 (74%) of cases. Microscopically, the tumors were characterized by basaloid and shadow cells accompanied by calcification and foreign body giant cells. Conclusions: Eyelid pilomatrixoma is rarely suspected clinically, and can be mistaken for cyst, chalazion, sebaceous carcinoma, and other tumors. Physicians should consider the possibility of pilomatrixoma in the eyelid area, especially in children or young female patients. Complete excision is curative, and diagnosis can generally be established by histopathological examination.

EMbedding and Backscattered Scanning Electron Microscopy: A Detailed Protocol for the Whole-Specimen, High-Resolution Analysis of Cardiovascular Tissues

Currently, an ultrastructural analysis of cardiovascular tissues is significantly complicated. Routine histopathological examinations and immunohistochemical staining suffer from a relatively low resolution of light microscopy, whereas the fluorescence imaging of plaques and bioprosthetic heart valves yields considerable background noise from the convoluted extracellular matrix that often results in a low signal-to-noise ratio. Besides, the sectioning of calcified or stent-expanded blood vessels or mineralised heart valves leads to a critical loss of their integrity, demanding other methods to be developed. Here, we designed a conceptually novel approach that combines conventional formalin fixation, sequential incubation in heavy metal solutions (osmium tetroxide, uranyl acetate or lanthanides, and lead citrate), and the embedding of the whole specimen into epoxy resin to retain its integrity while accessing the region of interest by grinding and polishing. Upon carbon sputtering, the sample is visualised by means of backscattered scanning electron microscopy. The technique fully preserves calcified and stent-expanded tissues, permits a detailed analysis of vascular and valvular composition and architecture, enables discrimination between multiple cell types (including endothelial cells, vascular smooth muscle cells, fibroblasts, adipocytes, mast cells, foam cells, foreign-body giant cells, canonical macrophages, neutrophils, and lymphocytes) and microvascular identities (arterioles, venules, and capillaries), and gives a technical possibility for quantitating the number, area, and density of the blood vessels. Hence, we suggest that our approach is capable of providing a pathophysiological insight into cardiovascular disease development. The protocol does not require specific expertise and can be employed in virtually any laboratory that has a scanning electron microscope.

DIFFUSE IDIOPATHIC PULMONARY NEUROENDOCRINE HYPERPLASIA IN A PATIENT WITH MYCOBACTERIUM AVIUM COMPLEX

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH) is a preneoplastic lesion that can progress to carcinoid tumors. It differs from reactive hyperplasia in its expression of tumor antigens such as Ki67 as well as the possibility of progression to carcinoid tumors. We present a case of an elderly female with a dry cough who was found to have a lung nodule showing granulomatous inflammation and a focus of neuroendocrine cell hyperplasia suggesting DIPNECH. CASE PRESENTATION: A 78-year-old female with a history of rheumatoid arthritis, breast cancer post excision and radiation therapy, presented with dry cough for a few months. She had a ten-pack-year history of smoking and quit eight years ago. She denied fevers, chills, night sweats, or acute weight changes. Chest CT and PET scan revealed a right middle lobe (RML) lung nodule with increased metabolic activity. EBUS and bronchoscopy specimens did not reveal any organisms or abnormal cytology. The patient underwent wedge resection of the RML. Pathology revealed extensive chronic inflammatory infiltrate with necrotizing granulomas and sparse foreign body giant cells, and a focus of bland appearing cells that stained positive for chromogranin and synaptophysin indicating neuroendocrine differentiation. MiB-1 proliferation index was 1%. Tissue culture grew MAC. A diagnosis of DIPNECH was established. On resection of the nodule, our patient's symptoms resolved, and she required no further therapy. On follow-up at 1.5 years, she was asymptomatic. DISCUSSION: DIPNECH is a rare lung condition presenting mainly with dry cough. CT chest can show solitary or bilateral pulmonary nodules, mosaic perfusion, bronchial wall thickening, ground-glass opacities, air trapping, or bronchiectasis. MiB-1 (antibody to Ki67) expressed in her case indicates tumor antigen expression supporting a diagnosis of DIPNECH vs. reactive hyperplasia. The miB-1 index was 1%, predicting low mitotic activity and a better prognosis. Tissue cultures of her resected specimen grew MAC. MAC is not known to be associated with such a preneoplastic condition. As per our literature review, only two other cases have been reported that describe the concurrence of pulmonary neuroendocrine growth and lung infection. MAC was associated in both these cases. Overall, most patients with DIPNECH experience a stable clinical course. However, severe clinical decline has been reported in a few. CONCLUSIONS: DIPNECH is a rare preneoplastic condition with a good prognosis, although it can sometimes progress to carcinoid tumors with clinical deterioration. Identification of risk factors may be helpful in timely diagnosis and treatment of DIPNECH. MAC is one such factor that seems to be associated with DIPNECH. Further studies should be undertaken to investigate their relationship. REFERENCE #1: Böhm J, Koch S, Gais P, Jütting U, Präuer HW, Höfler H. Prognostic value of MIB-1 in neuroendocrine tumours of the lung. J Pathol. 1996;178(4):402-409. doi:10.1002/(SICI)1096-9896(199604)178:4<402::AID-PATH498>3.0.CO;2-5 REFERENCE #2: Chassagnon G, Favelle O, Marchand-Adam S, De Muret A, Revel MP. DIPNECH: when to suggest this diagnosis on CT. Clin Radiol. 2015;70(3):317-325. doi:10.1016/j.crad.2014.10.012 REFERENCE #3: Krvavac A, Patel PH, Kamel G, Najmuddin M, Nayak RP, Patolia S. Pulmonary Neuroendocrine Cell Hyperplasia in a Patient with Mycobacterium avium Complex. Am J Respir Crit Care Med. 2018 Nov 1;198(9):e109-e110. doi: 10.1164/rccm.201801-0199IM. PMID: 30130431. DISCLOSURES: No relevant relationships by Lipisha Agarwal, source=Web Response No relevant relationships by Divyansh Bajaj, source=Web Response No relevant relationships by Chinmay Jani, source=Web Response No relevant relationships by Joseph Khoory, source=Web Response No relevant relationships by Abdullah Melhim, source=Web Response No relevant relationships by Gabriel Ryan, source=Web Response No relevant relationships by Harpreet Singh, source=Web Response

Inflammatory and regenerative processes in bioresorbable synthetic pulmonary valves up to two years in sheep–Spatiotemporal insights augmented by Raman microspectroscopy

In situ heart valve tissue engineering is an emerging approach in which resorbable, off-the-shelf available scaffolds are used to induce endogenous heart valve restoration. Such scaffolds are designed to recruit endogenous cells in vivo, which subsequently resorb polymer and produce and remodel new valvular tissue in situ. Recently, preclinical studies using electrospun supramolecular elastomeric valvular grafts have shown that this approach enables in situ regeneration of pulmonary valves with long-term functionality in vivo. However, the evolution and mechanisms of inflammation, polymer absorption and tissue regeneration are largely unknown, and adverse valve remodeling and intra- and inter-valvular variability have been reported. Therefore, the goal of the present study was to gain a mechanistic understanding of the in vivo regenerative processes by combining routine histology and immunohistochemistry, using a comprehensive sheep-specific antibody panel, with Raman microspectroscopy for the spatiotemporal analysis of in situ tissue-engineered pulmonary valves with follow-up to 24 months from a previous preclinical study in sheep. The analyses revealed a strong spatial heterogeneity in the influx of inflammatory cells, graft resorption, and foreign body giant cells. Collagen maturation occurred predominantly between 6 and 12 months after implantation, which was accompanied by a progressive switch to a more quiescent phenotype of infiltrating cells with properties of valvular interstitial cells. Variability among specimens in the extent of tissue remodeling was observed for follow-up times after 6 months. Taken together, these findings advance the understanding of key events and mechanisms in material-driven in situ heart valve tissue engineering. Statement of significanceThis study describes for the first time the long-term in vivo inflammatory and regenerative processes that underly in situ heart valve tissue engineering using resorbable synthetic scaffolds. Using a unique combinatorial analysis of immunohistochemistry and Raman microspectroscopy, important spatiotemporal variability in graft resorption and tissue formation was pinpointed in in situ tissue-engineered heart valves, with a follow-up time of up to 24 months in sheep. This variability was correlated to heterogenous regional cellular repopulation, most likely instigated by region-specific differences in surrounding tissue and hemodynamics. The findings of this research contribute to the mechanistic understanding of in situ tissue engineering using resorbable synthetics, which is necessary to enable rational design of improved grafts, and ensure safe and robust clinical translation.

Florid Foreign Body-type Giant Cell Response to Keratin Is Associated With Improved Overall Survival in Patients Receiving Preoperative Therapy for Esophageal Squamous Cell Carcinoma.

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

Fibrin polymer on the surface of biomaterial implants drives the foreign body reaction

Implantation of biomaterials and medical devices in the body triggers the foreign body reaction (FBR) which is characterized by macrophage fusion at the implant surface leading to the formation of foreign body giant cells and the development of the fibrous capsule enveloping the implant. While adhesion of macrophages to the surface is an essential step in macrophage fusion and implanted biomaterials are known to rapidly acquire a layer of host proteins, a biological substrate that is responsible for this process in vivo is unknown. Here we show that mice with genetically imposed fibrinogen deficiency display a dramatic reduction of macrophage fusion on biomaterials implanted intraperitoneally and subcutaneously and are protected from the formation of the fibrin-containing fibrous capsule. Furthermore, macrophage fusion on biomaterials implanted in FibAEK mice that express a mutated form of fibrinogen incapable of thrombin-mediated polymerization was strongly reduced. Despite the lack of fibrin, the capsule was formed in FibAEK mice, although it had a different composition and distinct mechanical properties than that in wild-type mice. Specifically, while mononuclear α-SMA-expressing macrophages embedded in the capsule of both strains of mice secreted collagen, the amount of collagen and its density in the tissue of FibAEK mice was reduced. These data identify fibrin polymer as a key biological substrate driving the development of the FBR.

A Histopathologic Approach to Uterine Niche: What to Expect and to Report in Hysteroscopy-Resected Isthmocele Specimens

As one of the emerging complications of caesarean sections (CSs), pathologists will have an important role in handling samples of uterine niches. An isthmocele is a defect at the site of a previous CS scar resulting in a variety of symptoms and niche-related subfertility. There is a deficiency in the literature of the histopathologic features of hysteroscopy-resected isthmocele ridges. Our aim is to fill this gap to highlight what to expect to see and what important findings to report to guide gynecologists to the results of hysteroscopic isthmoplasty in relation to symptoms improvement, fertility restoration, and potential complications. We found 22 cases of hysteroscopy-resected isthmoceles by performing a retrospective review study. The majority of the women were symptomatic with secondary infertility. The resected isthmocele edges were lined by endocervical, endometrial, and isthmic mucosa either combined or isolated depending on each case. Isthmoceles could be classified depending on the predominant lining mucosa into endocervical-isthmoendocervical (low) and endometrial-isthmic (high-intermediate) niches. This could be correlated with certain symptoms. The edges showed variably thickened fibrous and fibromuscular stromal tissue with characteristic thick-walled blood vessels. Some cases showed miscellaneous findings such as hemosiderin pigments with foreign body giant cell reaction and placental implantation site tissue reflecting a previous history of surgical repair and scar pregnancy. Cauterization artifacts may impose interpretation challenges for pathologists. Utility of certain special stains helps delineate the nature of badly cauterized tissues. It is important to report certain histologic findings in isthmocele samples to correlate with clinical findings and guide gynecologists.

RADIOGRAPHIC FINDINGS OF DENTIGEROUS CYSTS WITH CHOLESTEROL GRANULOMA

<h3>BACKGROUND</h3> Dentigerous cysts are common benign odontogenic cysts.¹ A dentigerous cyst is characterized by an epithelium attachment that is associated with the crown of an unerupted tooth and appears radiographically as a well-defined radiolucency.^2,3 The dentigerous cyst may be a cholesterol granuloma histopathologically when it is associated with numerous cholesterol clefts with foam cells, foreign body giant cells, and macrophages filled with hemosiderin.⁴ Cholesterol granuloma often occurs in the middle ear and may be found in other sites.⁵ There are very few reported cases of cholesterol granuloma in the jaws. <h3>CASE REPORT</h3> We present 4 cases of dentigerous cysts with cholesterol granuloma. All 3 lesions were in the mandible. The first patient was a 34-year-old man who had a lesion in his right mandibular ramus. The second patient was a 45-year-old man with a lesion in the left posterior mandible. The third patient was a 77-year-old man with 2 lesions in the posterior mandible bilaterally. The lesions were mostly well defined. Three were unilocular and one multilocular with sclerotic margins, suggestive of peripheral bone reaction to a possible inflammatory process. The histopathologic diagnosis of these cases was dentigerous cyst with cholesterol granuloma. <h3>DISCUSSION/CONCLUSIONS</h3> The pathogenesis of cholesterol granuloma is still unclear.⁴ Cholesterol granuloma may form because of either possible disruption of ventilation and/or improper drainage and hemorrhage into a closed cavity.⁵ Cholesterol granuloma could lead to the expansion of the lesion and may have a leading role in cyst growth. The formation of large cholesterol crystals causes a foreign body reaction that releases macrophages and multinucleated giant cells. The cholesterol granulomas resist the action of phagocytes and continue to release inflammatory and bone resorptive products that may lead to expansion along with aggressive radiographic features.

Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs.

Decellularization of xenogeneic heart valves might lead to excellent regenerative implants, from which many patients could benefit. However, this material carries various xenogeneic epitopes and thus bears a considerable inherent immunological risk. Here, we investigated the regenerative and immunogenic potential of xenogeneic decellularized heart valve implants using pigs deficient for the galactosyltransferase gene (GGTA1-KO) as novel large animal model. Decellularized aortic and pulmonary heart valves obtained from sheep, wild-type pigs or GGTA1-KO pigs were implanted into GGTA1-KO pigs for 3, or 6 months, respectively. Explants were analyzed histologically, immunhistologically (CD3, CD21 and CD172a) and anti-αGal antibody serum titers were determined by ELISA. Xenogeneic sheep derived implants exhibited a strong immune reaction upon implantation into GGTA1-KO pigs, characterized by massive inflammatory cells infiltrates, presence of foreign body giant cells, a dramatic increase of anti-αGal antibody titers and ultimately destruction of the graft, whereas wild-type porcine grafts induced only a mild reaction in GGTA1-KO pigs. Allogeneic implants, wild-type/wild-type and GGTA1-KO/GGTA1-KO valves did not induce a measurable immune reaction. Thus, GGTA1-KO pigs developed a 'human-like' immune response toward decellularized xenogeneic implants showing that immunogenicity of xenogeneic implants is not sufficiently reduced by decellularization, which detracts from their regenerative potential.

The intensity of the foreign body response to polyether-polyurethane implant in diabetic mice is strain-dependent.

A number of genetic factors have been linked to the development of diabetes, a condition that often requires implantable devices such as glucose sensors. In normoglycaemic individuals, this procedure induces a foreign body reaction (FBR) that is detrimental to bioimplant functionality. However, the influence of the genetic background on this reaction in diabetes has not been investigated. We examined the components of FBR (capsule thickness, collagen deposition, mast cell and foreign body giant cell number) in subcutaneous implants of polyether polyurethane (SIPP) in streptozotocin (STZ)-induced diabetes in Swiss, C57BL/6 and Balb/c mice. The fasting blood glucose levels before STZ injections were 133.5±5.1mg/dL, after the treatment increased 68.4% in Swiss mice, 62.4% in C57BL/6 and 30.9% in Balb/c mice. All FBR features were higher in implants of Swiss and C57BL/6 mice compared with those in implants of Balb/c. Likewise, the apoptotic index was higher in implants of diabetic Swiss and C57BL/6 mice whose glycaemic levels were the highest. Our findings show an association between the severity of hyperglycaemic levels and the intensity of the FBR to SIPP. These important strain-related differences in susceptibility to diabetes and the intensity of the FBR must be considered in management using implantable devices in diabetic individuals.

A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus

BackgroundImplantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors.Methods343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry.Results61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p < 0.02). Mean length of time of implantation of occluded VCs, 33.22 months was greater than for non-occluded VCs, 23.8 months (p = 0.02). Patients with myelomeningocele had a greater probability of having an occluded VC (p = 0.0426). VCs with occlusions had greater numbers of macrophages and astrocytes in comparison to non-occluded VCs (p < 0.01). Microglia comprised only 2–6% of the VC-obstructing tissue aggregates. Histologic analysis showed choroid plexus occlusion in 24%, vascularized glial tissue occlusion in 24%, prevalent lymphocytic inflammation in 29%, and foreign body giant cell reactions in 5% and no ependyma.ConclusionOur data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence.

Morphological Features of Foreign Body Giant Cells in Experimental Conditions

Background: The purpose of our work was determined by the accumulation of a significant amount of experimental material under the conditions of implantation of a foreign body, a mesh implant, into the region of the anterior abdominal wall in order to obtain experimental inflammation, in which foreign body giant cells (FBGCs) were constantly visualized as reactive formations. This research aimed to study the dynamics of morphological changes in FBGCs under conditions of experimental implantation of a foreign body, a mesh implant, and the possible mechanism of their formation Methods and Results: This study was carried out on male Wistar rats, in which a foreign body was implanted—a mesh endoprosthesis made of polypropylene—in the region of the anterior abdominal wall under the aponeurosis of the rectus abdominis muscles. A section of the anterior abdominal wall with the implanted endoprosthesis was excised on Days 10, 21, 30, and 60 after surgery, fixed in 10% buffered formalin solution. The obtained samples were embedded in paraffin according to standard prescriptions; histological sections with a thickness of 5-7µm were made and stained with H&amp;E, according to the methods of Van Gieson and Mallory, and an immunohistochemical study was performed using the marker of cell proliferation (Ki-67). The revealed structural features of multinucleated cells were recorded by microphotography using a photo attachment and a Levenhuk video camera (USA). During the study, it was revealed that the amount, functional activity and morphological diversity of FBGCs gradually increased, reaching a maximum by Day 30 of the experiment. At a later date, some of them died, while the remaining part was differentiated, splitting into small multinucleated cells and mononuclear elements, morphologically identical to macrophages and fibroblasts. The formation of FBGCs continued as long as the mesh implant was in the body. Conclusion: FBGCs are reactive formations that arise in response to various endo- and exogenous irritation.

Cholesterol granuloma of the maxillary sinus: a forgotten entity

Aim of the study: Cholesterol granuloma is a histological entity which consists of granulation tissue in which a large quantity of cholesterol crystals provoke foreign body giant cell formation. Cholesterol granulomas are often found in the middle ear with rare presentation in the paranasal sinus. We would like to highlight the diagnostic challenges and the management of maxillary sinus cholesterol granuloma in a young woman presenting as a unilateral nasal mass. Case study: We report a young woman with cholesterol granuloma of maxillary sinus who initially presented with unilateral nasal obstruction. Rigid nasoendoscopy and imaging were suggestive of an antrochoanal polyp. Ipsilateral functional endoscopic sinus surgery was done successfully. Conclusion: Albeit rare, cholesterol granuloma ought to be considered a differential diagnosis in a sinonasal tumour. This case report highlights the rare presentation of maxillary sinus cholesterol granuloma which ought to be considered a differential diagnosis of a unilateral nasal mass.

Initial immune response to a FRET-based MMP sensor-immobilized silk fibroin hydrogel in vivo

To investigate the initial immune response to biodegradable silk fibroin (SF) hydrogels in vivo, a Förster/fluorescence resonance energy transfer (FRET)-based sensor was developed to detect matrix metalloproteinase (MMP) activity (FRET-MMPS) and immobilized to SF hydrogel. FRET-MMPS immobilized to SF hydrogel in vitro displayed intra-molecular FRET more than inter-molecular FRET, and MMP activity was detected through a decrease in FRET signal intensity. Then, the SF hydrogel modified with FRET-MMPS was implanted into mice subcutaneously, and it was observed that the FRET signal intensity decreased significantly soon (< 3 h) after implantation. Although the intensity exhibited a sharp decrease toward 24 h post-implantation, histological evaluation proved that bulk-level hydrogel degradation, such as breakdown, was mainly caused by macrophages and foreign body giant cells on a timescale of weeks. These results indicated that, immediately upon implantation, active MMPs reached the SF hydrogel and began cleaving SF networks, which might result in the loosening of the networks and then enabled immune cells, such as macrophages, to start the bulk-level hydrogel degradation. The sensor clarified the initial immune response to SF hydrogels and will provide clues for designing the biodegradation behaviors of scaffolds for regenerative medicine. Statement of significanceSilk fibroin (SF) materials are degraded gradually by the immune response. Immune cells, such as macrophages, break down implanted SF materials on a timescale of weeks or months, but the initial (< 24 h) immune response to SF materials remains unclear. In this study, SF hydrogels modified with Förster/fluorescence resonance energy transfer (FRET)-based matrix metalloproteinase (MMP) sensors were implanted in mice and within 3 h post-implantation, the SF hydrogels were degraded by MMPs. Although this molecular-level biodegradation was not correlated with the hydrogel breakdown, the MMPs were likely to loosen the SF networks to enable immune cells to infiltrate and degrade the hydrogel. This is the first study to unveil the initial stage of immune response to biomaterials.

Inflammatory and Regenerative Processes in Bioresorbable Synthetic Pulmonary Valves Up to 2 Years in Sheep: Spatiotemporal Insights Augmented by Raman Microspectroscopy

In situ heart valve tissue engineering is an emerging approach in which resorbable, off-the-shelf available scaffolds are used to induce endogenous heart valve restoration. Such scaffolds are designed to recruit endogenous cells in vivo, which subsequently resorb polymer and produce and remodel new valvular tissue in situ. Recently, preclinical studies using electrospun supramolecular elastomeric valvular grafts have shown that this approach enables in situ regeneration of pulmonary valves with long-term functionality in vivo. However, the evolution and mechanisms of inflammation, polymer absorption and tissue regeneration are largely unknown, and adverse valve remodeling and intra- and inter-valvular variability have been reported. Therefore, the goal of the present study was to gain a mechanistic understanding of the in vivo regenerative processes by combining routine histology and immunohistochemistry, using a comprehensive sheep-specific antibody panel, with Raman microspectroscopy for the spatiotemporal analysis of in situ tissue-engineered pulmonary valves with follow-up to 24 months from a previous preclinical study in sheep. The analyses revealed a strong spatial heterogeneity in the influx of inflammatory cells, graft resorption, and foreign body giant cells. Collagen maturation occurred predominantly between 6 and 12 months after implantation, which was accompanied by a progressive switch to a more quiescent phenotype of infiltrating cells with properties of valvular interstitial cells. Variability among specimens in the extent of tissue remodeling was observed for follow-up times after 6 months. Taken together, these findings advance the understanding of key events and mechanisms in material-driven in situ heart valve tissue engineering.

Effects of Cyanoacrylate in Rabbits with Induced Achilles Tendon Rupture.

BackgroundIn this study, we aimed to investigate the effects of N-butyl-2-cyanoacrylate (cyanoacrylate) on the biomechanical and histopathological aspects of tendon healing in a rabbit model of Achilles tendon injury.Material/MethodsIn total, 36 rabbits were randomized to experimental (cyanoacrylate) and control groups (n=36 tendons in each group). A simple suture was used in the control group and a simple suture plus cyanoacrylate was used in the experimental group.Nine rabbits from each group were euthanized at week 4 and week 6 after surgery for histopathological and biomechanical testing.ResultsGranulation tissue formation was significantly greater in the experimental group in week 4 and week 6 than in the control group. Foreign body giant cell formation was significantly higher in the experimental group in week 4 and week 6. The maximum rupture force was significantly higher in the experimental group in week 4 and week 6 than in the control group. Elasticity and stiffness were comparable between groups in week 4; however, stiffness, but not elasticity, was significantly higher in the experimental group in week 6.ConclusionsIn the short term, cyanoacrylate enhanced tendon endurance in both a histopathological and biomechanical manner. We conclude that the early initiation of rehabilitation in patients may be safe in cases of cyanoacrylate use for surgical repair of tendon injury.

Experimental Study Comparing Structural Changes Induced by Biologic Versus Synthetic Mesh Implants in Nephropexy

Background: The study suggests that the use of the extracellular bovine-derived peritoneum matrix as a new biological implant opens up new prospects for nephropexy.&#x0D; Materials and Methods: Experimental nephropexy was performed in 64 white shorthaired adult rats, divided for 2 groups: extracellular bovine-derived peritoneum matrix, UltraPro mesh. Implants were 1,5*1,5cm per one animal. Observation periods were 7, 21, 30 and 180 days. The tissue was stain with H&amp;E, Van Gieson’s with pikro-fuchin. Cellular infiltrate was evaluated by counting granulocytes, mononuclear cells, and foreign-body giant cells on five high-magnification images for each stained section (×400).&#x0D; Results: The use of the extracellular bovine-derived peritoneum matrix induced less intense and less prolonged chronic inflammatory response, as well as intense production of new collagen fibers more similar to the native connective tissue in terms of their histologic structure. The UltraPro mesh induced moderately persistent chronic inflammatory response throughout the 6- month study period.&#x0D; Conclusion: Histologic evaluation demonstrates high biocompatibility of both the extracellular bovine-derived peritoneum matrix, and the UltraPro mesh implants.The results of using new biological material are not worse than synthetic mesh. The data obtained justify further research of the extracellular bovine-derived peritoneum matrix as a plastic material for nephropexy.

Effects of Titanium Corrosion Products on In Vivo Biological Response: A Basis for the Understanding of Osseointegration Failures Mechanisms

Corrosion resistance is a key feature of titanium biocompatibility. However, Ti surfaces exposed to critical environments (such as, chronic infection and inflammation) can undergo corrosion processes in vivo, leading to an unfavorable biological response and clinical failure, which remains poorly explored. In this study, we characterized an experimental model to replicate the surface features of Ti corrosion process observed within in vivo failures, and the cellular, tissue and molecular events associated with corroded Ti surface implantation into subcutaneous and bone tissue of C57Bl/6 mice. Prior to in vivo implantation, commercially pure Ti Commercially pure titanium and Ti–6Al–4V alloy (Ti64) specimens were exposed to electrochemical polarization in 30% citric acid, while being polarized at 9 V against a saturated calomel electrode for 20 min. The electrochemical attack induced accelerated corrosion on both Ti-based specimens, producing structural and chemical changes on the surface, comparable to changes observed in failed implants. Then, microscopy and molecular parameters for healing and inflammation were investigated following control and corroded Ti implantation in subcutaneous (cpTi disks) and oral osseointegration (Ti64 screws) models at 3, 7, 14 and 21 days. The host response was comparatively evaluated between control and corroded Ti groups by microCT (bone), histology (H&amp;amp;E, histomorphometry, immunostaining and picrosirius red), and real-time PCR array for inflammatory and healings markers. Corroded cpTi disks and Ti64 screws induced a strong foreign body response (FBR) from 3 to 21 days-post implantation, with unremitting chronic inflammatory reaction lasting up to 21 days in both subcutaneous and osseointegration models. In the subcutaneous model, FBR was accompanied by increased amount of blood vessels and their molecular markers, as well as increased TRAP+ foreign body giant cell count. In the osseointegration model, failures were identified by an osteolytic reaction/bone loss detected by microCT and histological analyses. The corroded devices were associated with a dominant M1-type response, while controls showed transient inflammation, an M2-type response, and suitable healing and osseointegration. In conclusion, corrosion of Ti-based biomaterials induced exacerbated inflammatory response in both connective tissue and bone, linked to the upregulation of fibrosis, pro-inflammatory and osteoclastic markers and resulted in unfavorable healing and osseointegration outcomes.

Honeycomb scaffolds capable of ectopic osteogenesis: Histological evaluation of osteoinduction mechanism

AbstractScaffolds capable of inducing ectopic osteogenesis (i.e., osteoinduction) have the potential to treat congenital and massive bone defects. However, the mechanisms underlying osteoinduction remain elusive, largely because of rapid tissue changes occurring early in the process. A model with decelerated osteoinduction is, therefore, needed. Here, we developed carbonate apatite honeycomb scaffolds capable of osteoinduction in rabbit muscle, which inherently exhibits minimal osteoinduction. The key events observed were: (1) fibrin accumulation in scaffolds at week 1; (2) appearance of tartrate‐resistant acid phosphatase (TRAP)‐ and RAM11‐positive cells and formation of collagen fibers and blood vessels between weeks 2 and 3; (3) appearance of osteocalcin‐positive cells and decrease in the number of TRAP‐positive cells between weeks 3 and 4; (4) continuous proliferation of osteocalcin‐positive cells at postoperative week 4 and formation of osteoid and mineralized tissues at weeks 8 and 12, respectively. These findings suggest that the appearance of TRAP‐positive cells that are considered foreign body giant cells is essential for collagen formation, angiogenesis, and osteogenesis. These insights may aid in the development of scaffolds for bone tissue engineering.

Prognostic impact of sterilized lymph nodes in esophageal squamous cell carcinomas after neoadjuvant chemoradiotherapy

BackgroundThe prognostic importance of sterilized lymph nodes (SLN) remains unclear in patients with esophageal squamous cell carcinomas (ESCC) treated by neoadjuvant chemoradiotherapy (nCRT). This study aimed to determine whether SLN predicted disease-free survival (DFS) in ESCC. MethodsWe enrolled 246 eligible patients who were divided into SLN (+) and SLN (-) group according to the presence or absence of fibrosis, necrosis, calcifications and/or foreign body giant cell reactions in the negative lymph nodes specimens. The prognostic value of SLN was determined using univariate and multivariate analyses. The prognostic strength of counting SLN as positive lymph nodes was evaluated using the difference of Akaike information criterion (ΔAIC). ResultsA total of 61 SLN were identified in 38 (15.4%) patients. There was no significant difference in baseline characteristics between SLN (+) and SLN (-) group. The most frequently detected SLN in the thoracic cavity and abdominal cavity were those along bilateral recurrent laryngeal nerve (21/38,55.3%) and left gastric artery (13/24,60.9%), respectively. The univariate and multivariate analyses showed SLN was an independent prognostic factor for worse DFS in the whole cohort (HR = 2.05, 95%CI = 1.08–3.90, P = 0.029). The SLN (+) group additionally correlated with worse 5-year DFS than SLN (-) group in the ypT0, ypN0 and pCR subgroups. Counting SLN as positive lymph nodes showed better prognostic strength than ignoring them. ConclusionSLN was of prognostic significance for worse DFS in patients with ESCC, particularly in patients with good response to nCRT.