Small Intestinal Submucosa Hydrogel Loaded With Gastrodin for the Repair of Achilles Tendinopathy.

Achilles tendinopathy (AT) is an injury caused by overuse of the Achilles tendon or sudden force on the Achilles tendon, with a considerable inflammatory infiltrate. As Achilles tendinopathy progresses, inflammation and inflammatory factors affect the remodeling of the extracellular matrix (ECM) of the tendon. Gastrodin(Gas), the main active ingredient of Astrodia has anti-inflammatory, antioxidant, and anti-apoptotic properties. The small intestinal submucosa (SIS) is a naturally decellularized extracellular matrix(dECM)material and has a high content of growth factors as well as good biocompatibility. However, the reparative effects of SIS and Gas on Achilles tendinopathy and their underlying mechanisms remain unknown. Here, it is found that SIS hydrogel loaded with gastrodin restored the mechanical strength of the Achilles tendon, facilitated ECM remodeling, and restored ordered collagen arrangement by promoting the translocation of protein synthesis. It also decreases the expression of inflammatory factors and reduces the infiltration of inflammatory cells by inhibiting the NF-κB signaling pathway. It is believed that through further research, Gas + SIS may be used in the future for the treatment of Achilles tendinopathy and other Achilles tendon injury disorders.

A 3D-printed scaffold composed of Alg/HA/SIS for the treatment of diabetic bone defects.

Background: Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair. Method: In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and in vitro biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the in vivo biological effect of the scaffold after implantation. Results: The in vitro and in vivo results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering. Conclusion: The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances in vitro and in vivo, which properties are well-suited with the requirement for treating diabetic bone defects. Translational potential of this article: The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.

Therapeutic application of decellularized porcine small intestinal submucosa scaffold in conjunctiva reconstruction.

The objective of this study was to investigate the biological feasibility and surgical applicability of decellularized porcine small intestinal submucosa (DSIS) in conjunctiva reconstruction. A total of 52 Balb/c mice were included in the study. We obtained the DSIS by decellularization, evaluated the physical and biological properties of DSIS in vitro, and further evaluated the effect of surgical transplantation of DSIS scaffold in vivo. The histopathology and ultrastructural analysis results showed that the scaffold retained the integrity of the fibrous morphology while removing cells. Biomechanical analysis showed that the elongation at break of the DSIS (239.00 ± 12.51%) were better than that of natural mouse conjunctiva (170.70 ± 9.41%, P < 0.05). Moreover, in vivo experiments confirmed the excellent biocompatibility of the decellularized scaffolds. In the DSIS group, partial epithelialization occurred at day-3 after operation, and the conjunctival injury healed at day-7, which was significantly faster than that in human amniotic membrane (AM) and sham surgery (SHAM) group (P < 0.05). The number and distribution of goblet cells of transplanted DSIS were significantly better than those of the AM and SHAM groups. Consequently, the DSIS scaffold shows excellent biological characteristics and surgical applicability in the mouse conjunctival defect model, and DSIS is expected to be an alternative scaffold for conjunctival reconstruction.

Multi-Omics Characterization of Colon Mucosa and Submucosa/Wall from Crohn's Disease Patients.

Crohn's disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. However, most studies have focused on the intestinal mucosa, overlooking the contribution of the intestinal wall in Crohn's disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn's disease and identifying potential biomarkers. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand chronic refractory disease elements to achieve transmural healing. The results revealed similarities and differences in gene and protein expression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease, such as decreased RTN4 isoforms (RTN4B2 and RTN4C) in the submucosa/wall, which may be related to the dysregulation of enteric neural processes. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.

Reinforcing decellularized small intestine submucosa with cellulose acetate nanofibrous and silver nanoparticles as a scaffold for wound healing applications.

BACKGROUND: The formation of chronic wounds accounts for considerable costs in health care systems. Despite the several benefits of decellularized small intestinal submucosa (SIS) as an appropriate scaffold for different tissue regeneration, it has shortcomings such as lack of antibacterial features and inappropriate mechanical properties for skin tissue regeneration. We aimed to examine the efficacy and safety of decellularized SIS scaffold enhanced with cellulose acetate (CA) and silver (Ag) nanoparticles (NPs) for healing full-thickness wounds. METHODS AND RESULTS: The scaffolds were prepared by decellularizing bovine SIS and electrospinning CA/Ag nanoparticles and characterized using a transmission electron microscope (TEM), scanning electron microscope (SEM), tensile testing, and X-ray diffraction. In vivo evaluations were performed using full-thickness excisions covered with sterile gauze as the control group, SIS, SIS/CA, and SIS/CA/Ag scaffolds on the dorsum of twenty male Wistar rats divided into four groups randomly with 21-days follow-up. All in vivo specimens underwent Masson's trichrome (MT) staining for evaluation of collagen deposition, transforming growth factor-ß (TGF-ß) immunohistochemistry (IHC), and Haematoxylin Eosin (H&E) staining. The IHC and MT data were analyzed with the ImageJ tool by measuring the stained area. The TEM results revealed that Ag nanoparticles are successfully incorporated into CA nanofibers. Assessment of scaffolds hydrophilicity demonstrated that the contact angle of SIS/CA/Ag scaffold was the lowest. The in vivo results indicated that the SIS/CA/Ag scaffold had the most significant wound closure. H&E staining of the in vivo specimens showed the formation of epidermal layers in the SIS/CA/Ag group on day 21. The percentage of the stained area of MT and TGF-ß IHC staining's was highest in the SIS/CA/Ag group. CONCLUSION: The decellularized SIS/CA/Ag scaffolds provided the most significant wound closure compared to other groups and caused the formation of epidermal layers and skin appendages. Additionally, the collagen deposition and expression of TGF-ß increased significantly in SIS/CA/Ag group.

Human umbilical cord mesenchymal stem cells combined with porcine small intestinal submucosa promote the healing of full-thickness skin injury in SD rats.

Aim: To assess the therapeutic potential of human umbilical cord mesenchymal stem cells (hUCMSCs) combined with porcine small intestinal submucosa (SIS) on full-thickness skin injuries in rats. Methods: We established full-thickness skin injury models in Sprague-Dawley rats, dividing them into blank control, SIS, hUCMSCs and hUCMSCs combined with SIS. We monitored wound healing, scores and area, and analyzed inflammatory cells, microvessel density and collagen fibers after 12 days. Results: The blank group showed no healing, forming a scar of 0.6 × 0.5 cm2, while SIS and hUCMSCs groups exhibited incomplete healing with 0.4 × 0.5 cm2 scabs. Wound healing was significantly better in the hUCMSCs combined with the SIS group. Conclusion: Local application of hUCMSCs combined with SIS enhances full-thickness skin injury wound healing in rats.

Our skin protects us from infections and injuries, but severe damage can lead to health problems. In this study, we explored a promising new treatment to enhance skin healing. We used mesenchymal stem cells derived from umbilical cords in combination with a biological material called porcine small intestinal submucosa (SIS) to conduct experiemnts on rats with skin wounds. This treatment led to much better healing in rats with deep skin wounds compared with standard approaches. This approach is promising for treating severe skin injuries, offering hope for quicker recovery and better outcome, including faster recovery, reduced pain and inflammation and less scarring.

Gastroprotective Effect of Quercus infectoria Olivier Galls on Ethanol-Induced Gastritis in Rats.

One of the common inflammatory disorders that substantially affects the stomach and its mucosa is gastritis. It can be induced by non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, alcohol, Helicobacter pylori infection, and stress. These factors affect cellular regeneration, mucus production, and bicarbonate secretion, resulting finally in inflammation and ulceration. Ethanol-induced gastritis is one of the commonly used models for studying the pathology of gastritis and investigating the effect of drugs in managing the disease. Several drugs, such as proton pump inhibitors (PPIs), are available to control and correct the pathological signs of gastritis; however, the side effects of such drugs represent an obstacle to their applications in many cases. Quercus infectoria (QI) Olivier galls are formed as a pathological response to wasp insults to the tree. They are rich in several bioactive molecules, e.g., gallotannins that have been shown to be effective in several inflammatory conditions due to their antioxidant and anti-inflammatory potentials. In this study, we aimed to evaluate the therapeutic potential of QI gall extract (QIGE) in treating ethanol-induced gastritis in rats. To test this, 20 adult male Swiss rats were divided into four groups: healthy control, ethanol-treated (80% in water, 5 ml/kg, per oral gavage), ethanol + omeprazole (20 mg/kg, per oral gavage), and ethanol + QIGE (300 mg/kg, per oral gavage). QIGE was administered for seven days before ethanol administration, which took place three hours after the last QIGE dose. Three hours after ethanol intake, animals were euthanized, gastric content was collected, and stomach tissue was examined for macroscopic changes and then fixed to be further utilized for histological assessment by hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Masson's trichrome staining. Ethanol treatment significantly decreased gastric pH and increased gastric acidity compared to healthy control. It also induced clear morphological and histological damage and ulceration, depleted mucus on the gastric epithelium, and induced edema and collagen deposition in gastric submucosa. The QIGE treatment ameliorated the changes in gastric pH and total acidity. It also protected stomach tissue from ethanol-induced ulceration, histopathological changes, edema, and collagen deposition. The protective effects of QIGE were comparable to those of omeprazole. In conclusion, QI gall extract possesses a promising gastroprotective effect against ethanol-induced gastritis.

Small intestinal submucosa graft bulbar urethroplasty is a viable technique: results compared to buccal mucosa graft urethroplasty after propensity score matching.

PURPOSE: Small intestinal submucosa (SIS) graft urethroplasty has been employed to decrease buccal mucosa morbidity and facilitate the procedure. The first published series had a short follow-up, inhomogeneous patient selection, and a lack of a control group. Our purpose is to report treatment outcomes at 13 years in a propensity score-matched cohort comparing bulbar urethroplasty with SIS (SISU) or buccal mucosa (BMU). METHODS: From our institutional database of 1132 bulbar urethroplasties, we used propensity score matching with the nearest-neighbor method without replacement to generate a study sample of 25 BMU and 25 SISU. Failure was defined as any treatment after urethroplasty. Survival analyses were used to analyze treatment failure occurrence with data censored at 156mo. RESULTS: Matching resulted in a complete correction of bias between the two samples except for the follow-up duration, which was slightly longer in the SIS group. The cumulative treatment success probability of BMU and SISU at 156mo was 83.4% and 68%, respectively. At multivariable Cox regression, SIS graft, previous urethrotomy, stricture length, and lower postoperative Qmax (within 2mo after catheter removal) were predictors of failure. Stricture length had a more remarkable effect in SISU, with estimated survival probabilities from the Cox model lower than 80% in strictures > = 3 cm. CONCLUSION: SIS has poorer outcomes compared to BM but may still be useful when BM grafting is not possible. The best candidates for SISU, with similar success to BMU, are patients with strictures shorter than 3 cm, preferably without a history of DVIU.

Growth capacity of a Wharton's Jelly derived mesenchymal stromal cells tissue engineered vascular graft used for main pulmonary artery reconstruction in piglets.

Background: Surgical treatment of congenital heart defects affecting the right ventricular outflow tract (RVOT) often requires complex reconstruction and multiple reoperations due to structural degeneration and lack of growth of currently available materials. Hence, alternative approaches for RVOT reconstruction, which meet the requirements of biocompatibility and long-term durability of an ideal scaffold, are needed. Through this full scale pre-clinical study, we demonstrated the growth capacity of a Wharton's Jelly derived mesenchymal stromal cells (WJ-MSC) tissue engineered vascular graft used in reconstructing the main pulmonary artery in piglets, providing proof of biocompatibility and efficacy. Methods: Sixteen four-week-old Landrace pigs were randomized to undergo supravalvar Main Pulmonary Artery (MPA) replacement with either unseeded or WJ-MSCs-seeded Small Intestinal Submucosa-derived grafts. Animals were followed up for 6 months by clinical examinations and cardiac imaging. At termination, sections of MPAs were assessed by macroscopic inspection, histology and fluorescent immunohistochemistry. Results: Data collected at 6 months follow up showed no sign of graft thrombosis or calcification. The explanted main pulmonary arteries demonstrated a significantly higher degree of cellular organization and elastin content in the WJ-MSCs seeded grafts compared to the acellular counterparts. Transthoracic echocardiography and cardiovascular magnetic resonance confirmed the superior growth and remodelling of the WJ-MSCs seeded conduit compared to the unseeded. Conclusion: Our findings indicate that the addition of WJ-MSCs to the acellular scaffold can upgrade the material, converting it into a biologically active tissue, with the potential to grow, repair and remodel the RVOT.

The application of small intestinal submucosa in tissue regeneration.

The distinctive three-dimensional architecture, biological functionality, minimal immunogenicity, and inherent biodegradability of small intestinal submucosa extracellular matrix materials have attracted considerable interest and found wide-ranging applications in the domain of tissue regeneration engineering. This article presents a comprehensive examination of the structure and role of small intestinal submucosa, delving into diverse preparation techniques and classifications. Additionally, it proposes approaches for evaluating and modifying SIS scaffolds. Moreover, the advancements of SIS in the regeneration of skin, bone, heart valves, blood vessels, bladder, uterus, and urethra are thoroughly explored, accompanied by their respective future prospects. Consequently, this review enhances our understanding of the applications of SIS in tissue and organ repair and keeps researchers up-to-date with the latest research advancements in this area.

Entire Mitral Valve Reconstruction Using Porcine Extracellular Matrix: Adding a Ring Annuloplasty.

PURPOSE: This study investigated the implications of inserting a flexible annuloplasty ring after reconstructing the entire mitral valve in a porcine model using a previously investigated tube graft design made of 2-ply small intestinal submucosa extracellular matrix (CorMatrix®). METHODS: An acute model with eight 80-kg pigs, each acting as its own control, was used. The entire mitral valve was reconstructed with a 2-ply small intestinal submucosa extracellular matrix tube graft (CorMatrix®). Subsequently, a Simulus® flexible ring was inserted. The characterization was based on mitral annular geometry and valvular dynamics with sonomicrometry and echocardiography. RESULTS: After adding the ring annuloplasty, the in-plane annular dynamics were more constant throughout the cardiac cycle compared to the reconstruction alone. However, the commissure-commissure distance was statistically significantly decreased [35.0 ± 3.4 mm vs. 27.4 ± 1.9 mm, P < 0.001, diff = - 7.6 mm, 95% CI, - 9.8 to (-5.4) mm] after ring insertion, changing the physiological annular D-shape into a circular shape which created folds at the coaptation zone resulting in a central regurgitant jet on color Doppler. CONCLUSION: We successfully reconstructed the entire mitral valve using 2-ply small intestinal submucosal extracellular matrix (CorMatrix®) combined with a flexible annuloplasty. The annuloplasty reduced the unphysiological systolic widening previously found with this reconstructive technique. However, the Simulus flex ring changed the physiological annular D-shape into a circular shape and hindered a correct unfolding of the leaflets. Thus, we do not recommend a flexible ring in conjunction with this reconstructive technique; further investigations are needed to discover a more suitable remodelling annuloplasty.

Preclinical Evaluation of Bioactive Small Intestinal Submucosa-PMMA Bone Cement for Vertebral Augmentation.

In vertebroplasty and kyphoplasty, bioinert poly(methyl methacrylate) (PMMA) bone cement is a conventional filler employed for quick stabilization of osteoporotic vertebral compression fractures (OVCFs). However, because of the poor osteointegration, excessive stiffness, and high curing temperature of PMMA, the implant loosens, the adjacent vertebrae refracture, and thermal necrosis of the surrounding tissue occurs frequently. This investigation addressed these issues by incorporating the small intestinal submucosa (SIS) into PMMA (SIS-PMMA). In vitro analyses revealed that this new SIS-PMMA bone cement had improved porous structure, as well as reduced compressive modulus and polymerization temperature compared with the original PMMA. Furthermore, the handling properties of SIS-PMMA bone cement were not significantly different from PMMA. The in vitro effect of PMMA and SIS-PMMA was investigated on MC3T3-E1 cells via the Transwell insert model to mimic the clinical condition or directly by culturing cells on the bone cement samples. The results indicated that SIS addition substantially enhanced the proliferation and osteogenic differentiation of MC3T3-E1 cells. Additionally, the bone cement's biomechanical properties were also assessed in a decalcified goat vertebrae model with a compression fracture, which indicated the SIS-PMMA had markedly increased compressive strength than PMMA. Furthermore, it was proved that the novel bone cement had good biosafety and efficacy based on the International Standards and guidelines. After 12 weeks of implantation, SIS-PMMA indicated significantly more osteointegration and new bone formation ability than PMMA. In addition, vertebral bodies with cement were also extracted for the uniaxial compression test, and it was revealed that compared with the PMMA-implanted vertebrae, the SIS-PMMA-implanted vertebrae had greatly enhanced maximum strength. Overall, these findings indicate the potential of SIS to induce efficient fixation between the modified cement surface and the host bone, thereby providing evidence that the SIS-PMMA bone cement is a promising filler for clinical vertebral augmentation.

[Effects of different polymers on biomimetic mineralization of small intestine submucosal scaffolds].

OBJECTIVE: To explore the effects of different polymers on in vitro biomimetic mineralization of small intestinal submucosa (SIS) scaffolds, and to evaluate the physicochemical properties and biocompatibility of the SIS scaffolds. METHODS: The SIS scaffolds prepared by freeze-drying method were immersed in simulated body fluid (SBF), mineralized liquid containing polyacrylic acid (PAA) and mine-ralized liquid containing PAA and polyaspartic acid (PASP). After two weeks in the mineralized solution, the liquid was changed every other day. SBF@SIS, PAA@SIS, PAA/PASP@SIS scaffolds were obtained. The SIS scaffolds were used as control group to evaluate their physicochemical properties and biocompatibility. We observed the bulk morphology of the scaffolds in each group, analyzed the microscopic morphology by environment scanning electron microscopy and determined the porosity and pore size. We also analyzed the surface elements by energy dispersive X-ray spectroscopy (EDX), analyzed the structure of functional groups by Flourier transformed infrared spectroscopy (FTIR), detected the water absorption rate by using specific gravity method, and evaluated the compression strength by universal mechanical testing machine. The pro-cell proliferation effect of each group of scaffolds were evaluated by CCK-8 cell proliferation method. RESULTS: Under scanning electron microscopy, the scaffolds of each group showed a three-dimensional porous structure with suitable pore size and porosity, and crystal was observed in all the mineralized scaffolds of each group, in which the crystal deposition of PAA/PASP@SIS scaffolds was more regular. At the same time, the collagen fibers could be seen to thicken. EDX analysis showed that the characteristic peaks of Ca and P were found in the three groups of mineralized scaffolds, and the highest peaks were found in the PAA/PASP@SIS scaffolds. FTIR analysis proved that all the three groups of mineralized scaffolds were able to combine hydroxyapatite with SIS. All the scaffolds had good hydrophilicity. The compressive strength of the mineralized scaffold in the three groups was higher than that in the control group, and the best compressive strength was found in PAA/PASP@SIS scaffold. The scaffolds of all the groups could effectively adsorb proteins, and PAA/PASP@SIS group had the best adsorption capacity. In the CCK-8 cell proliferation experiment, the PAA/PASP@SIS scaffold showed the best ability to promote cell proliferation with the largest number of living cells observed. CONCLUSION: Compared with other mineralized scaffolds, PAA/PASP@SIS scaffolds prepared by mineralized solution containing both PAA and PASP have better physicochemical properties and biocompatibility and have potential applications in bone tissue engineering.

Application of multi-layer porcine small intestinal submucosa for the reconstruction of deep corneal defects in cats.

OBJECTIVE: This study documented the application of porcine small intestinal submucosa (SIS) as a stand-alone scaffold for treating deep corneal defects in cats. METHODS: Medical records of 20 cats with deep stromal ulcers, perforations, or corneal sequestra that underwent surgical treatment with SIS grafts between 2021 and 2022 were retrospectively reviewed. Data on re-epithelialization time, corneal transparency score, and complications were collected to analyze the reconstruction of deep corneal defects after SIS biomaterial implantation. RESULTS: All cats were unilaterally affected. The corneal defects varied in size, with a median diameter of 8.3 mm (range: 3-15 mm). Re-epithelialization of the SIS graft was completed 16-32 days after surgery (median, 22.3 days). No, mild, or moderate corneal transparency was detected in 90% of the cases. Complications were observed in eight cases (40%), including aqueous leakage (10%), partial SIS malacia (25%), and persistent bullous keratopathy (5%). The follow-up period ranged 90-725 days, with a median duration of 255 days. The SIS graft was successfully applied as a single scaffold in 17 of 20 cases (85%). CONCLUSION: The results of this study suggest that the application of commercial SIS is an effective surgical technique for managing deep corneal defects in cats.

Enhancing cartilage regeneration and repair through bioactive and biomechanical modification of 3D acellular dermal matrix.

Acellular dermal matrix (ADM) shows promise for cartilage regeneration and repair. However, an effective decellularization technique that removes cellular components while preserving the extracellular matrix, the transformation of 2D-ADM into a suitable 3D scaffold with porosity and the enhancement of bioactive and biomechanical properties in the 3D-ADM scaffold are yet to be fully addressed. In this study, we present an innovative decellularization method involving 0.125% trypsin and 0.5% SDS and a 1% Triton X-100 solution for preparing ADM and converting 2D-ADM into 3D-ADM scaffolds. These scaffolds exhibit favorable physicochemical properties, exceptional biocompatibility and significant potential for driving cartilage regeneration in vitro and in vivo. To further enhance the cartilage regeneration potential of 3D-ADM scaffolds, we incorporated porcine-derived small intestinal submucosa (SIS) for bioactivity and calcium sulfate hemihydrate (CSH) for biomechanical reinforcement. The resulting 3D-ADM+SIS scaffolds displayed heightened biological activity, while the 3D-ADM+CSH scaffolds notably bolstered biomechanical strength. Both scaffold types showed promise for cartilage regeneration and repair in vitro and in vivo, with considerable improvements observed in repairing cartilage defects within a rabbit articular cartilage model. In summary, this research introduces a versatile 3D-ADM scaffold with customizable bioactive and biomechanical properties, poised to revolutionize the field of cartilage regeneration.

Linking inflammation and angiogenesis with fibrogenesis: Expression of FXIIIA, MMP-9, and VEGF in oral submucous fibrosis.

OBJECTIVES: Interplay of Factor XIIIa (FXIIIa), a transglutaminase, responsible for cross-linking of matrix proteins, Matrix Metalloproteinase-9 (MMP-9), a gelatinase, and Vascular Endothelial Growth Factor (VEGF), an angiogenic inducer, were studied in relation to fibrogenesis and disease progression in oral submucous fibrosis (OSMF). MATERIAL AND METHODS: Immunohistochemical expression of markers was studied in 60 formalin-fixed paraffin-embedded tissue blocks of OSMF and 20 normal oral mucosal tissues. FXIIIa was studied quantitatively while MMP-9 and VEGF were assessed semi-quantitatively. Expression was compared with histopathological grades of OSMF. RESULTS: FXIIIa expression significantly increased in OSMF (p-value 0.000). However, expression decreased and cells became quiescent with increasing grades (p-value 0.000). MMP-9 (p-value epithelium 0.011, p-value connective tissue 0.000) and VEGF expression (p-value epithelium 0.000, connective tissue 0.000) increased in OSMF. A negative correlation between FXIIIa and MMP-9 (-0.653) in early grade (p-value of 0.021) and a positive correlation between FXIIIa and VEGF (0.595) (p-value of 0.032) was found in the moderate grade OSMF. Regression analysis showed a significant association (p<0.01) of FXIIIa in OSMF and with increasing grades of OSMF. CONCLUSION: FXIIIa may play a crucial role in initiation of fibrosis in OSMF. MMP-9 may have a diverse role to play in OSMF as a regulator of fibrosis. VEGF may show an angio-fibrotic switch and contribute to fibrosis in OSMF. These cytokines may show altered function and can contribute to fibrosis and chronicity of disease due to changes in the microenvironment. Tissue stiffness in OSMF itself creates an environment that enhances the chronicity of the disease.

Implementation of esophageal endoscopic submucosal dissection in Spain: Results from the nationwide registry. / Implementación de la disección endoscópica submucosa esofágica en España: resultados del registro nacional.

INTRODUCTION AND AIMS: The outcomes of endoscopic submucosal dissection (ESD) in the esophagus have not been assessed in our country. Our primary aim was to analyze the effectiveness and safety of the technique. MATERIAL AND METHODS: Analysis of the prospectively maintained national registry of ESD. We included all superficial esophageal lesions removed by ESD in 17 hospitals (20 endoscopists) between January 2016 and December 2021. Subepithelial lesions were excluded. The primary outcome was curative resection. We conducted a survival analysis and used logistic regression analysis to assess predictors of non-curative resection. RESULTS: A total of 102 ESD were performed on 96 patients. The technical success rate was 100% and the percentage of en-bloc resection was 98%. The percentage of R0 and curative resection was 77.5% (n=79; 95%CI: 68%-84%) and 63.7% (n=65; 95%CI: 54%-72%), respectively. The most frequent histology was Barrett-related neoplasia (n=55 [53.9%]). The main reason for non-curative resection was deep submucosal invasion (n=25). The centers with a lower volume of ESD obtained worse results in terms of curative resection. The rate of perforation, delayed bleeding and post-procedural stenosis were 5%, 5% and 15.7%, respectively. No patient died or required surgery due to an adverse effect. After a median follow-up of 14months, 20patients (20.8%) underwent surgery and/or chemoradiotherapy, and 9 patients died (mortality 9.4%). CONCLUSIONS: In Spain, esophageal ESD is curative in approximately two out of three patients, with an acceptable risk of adverse events.

Hydroxyapatite-Coated Small Intestinal Submucosa Membranes Enhanced Periodontal Tissue Regeneration through Immunomodulation and Osteogenesis via BMP-2/Smad Signaling Pathway.

Periodontitis, a chronic infection causing periodontal tissue loss, may be effectively addressed with in situ tissue engineering. Small intestinal submucosa (SIS) offers exceptional biocompatibility and biodegradability but lacks sufficient osteoconductive and osteoinductive properties. This study develops and characterizes SIS coated with hydroxyapatite (SIS-HA) and gelatin methacrylate hydroxyapatite (SIS-Gel-HA) using biomineralization and chemical crosslinking. The impact on periodontal tissue regeneration is assessed by evaluating macrophage immune response and osteogenic differentiation potential of periodontal ligament stem cells (PDLSCs) in vitro and rat periodontal defects in vivo. The jejunum segment, with the highest collagen type I content, is optimal for SIS preparation. SIS retains collagen fiber structure and bioactive factors. Calcium content is 2.21% in SIS-HA and 2.45% in SIS-Gel-HA, with no significant differences in hydrophilicity, physicochemical properties, protein composition, or biocompatibility among SIS, SIS-HA, SIS-Gel, and SIS-Gel-HA. SIS is found to upregulate M2 marker expression, both SIS-HA and SIS-Gel-HA enhance the osteogenic differentiation of PDLSCs through the BMP-2/Smad signaling pathway, and SIS-HA demonstrates superior in vitro osteogenic activity. In vivo, SIS-HA and SIS-Gel-HA yield denser, more mature bones with the highest BMP-2 and Smad expression. SIS-HA and SIS-Gel-HA demonstrate enhanced immunity-osteogenesis coupling, representing a promising periodontal tissue regeneration approach.

Successful Use of Acellular Small Intestinal Submucosa Graft in Vaginal Reconstruction.

PURPOSE: Various techniques for neovaginal construction have been employed in the pediatric and adult populations, including the use of intestinal segments, buccal mucosal grafts, and skin grafts. Small intestinal submucosa (SIS) extracellular matrix grafts have been described as a viable alternative, though prior experience is limited. Our purpose was to assess operative characteristics and patient outcomes with neovaginal construction using SIS grafts. METHODS: Thirteen patients underwent vaginoplasty with acellular porcine SIS grafts at our institution between 2018 and 2022. Operative and clinical data, postoperative mold management, vaginal dilating length, and complications were reviewed. RESULTS: Age at time of repair ranged from 13 to 30 years (median 19 years). Patient diagnosis included cloacal anomalies (n = 4), Mayer-Rokitansky-Küster-Hauser syndrome (n = 4), isolated vaginal atresia with or without a transverse vaginal septum (n = 4), and vaginal rhabdomyosarcoma requiring partial vaginectomy (n = 1). Following dissection of the neovaginal space, a silicon mold wrapped with SIS graft was placed with retention sutures and removed on postoperative day 7. Median (IQR) operative time was 171 (118-192) minutes, estimated blood loss was 10 (5-20) mL, and length of stay was 2 (1-3) days. The follow-up period ranged from 3 to 47 months (median 9 months). Two patients developed postoperative vaginal stenosis that resolved with dilation under anesthesia. Mean vaginal length on latest follow-up was 8.97 cm. All thirteen patients had successful engraftment and progressed to performing self-dilations or initiating intercourse to maintain patency. There were no cases of graft reaction or graft extrusion. CONCLUSIONS: We conclude that acellular small intestinal submucosa grafts are effective and safe alternatives for mold coverage in neovaginal construction. Our experience demonstrates minimal perioperative morbidity, early mold removal, and progression to successful dilation with maintenance of a functional vaginal length. Future study on sexual outcomes, patient satisfaction, and comparison against alternative techniques has been initiated. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective Study.

Foreign Body Reaction Requiring Re-Exploration After Tympanoplasty With Porcine Small Intestinal Submucosa Reconstruction.

OBJECTIVE: We present the first published case of large foreign body reaction to Biodesign (Cook Medical, Bloomington, IN), an acellular otologic graft matrix derived from porcine small intestinal submucosa, after use in tympanoplasty surgery in a patient without previous exposure to meat products. METHODS: A single case report of a 39-year-old female who developed tinnitus, ear drainage, and large fibrotic mass in external auditory canal and extending into middle ear after Type I medial graft tympanoplasty with Biodesign Graft. Left endoscopic microdissection and resection of the tympanic membrane and middle ear fibrotic mass were performed. MAIN FINDINGS: Surgical excision of the fibrous mass required extensive microdissection to ensure preservation of the ossicles and chorda tympani. Postoperatively, hearing improved and otalgia and otorrhea resolved. CONCLUSIONS: We report the first case of post-tympanoplasty reaction with the use of Biodesign acellular porcine graft in a patient with no previous known exposure to meat products. Although this presentation appears to be rare, it reinforces the need for careful patient selection and counseling around the use of porcine or other foreign grafts.