Efficacy & safety of EUS-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) in Roux-en-Y gastric bypass anatomy: a systematic review & meta-analysis.

BACKGROUND: In patients with Roux-en-Y gastric bypass (RYGB) anatomy, laparoscopic endoscopic retrograde cholangiopancreatography (LA-ERCP) and enteroscopy-assisted ERCP (E-ERCP) have been utilized to achieve pancreaticobiliary access. Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) has recently emerged as an alternate and efficient approach. As data regarding EDGE continues to evolve, concerns about safety and efficacy remain, limiting wide adoptability. We performed a systematic review and meta-analysis to assess the safety and efficacy of EDGE and compare it to the current standard of care. METHODS: A comprehensive search of major databases (inception to Nov 2022) identified published studies on EDGE. A random-effects model was used to calculate the pooled rates and heterogeneity (I2). Risk ratio (RR) and standardized difference in means (SMD) were utilized for head-to-head comparison analysis between EDGE vs. LA-ERCP and EDGE vs. E-ERCP. Primary outcomes assessed pooled EDGE safety (adverse events) and efficacy (technical/clinical success). Secondary outcomes assessed efficacy and safety profiles via a comparative analysis of EDGE vs. LA-ERCP and EDGE vs. E-ERCP. RESULTS: A total of 16 studies (470 patients) were included. EDGE pooled technical success (TS) rate was 96% (95% CI 92-97.6, I2 = 0), and clinical success was 91% (85-95, I2 = 0). Pooled rate of all adverse events with EDGE was 17% (14-24.6, I2 = 32%). On sub-group analysis, these included failure of fistula closure 17% (10-25.5, I2 = 48%), stent migration 7% (4-12, I2 = 51%), bleeding 5% (3.2-7.9, I2 = 0), post-EDGE weight gain 4% (2-9, I2 = 0), perforation 4% (2.1-5.8, I2 = 0), and post-ERCP pancreatitis 2% (1-5, I2 = 0). EDGE TS was comparable to LA-ERCP (97% vs. 98%; RR, 1.00; CI, 0.85-1.17, p = 0.95) and E-ERCP (100% vs. 66%; RR, 1.26; CI, 0.99-1.6, p = 0.06). No statistical difference was noted in adverse events between EDGE and LA-ERCP (13% vs. 17.6%; RR, 0.61; CI, 0.28-1.35, p = 0.52) and E-ERCP (9.6% vs. 16%; RR, 0.61; CI, 0.28-1.35, p = 0.22). EDGE procedure time and hospital stay were shorter than LA-ERCP and E-ERCP (p < 0.001). CONCLUSION: Our analysis shows that EDGE is safe and efficacious to the current standard of care. Further head-to-head comparative trials are needed to validate our findings.

Proton Pump Inhibitors Versus Histamine-2-Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients: A Meta-analysis and Trial Sequential Analysis.

GOALS AND BACKGROUND: Stress ulcer prophylaxis has been shown to lower gastrointestinal bleeding (GIB) rates. Various agents have been studied, and the optimal strategy continues to be contested. This study evaluates the efficacy between proton pump inhibitors (PPIs) and histamine-2-receptor antagonists. Small sample sizes and methodology flaws limited prior studies. STUDY: A systematic search of MEDLINE, EMBASE, CENTRAL, Web of Science, and ClinicalTrials.gov for randomized controlled trials reporting the use of PPI and histamine-2-receptor antagonist reporting rates of GIB and standardized intensive care outcomes. Risk ratios (RR) and standardized mean difference (SMD) with 95% confidence intervals (CIs). A trial sequential analysis was performed to guard against errors. RESULTS: A total of 14 randomized controlled trials of 28,526 patients with a mean age of 57.83±17.35 years and 30.82% females. In our pooled analysis, PPI outperformed its comparator (RR: 0.68; 95% CI: 0.57-0.82) in clinically significant GIB. PPI re-demonstrated significant reduction in overt GIB (RR: 0.61; 95% CI: 0.39-0.97). No differences between groups was noted toward all-cause mortality (RR: 1.05; 95% CI: 1.00-1.10) or incidence of pneumonia (RR: 1.11; 95% CI: 0.82-1.51). Duration of stay (SMD: 0.07; 95% CI: -0.04-0.17) and ventilator days (SMD: 0.01; 95% CI: -0.01-0.04) were indifferent between the groups. CONCLUSIONS: Among critically ill patients, PPI was associated with reduced clinically significant or overt GIB. No differences in pneumonia were seen with the use of either agent. Trial sequential analysis for clinically significant GIB ruled out the risk for false-positive results, and thereby it is unlikely that future trials will affect our conclusions.

Barriers and Facilitators to Colorectal Cancer Screening in African-American Men.

BACKGROUND: African-Americans rank last among all racial groups for age-adjusted colorectal cancer mortality, 5-year survival rates, and rates of screening. Access to care does not fully explain racial disparities in rates of CRC and mortality. Sociocultural attitudes can predict probabilities of CRC screening. AIMS: The objective of this study is to identify factors that influence colorectal cancer screening behavior in African-American men. METHODS: Semi-structured interviews were conducted among 32 African-American men. Transcripts were analyzed using MAXQDA software. We then conducted a cross-sectional survey of 103 African-American men, using previously validated scales related to colorectal cancer screening and determinants. Data were analyzed with SPSS. RESULTS: In the interview phase, beliefs relating to masculinity emerged as factors that hindered participation in screening. Overwhelmingly, participants felt that having an in-depth discussion about colorectal cancer with their provider was critical to enabling them to get screened. The survey phase demonstrated that most participants had poor colorectal cancer knowledge, as only 16% passed the knowledge test. Forty-eight percentage agreed that their provider did not recommend getting screened. Those who had been previously screened for colorectal cancer scored higher in total and on all subsets of the masculinity index than those who had not (p < .01). The most persuasive messages were those related to themes of masculinity. CONCLUSION: This study provides a novel sociocultural perspective about colorectal cancer screening in African-American men. Our findings highlight the importance of family, masculinity, and community when promoting colorectal cancer screening to this population.

Lymph node involvement in gastric adenocarcinoma.

BACKGROUND: Endoscopic management of early gastric cancer is limited by the risk of lymph node metastasis. We aimed to examine the incidence and predictors of nodal metastasis in early gastric adenocarcinoma in a large national US cohort. METHODS: Cases were abstracted from the National Cancer Database from 2004 to 2016. The incidence and predictors of lymph node involvement for patients with Tis, T1a, and T1b tumors were examined. RESULTS: A total of 202,216 cases of gastric adenocarcinoma were identified in the NCDB. Cases with unknown patient or tumor characteristics, presence of other cancers, and prior neoadjuvant chemotherapy or radiotherapy were excluded. 1839 cases of Tis, T1a, and T1b tumors were identified. Lymph node metastases were present in 18.1% of patients. Lymphovascular invasion (LVI), high-grade histology, stage T1b, and larger size (> 3 cm) were independently associated with an increased risk of nodal metastasis on multivariate analysis (P < 0.05). The presence of LVI was the strongest predictor of nodal metastasis with an OR (95% CI) of 5.7 (4.3-7.6), P < 0.001. No lymph node metastasis was found in any Tis tumors. Small T1a low-grade tumors with no LVI had a low risk of nodal metastasis (0.6% < 2 cm and 0.9% < 3 cm). CONCLUSION: In this large national cohort, size, lymphovascular invasion, higher grade histology, and T stage were independently associated with lymph node metastasis. For patients with low-grade tumors, < 3 cm, without lymphovascular invasion, the risk of nodal involvement was very low, suggesting that this Western cohort could be considered for endoscopic resection.

Function and regulation of thermosensitive ion channel TRPV4 in the immune system.

Transient receptor potential vanilloid sub-type 4 (TRPV4) is a six transmembrane protein that acts as a non-selective Ca2+ channel. Notably, TRPV4 is present in almost all animals, from lower eukaryotes to humans and is expressed in diverse tissue and cell types. Accordingly, TRPV4 is endogenously expressed in several types of immune cells that represent both innate and adaptive immune systems of higher organism. TRPV4 is known to be activated by physiological temperature, suggesting that it acts as a molecular temperature sensor and thus plays a key role in temperature-dependent immune activation. It is also activated by diverse endogenous ligands, lipid metabolites, physical and mechanical stimuli. Both expression and function of TRPV4 in various immune cells, including T cells and macrophages, are also modulated by multiple pro- and anti-inflammatory compounds. The results from several laboratories suggest that TRPV4 is involved in the immune activation, a phenomenon with evolutionary significance. Because of its diverse engagement in the neuronal and immune systems, TRPV4 is a potential therapeutic target for several immune-related disorders.

A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

Impact of early aggressive fluid resuscitation in acute pancreatitis.

BACKGROUND/OBJECTIVES: Acute pancreatitis management guidelines recommend early aggressive hydration to improve clinical outcomes. We aim to evaluate the influence of early fluid therapy (total intravenous fluids in the first 24 h [IVF/24hrs]) on clinical outcomes in patients with acute pancreatitis. METHODS: This was a retrospective chart review of all patients admitted for acute pancreatitis between July 2011 to December 2015. IVF/24hrs was categorized into 3 groups according to tertiles. Logistic regression was performed to evaluate predictors of persistent organ failure and in-hospital mortality. RESULTS: A total of 310 patients were included: Conservative (IVF/24hrs < 2.8L, n = 102), Moderate (IVF/24hrs 2.8-4.475L, n = 105) and Aggressive (IVF/24hrs ≥ 4.475, n = 103). Most patients (80.6%) were African Americans, 91.3% had mild acute pancreatitis (BISAP score ≤ 2). The Aggressive IVF group had higher incidence of persistent organ failure (16.5% vs 4.9% and 7.6%, p = 0.013), and longer length of hospital stay (9.2 ± 10.7 vs 6.5 ± 7.3 and 6.8 ± 5.7 days, P = 0.032). However, IVF/24hr did not correlate with length of hospital stay (PCC 0.08, p = 0.174). On multivariate analysis, only organ failure at admission was an independent predictor of persistent organ failure (OR 16.1, p < 0.001). Persistent organ failure and local complications were found to be the only independent predictors in-hospital mortality (OR 27.6, p < 0.001 and OR 16.95, p = 0.001 respectively). There was no difference in clinical outcomes in African Americans compared to other races. CONCLUSIONS: More aggressive early IVF therapy in a predominantly mild acute pancreatitis cohort, was not associated with improvement in persistent organ failure, length of hospital stay, or in-hospital mortality.

Artificial intelligence (AI) real-time detection vs. routine colonoscopy for colorectal neoplasia: a meta-analysis and trial sequential analysis.

GOALS AND BACKGROUND: Studies analyzing artificial intelligence (AI) in colonoscopies have reported improvements in detecting colorectal cancer (CRC) lesions, however its utility in the realworld remains limited. In this systematic review and meta-analysis, we evaluate the efficacy of AI-assisted colonoscopies against routine colonoscopy (RC). STUDY: We performed an extensive search of major databases (through January 2021) for randomized controlled trials (RCTs) reporting adenoma and polyp detection rates. Odds ratio (OR) and standardized mean differences (SMD) with 95% confidence intervals (CIs) were reported. Additionally, trial sequential analysis (TSA) was performed to guard against errors. RESULTS: Six RCTs were included (4996 participants). The mean age (SD) was 51.99 (4.43) years, and 49% were females. Detection rates favored AI over RC for adenomas (OR 1.77; 95% CI: 1.570-2.08) and polyps (OR 1.91; 95% CI: 1.68-2.16). Secondary outcomes including mean number of adenomas (SMD 0.23; 95% CI: 0.18-0.29) and polyps (SMD 0.23; 95% CI: 0.17-0.29) detected per procedure favored AI. However, RC outperformed AI in detecting pedunculated polyps. Withdrawal times (WTs) favored AI when biopsies were included, while WTs without biopsies, cecal intubation times, and bowel preparation adequacy were similar. CONCLUSIONS: Colonoscopies equipped with AI detection algorithms could significantly detect previously missed adenomas and polyps while retaining the ability to self-assess and improve periodically. More effective clearance of diminutive adenomas may allow lengthening in surveillance intervals, reducing the burden of surveillance colonoscopies, and increasing its accessibility to those at higher risk. TSA ruled out the risk for false-positive results and confirmed a sufficient sample size to detect the observed effect. Currently, these findings suggest that AI-assisted colonoscopy can serve as a useful proxy to address critical gaps in CRC identification.

Retrospective Multicenter Matched Controlled Comparison of Endoscopic Retrograde Cholangiopancreatography in Pediatric Patients: A 10-year Experience.

INTRODUCTION: This study was designed to evaluate outcomes in pediatric patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) as compared with an American Society of Gastrointestinal Endoscopy (ASGE) complexity grade-matched adult cohort. METHOD: In this retrospective case-control study, ERCPs performed in pediatric patients from January 2008 to December 2018 in 2 tertiary referral hospitals were compared with a complexity-matched adult control group with similar procedural indications. Primary outcomes included the clinical success rate, technical success rate, and complication rate. Secondary outcomes included postprocedural admission rates, mode of sedation, procedure time, fluoroscopy time, hospitalization length, and the number of repeat procedures. RESULTS: Two hundred thirty-two ERCPs performed in 110 pediatric patients (average age 13.3) and 318 ERCPs performed in 160 ASGE grade-matched adult controls (average age 47.2 years) were analyzed. All procedures were therapeutic. There was no difference in the technical success rate (P = 0.2), clinical success rate (P = 0.5), complication rates (P = 0.1), and fluoroscopy time (P = 0.4), between the pediatric and adult cohorts. General anesthesia use and length of stay were significantly higher in the pediatric group (P = 0.0001). In subgroup analysis, technical (P = 0.2) and clinical success (P = 0.2) as well as complication rates (P = 0.6) were comparable between patients 10 years or less and patients 11 to 18 years within pediatric cohort. CONCLUSIONS: ERCP in pediatric cohorts appears to be safe and effective with equivalent outcomes relative to an ASGE complexity-matched adult cohort. Pediatric patients are more likely to require general anesthesia and have a longer average length of stay relative to adult controls.

Endoscopic Ultrasound-Guided Management of Chronic Pancreatitis.

PURPOSE OF REVIEW: The purpose of this review is to discuss the role of endoscopic ultrasound (EUS) in the diagnosis and treatment of chronic pancreatitis (CP). RECENT FINDINGS: EUS has evolved and become invaluable in diagnosing early CP with the use of elastography and contrast enhancement. Lumen-apposing metal stents have allowed for easier transmural drainage and necrosectomy for pancreatic pseudocyst and walled of necrosis. EUS-guided pancreatic duct drainage is being utilized for pancreatic duct complications including stenosis, stones, and duct disruptions that are not amendable to endoscopic retrograde cholangiopancreatography. EUS is an effective tool that assists with the diagnosis and treatment of CP. The technology continues to evolve allowing for diagnosis of CP in earlier stages, which enables more effective therapy. The development of new EUS-guided tools and techniques has improved the treatment of complications from CP.

Same-Admission Cholecystectomy Compared with Delayed Cholecystectomy in Acute Gallstone Pancreatitis: Outcomes and Predictors in a Safety Net Hospital Cohort.

OBJECTIVES: Recent studies have shown a decrease in gallstone-related complications if same-admission cholecystectomy (SAC) is performed in mild gallstone pancreatitis (GSP); however, SAC often is not performed in resource-limited settings such as safety net hospitals. The aims of this study were to evaluate the rate of SAC and compare a composite endpoint of recurrent biliary events in patients undergoing SAC with patients in the delayed cholecystectomy (DC) group. Secondary aims included evaluating the rate of recurrent pancreatitis in patients in the DC group, identifying the predictors for DC and the reasons for not undergoing SAC. METHODS: We reviewed 310 patients admitted in the past 5 years with the diagnosis of acute pancreatitis. Eighty patients were admitted for gallstone pancreatitis; 75% were African American, 18% were white, and the average age was 44 years with a mean body mass index of 30. Forty patients did not receive cholecystectomy before discharge. The DC and SAC groups were similar in body mass index, ethnicity, severity of pancreatitis, and complications. RESULTS: The DC group was significantly more likely to be older and with higher comorbidity indexes compared with the SAC group. Bedside Index of Severity in Acute Pancreatitis scores and revised Atlanta classification definitions were used to define severe acute pancreatitis; 10% (4) of patients had organ failure at 48 hours, whereas 17.5% (7) had a Bedside Index of Severity in Acute Pancreatitis scores ≥3. A total of 14 recurrent biliary events occurred in the DC group (14 of 40), which was 35% compared with 2 of 40 (5%) in the SAC group (P < 0.001). Of the 9 patients who developed recurrent pancreatitis, 8 were in the DC group (8 of 40, 20%, P = 0.02). Of the 40 patients in the DC group, only 14 patients eventually received a cholecystectomy documented in our hospital, with median-length postdischarge follow-up of approximately 6.5 months. On regression analysis, a Charlson Comorbidity Index >2 was the only significant predictor of DC. The most common reason for DC was no surgical consultation during the inpatient stay (22%). CONCLUSIONS: Our findings support existing evidence that DC is associated with a significantly increased risk of recurrent biliary events and pancreatitis. Furthermore, we report a 56% adherence to the current guidelines for SAC and report that the most common reason for not undergoing SAC was the absence of surgical consultation. We conclude that ensuring SAC in eligible patients should be a priority for safety net hospitals because it may help decrease hospital costs in the long term, and active efforts should be made to identify patients who may be less likely to receive SAC.

Identifying the barriers to gastric cancer care at safety-net hospitals: A novel comparison of a safety-net hospital to a neighboring quaternary referral academic center in the same healthcare system.

BACKGROUND: The three-delays model describes delays in seeking, reaching, and receiving care for vulnerable populations needing treatment. The dominant delay for patients with gastric adenocarcinoma (GAC) is unknown. We aimed to define patients with GAC who reached and received care at our regional safety-net hospital (Grady Memorial Hospital [GMH]) and our neighboring quaternary referral hospital (Emory University Hospital [EUH]). METHODS: Clinicopathologic data from National Cancer Database (NCDB) participating academic centers were compared with GMH from 2004 to 2014. Outcomes of patients undergoing surgery at GMH were compared to those at EUH. RESULTS: At presentation, compared to NCDB centers (n = 69 662), GMH patients (n = 154) were more often black (85.1 vs 17.2%; P < 0.001), uninsured (30.5 vs 4.7%; P < 0.001), have stage IV disease (43.5 vs 30.1%; P = 0.017), and received no treatment (40.3 vs 18.4%; P < 0.001). When only comparing patients who underwent curative-intent resection at GMH (n = 23) to EUH (n = 137), median overall survival was similar between both groups (GMH: median not reached; EUH: 59.8 mos; P = 0.785). CONCLUSION: Although vulnerable patients with GAC within a safety-net hospital present with later stages of the disease, those who received surgery have acceptable outcomes. Thus, efforts should be made to overcome barriers in seeking care.

Endoscopic management of pain in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and one of the leading causes of cancer mortality in the United States. Due to its aggressive behavior and lack of effective therapies, palliation plays a critical role in the management of the disease. Most patients with pancreatic cancer suffer from severe pain, which adversely predicts prognosis and significantly impacts the quality of life. Therefore pain management plays a central role in palliation. Non-steroidal anti-inflammatory drugs and opioid agents are often first line medications in pain management, but they do not target the underlying pathophysiology of pain and their use is limited by adverse effects and dependence. The proposed mechanisms of pain development in pancreatic cancer include neurogenic inflammation and ductal hypertension which may be targeted by endoscopic therapies. Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) and pancreatic duct stent placement are the two primary endoscopic modalities for palliative management in pancreatic cancer patients with refractory pain.  Other endoscopic treatments such as biliary stent placement and enteral stent placement for biliary and duodenal obstruction may also help palliate pain in addition to their role in decompression. This article reviews the existing evidence for these endoscopic interventions for pain management in pancreatic cancer.

ACUTE VENOUS THROMBOEMBOLISM IS COMMON FOLLOWING ACUTE NECROTIZING PANCREATITIS AND IS ASSOCIATED WITH WORSE CLINICAL OUTCOMES.

OBJECTIVES: While splanchnic vein thrombosis (SVT) is a well-known local complication of acute pancreatitis, extra-splanchnic VTE (ESVT) is inadequately studied. Here, we aim to explore the incidence of VTE in acute necrotizing pancreatitis (ANP) and the associated mortality. METHODS: This is a retrospective cohort study utilizing an electronic health record database. Adults with a diagnosis of ANP from January 2017 to December 2022 were identified using appropriate ICD-10-CM codes. The primary outcome was development of acute ESVT within one month of ANP. Secondary outcomes were 90-day mortality, 30-day rehospitalization, and oral anticoagulant (OAC) use in patients with ESVT. Propensity score matching (1:1) was performed for baseline characteristics and common comorbidities. RESULTS: 17,942 (7.11%) patients were diagnosed with ANP during the study period and about 10% (1,737) of them had a diagnosis of ESVT. Of all VTE, 61% were ESVT with or without SVT, and 63% (N = 1,799) were SVT. 90-day mortality (16.3% vs. 5.7%, risk ration, RR 2.86 [95% CI 2.29-3.56]) and 30-day rehospitalization (31% Vs 19%, RR 1.63 [95% CI 1.49-1.79]) were higher in patients with ESVT compared to non-VTE patients. 60% of patients with ESVT were on OAC and OAC use was associated with lower 90-day mortality (8.9% vs. 19.4%, RR 0.46) without increased risk of adverse events, like - acute gastrointestinal bleeding, intracranial bleeding, or need for packed red cell transfusion. CONCLUSIONS: Systemic VTE is common in patients with ANP and may contribute to increased mortality and risk of readmissions. Prospective studies can confirm our findings and explore the role of aggressive VTE prophylaxis in patients with ANP during hospital stay, and in the immediate ambulatory period.

Modulation of calcium-influx by carboxymethyl tamarind­gold nanoparticles promotes biomineralization for tissue regeneration.

Gold nanoparticles (AuNPs) have been reported to modulate bone tissue regeneration and are being extensively utilized in biomedical implementations attributable to their low cytotoxicity, biocompatibility and simplicity of functionalization. Lately, biologically synthesized nanoparticles have acquired popularity because of their environmentally acceptable alternatives for diverse applications. Here we report the green synthesis of AuNPs by taking the biopolymer Carboxymethyl Tamarind (CMT) as a unique reducing as well as a stabilizing agent. The synthesized CMT-AuNPs were analyzed by UV-vis spectrophotometer, DLS, FTIR, XRD, TGA, SEM and TEM. These results suggest that CMT-AuNPs possess an average size of 19.93 ± 8.52 nm and have long-term stability. Further, these CMT-AuNPs promote the proliferation together with the differentiation and mineralization of osteoblast cells in a "dose-dependent" manner. Additionally, CMT-AuNPs are non-toxic to SD rats when applied externally. We suggest that the CMT-AuNPs have the potential to be a suitable and non-toxic agent for differentiation and mineralization of osteoblast cells in vitro and this can be tested in vivo as well.

TRPV4 Activator-Containing CMT-Hy Hydrogel Enhances Bone Tissue Regeneration In Vivo by Enhancing Mitochondrial Health.

Treating different types of bone defects is difficult, complicated, time-consuming, and expensive. Here, we demonstrate that transient receptor potential cation channel subfamily V member 4 (TRPV4), a mechanosensitive, thermogated, and nonselective cation channel, is endogenously present in the mesenchymal stem cells (MSCs). TRPV4 regulates both cytosolic Ca2+ levels and mitochondrial health. Accordingly, the hydrogel made from a natural modified biopolymer carboxymethyl tamarind CMT-Hy and encapsulated with TRPV4-modulatory agents affects different parameters of MSCs, such as cell morphology, focal adhesion points, intracellular Ca2+, and reactive oxygen species- and NO-levels. TRPV4 also regulates cell differentiation and biomineralization in vitro. We demonstrate that 4α-10-CMT-Hy and 4α-50-CMT-Hy (the hydrogel encapsulated with 4αPDD, 10 and 50 nM, TRPV4 activator) surfaces upregulate mitochondrial health, i.e., an increase in ATP- and cardiolipin-levels, and improve the mitochondrial membrane potential. The same scaffold turned out to be nontoxic in vivo. 4α-50-CMT-Hy enhances the repair of the bone-drill hole in rat femur, both qualitatively and quantitatively in vivo. We conclude that 4α-50-CMT-Hy as a scaffold is suitable for treating large-scale bone defects at low cost and can be tested for clinical trials.