Study of Crystal Formation and Nitric Oxide (NO) Release Mechanism from S-Nitroso-N-acetylpenicillamine (SNAP)-Doped CarboSil Polymer Composites for Potential Antimicrobial Applications.

Stable and long-term nitric oxide (NO) releasing polymeric materials have many potential biomedical applications. Herein, we report the real-time observation of the crystallization process of the NO donor, S-nitroso-N-acetylpenicillamine (SNAP), within a thermoplastic silicone-polycarbonate-urethane biomedical polymer, CarboSil 20 80A. It is demonstrated that the NO release rate from this composite material is directly correlated with the surface area that the CarboSil polymer film is exposed to when in contact with aqueous solution. The decomposition of SNAP in solution (e.g. PBS, ethanol, THF, etc.) is a pseudo-first-order reaction proportional to the SNAP concentration. Further, catheters fabricated with this novel NO releasing composite material are shown to exhibit significant effects on preventing biofilm formation on catheter surface by Pseudomonas aeruginosa and Proteus mirabilis grown in CDC bioreactor over 14 days, with a 2 and 3 log-unit reduction in number of live bacteria on their surfaces, respectively. Therefore, the SNAP-CarboSil composite is a promising new material to develop antimicrobial catheters, as well as other biomedical devices.

An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity.

Particular alleles of HLA contribute to disease susceptibility and severity in many autoimmune conditions, but the mechanisms underlying these associations are often unknown. In this study, we demonstrate that the shared epitope (SE), an HLA-DRB1-coded sequence motif that is the single most significant genetic risk factor for erosive rheumatoid arthritis, acts as a signal transduction ligand that potently activates osteoclastogenesis, both in vitro and in vivo. The SE enhanced the production of several pro-osteoclastogenic factors and facilitated osteoclast (OC) differentiation in mouse and human cells in vitro. Transgenic mice expressing a human HLA-DRB1 allele that code the SE motif demonstrated markedly higher propensity for osteoclastogenesis and enhanced bone degradation capacity ex vivo. In addition, the SE enhanced the differentiation of Th17 cells expressing the receptor activator for NF-κB ligand. When the two agents were combined, IL-17 and the SE enhanced OC differentiation synergistically. When administered in vivo to mice with collagen-induced arthritis, the SE ligand significantly increased arthritis severity, synovial tissue OC abundance, and bone erosion. Thus, the SE contributes to arthritis severity by activating an OC-mediated bone-destructive pathway. These findings suggest that besides determining the target specificity of autoimmune responses, HLA molecules may influence disease outcomes by shaping the pathogenic consequences of such responses.

Alcohol associated liver disease and bariatric surgery: Current perspectives and future directions.

Bariatric surgery is a routinely performed procedure and is associated with a reduction in all-cause mortality in patients with obesity. However, bariatric surgery has also been linked to increased alcohol use with up to 30% of these patients developing alcohol use disorder (AUD). The mechanism of AUD after bariatric surgery is multifactorial and includes anatomic, metabolic, and neurohumoral changes associated with post-surgical anatomy. These patients are at increased risk of alcohol associated liver disease and, in some cases, require liver transplantation. In this article, we provide a scoping review of epidemiology, pathophysiology, and clinical outcomes of alcohol-related health conditions after bariatric surgery.

Sarcopenic obesity in patients awaiting liver transplant: Unique challenges for nutritional recommendations.

Sarcopenic obesity increases the risk of mortality in patients with liver disease awaiting liver transplantation and in the post-transplant period. Nutrition recommendations for individuals with sarcopenia differ from recommendations for patients with obesity or sarcopenic obesity. While these nutrition guidelines have been established in non-cirrhotic patients, established guidelines for liver transplant candidates with sarcopenic obesity are lacking. In this paper, we review existing literature on sarcopenic obesity in patients with chronic liver disease and address opportunities to improve nutritional counseling in patients awaiting liver transplantation.

History of Depression is Associated With Higher Prevalence of Hepatic Encephalopathy in Patients With Advanced Liver Disease.

BACKGROUND: Depression and hepatic encephalopathy are common in patients with advanced liver disease. Although these are distinct entities, they share several clinical features. In this analysis, we evaluated whether having a history of depression was associated with developing hepatic encephalopathy in patients with advanced liver disease. METHODS: We performed a retrospective cohort study of patients with cirrhosis referred for liver transplant. Patients were categorized into 1 of 2 groups: "history of depression" or "no history of depression." Multivariable logistic regression was used to evaluate history of depression as a potential independent predictor of hepatic encephalopathy. RESULTS: A total of 447 patients were included, of which 158 (35%) had a history of depression and 233 (52%) had experienced hepatic encephalopathy. Hepatic encephalopathy was more common in patients with a history of depression (63% vs 46%, P < .01). On multivariate analyses, depression history was independently associated with hepatic encephalopathy (aOR 2.3, 95% CI 1.4-3.6), along with alcohol associated cirrhosis (aOR 2.0, 95% CI 1.3-3.2), history of ascites (aOR 3.5, 95% CI 2.1-5.9) and presence of a trans-jugular intra-hepatic shunt (aOR 9.2, 95% CI 2.6-32.6). The relationship between history of depression and hepatic encephalopathy remained significant in a subgroup of patients with alcohol associated liver disease (P = .04). Among those with a history of depression, SNRI prescription was more common in the hepatic encephalopathy group (14% vs 3%), and SNRI prescription was as an independent predictor of hepatic encephalopathy in the multivariable model (OR 4.8, 95% CI 1.0-24.6) CONCLUSIONS: Patients with a history of depression were significantly more likely to experience hepatic encephalopathy. Patients with cirrhosis who have a history of depression should be closely monitored for the development of hepatic encephalopathy. Further research is needed to understand the nuances of this relationship and whether the use of certain psychiatric medications may modify the relationship between depression and hepatic encephalopathy.

Fibrosis progression in HCV carriers with mild hepatitis who possess the high-repetition variant of the DRD4 gene, a genetic marker for binge-drinking and risk-seeking behavior: a longitudinal study.

BACKGROUND: Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome. METHODS: A cohort of HCV patients with normal or near-normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology. RESULTS: HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up. CONCLUSIONS: The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.

The progression of hepatorenal syndrome-acute kidney injury in acute alcohol-associated hepatitis: renal outcomes after liver transplant.

Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a complication of advanced liver disease in patients with ascites and circulatory dysfunction. Little data remain on the relationship between HRS-AKI outcomes and different etiologies of liver disease post-liver transplant (LT). Objectives: The primary aim was to evaluate the effect of HRS-AKI on renal outcomes in patients with acute alcohol-associated hepatitis (AAH) compared to chronic liver disease (CLD) after LT. The secondary aim was to evaluate the impact of acuity and chronicity of alcohol-associated liver disease in patients with HRS-AKI post-LT renal outcomes. Design: A retrospective observational study of patients undergoing urgent inpatient liver transplant evaluation (LTE) for cirrhosis and AAH at single academic LT center between October 2017 and July 2021 was conducted. Methods: Patients with HRS-AKI were selected based on indication for LTE: acute AAHHRS or CLDHRS. CLDHRS was categorized by disease etiology: cirrhosis due to alcohol (A-CLDHRS) versus cirrhosis from other causes (O-CLDHRS). CLD patients without HRS-AKI were labeled CLDno HRS. Results: A total of 210 subjects underwent LTE; 25% were evaluated for AAH and 75% were evaluated for CLD. Hepatorenal syndrome was more common in subjects evaluated for AAH (37/47) than CLD (104/163) (78.7 versus 63.8%, p = 0.04). For the primary outcome, AAHHRS subjects required ⩾30 days post-LT renal replacement therapy (RRT) more often than subjects with CLDHRS (p = 0.02) and CLDno HRS (p < 0.01). There was no significant difference in other forms of long-term renal outcomes including kidney transplant referral and kidney transplant among cohorts. In subgroup analysis, 30-days post-LT RRT was more common in AAHHRS than in A-CLDHRS (p = 0.08). Logistic regression showed that AAHHRS conferred a 20× and 3.3× odds of requiring ⩾30 days post-LT RRT compared to CLDno HRS and CLDHRS, respectively. Postoperative complications were similar across cohorts, but had a significant effect on 30-day renal outcome post-LT. Conclusions: Patients with AAH were more likely to develop HRS and require RRT pre- and post-LT at our center. The etiology of hepatic decompensation and postoperative complications affect renal recovery post-LT. The systemic inflammation of AAH in addition to conditions favoring renal hypoperfusion may contribute to the unfavorable outcomes of HRS-AKI after LT in this patient population.

Kidney disease in patients with chronic liver disease: Does sex matter?

Kidney disease in patients with liver disease is serious and increases mortality. Up to 50% of patients hospitalized experience an episode of acute kidney injury. In general, men with liver disease are thought to be at increased risk of kidney disease. However, this association should be considered with caution because most studies use creatinine-based inclusion criteria, which is negatively biased against women. In this review, we synthesize data on sex differences in kidney disease in patients with chronic liver disease in the clinical setting and discuss potential physiologic underpinnings.

Management of an iatrogenic duodenal perforation with a helical tack system in a patient with pancreatic cancer complicated by gastric outlet obstruction.

Video 1Closure of an iatrogenic perforation with helical tack system and subsequent EUS-guided choledochoduodenostomy.

Delayed referral for liver transplant evaluation worsens outcomes in chronic liver disease patients requiring inpatient transplant evaluation.

BACKGROUND: Indications to refer patients with cirrhosis for liver transplant evaluation (LTE) include hepatic decompensation or a model for end stage liver disease (MELD-Na) score ≥ 15. Few studies have evaluated how delaying referral beyond these criteria affects patient outcomes. AIM: To evaluate clinical characteristics of patients undergoing inpatient LTE and to assess the effects of delayed LTE on patient outcomes (death, transplantation). METHODS: This is a single center retrospective cohort study assessing all patients undergoing inpatient LTE (n = 159) at a large quaternary care and liver transplant center between 10/23/2017-7/31/2021. Delayed referral was defined as having prior indication (decompensation, MELD-Na ≥ 15) for LTE without referral. Early referral was defined as referrals made within 3 mo of having an indication based on practice guidelines. Logistic regression and Cox Hazard Regression were used to evaluate the relationship between delayed referral and patient outcomes. RESULTS: Many patients who require expedited inpatient LTE had delayed referrals. Misconceptions regarding transplant candidacy were a leading cause of delayed referral. Ultimately, delayed referrals negatively affected overall patient outcome and an independent predictor of both death and not receiving a transplant. Delayed referral was associated with a 2.5 hazard risk of death. CONCLUSION: Beyond initial access to an liver transplant (LT) center, delaying LTE increases risk of death and reduces risk of LT in patients with chronic liver disease. There is substantial opportunity to increase the percentage of patients undergoing LTE when first clinically indicated. It is crucial for providers to remain informed about the latest guidelines on liver transplant candidacy and the transplant referral process.

COVID-19 associated liver injury: A general review with special consideration of pregnancy and obstetric outcomes.

Liver injury is an increasingly recognized extra-pulmonary manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Coronavirus disease 2019 (COVID-19) associated liver injury (COVALI) is a clinical syndrome encompassing all patients with biochemical liver injury identified in the setting of SARS-CoV-2 infection. Despite profound clinical implications, its pathophysiology is poorly understood. Unfortunately, most information on COVALI is derived from the general population and may not be applicable to individuals under-represented in research, including pregnant individuals. This manuscript reviews: Clinical features of COVALI, leading theories of COVALI, and existing literature on COVALI during pregnancy, a topic not widely explored in the literature. Ultimately, we synthesized data from the general and perinatal populations that demonstrates COVALI to be a hepatocellular transaminitis that is likely induced by systemic inflammation and that is strongly associated with disease severity and poorer clinical outcome, and offered perspective on approaching transaminitis in the potentially COVID-19 positive patient in the obstetric setting.

Lifestyle and silymarin: a fight against liver damage in NAFLD associated - prediabetic disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common in both prediabetic patients and healthy overweight individuals, yet it remains understudied. This study investigates the effects of hepatic steatosis on fibrosis and evaluates the major predictors of liver injury in prediabetes and whether this damage is reversible with Mediterranean diet and administration of the nutraceutical silymarin. METHODS: First, a case-control study was conducted in which 212 patients with prediabetes, not known to have NAFLD, and 126 healthy controls underwent clinical evaluation, transient elastography with measurement of liver stiffness (LS) and controlled attenuation parameter (CAP). Subsequently, the 212 prediabetic patients were enrolled into a prospective randomized interventional study: 104 were allocated to Mediterranean diet alone while 108 followed Mediterranean diet plus supplementation with silymarin (a flavonolignan complex isolated from Silybum marianum and Morus alba). The administered silymarin dose was 210 mg twice daily for 6 months. Clinical and instrumental evaluations were repeated at the end of the 6 month-study period. Prediabetics were genotyped for patatin like phospholipase domain containing 3 (PNPLA3). RESULTS: In the case-control study, 29% of prediabetic patients have significant fibrosis defined as LS ≥ 7.9 kPa vs only 3% of controls (p < 0.001). PNPLA3 genotype CG/GG are significantly associated with significant fibrosis LS ≥ 7.9 relative to CC genotype χ2(1) = 76.466, p < 0.001. Binomial regression analysis shows that increase in BMI, ALT and AST are significantly associated with increased likelihood of significant fibrosis (χ2(7) = 191.9, p < .001) prior to intervention. In the randomized interventional study, prediabetics following Mediterranean diet alone (group 1) experienced a significant regression of fibrosis and decrease in ALT, HbA1c, FBS after 6 months (p < 0.001); similar findings were observed in patients following Mediterranean diet plus silymarin regimen (group 2); group 2 had a significant decrease in HbA1c relative to group 1 (95% CI: 37.8-38.6 vs 39.5-40.3, p < 0.001). CONCLUSION: PNPLA3 genotype CG/GG and elevated BMI are the major predictors of significant fibrosis in prediabetic patients prior to intervention in this study. Mediterranean diet either alone or with silymarin treatment for 6 months leads to significant regression of liver damage and improvement of the glycemic profile in prediabetic patients. Yet, as combination treatment of silymarin with Mediterranean diet shows significant reduction of HbA1c when compared to diet alone, this suggests that silymarin may exert an independent anti-glycemic action.

Reduction of Thrombosis and Bacterial Infection via Controlled Nitric Oxide (NO) Release from S-Nitroso-N-acetylpenicillamine (SNAP) Impregnated CarboSil Intravascular Catheters.

Nitric oxide (NO) has many important physiological functions, including its ability to inhibit platelet activation and serve as potent antimicrobial agent. The multiple roles of NO in vivo have led to great interest in the development of biomaterials that can deliver NO for specific biomedical applications. Herein, we report a simple solvent impregnation technique to incorporate a nontoxic NO donor, S-nitroso-N-acetylpenicillamine (SNAP), into a more biocompatible biomedical grade polymer, CarboSil 20 80A. The resulting polymer-crystal composite material yields a very stable, long-term NO release biomaterial. The SNAP impregnation process is carefully characterized and optimized, and it is shown that SNAP crystal formation occurs in the bulk of the polymer after solvent evaporation. LC-MS results demonstrate that more than 70% of NO release from this new composite material originates from the SNAP embedded CarboSil phase, and not from the SNAP species leaching out into the soaking solution. Catheters prepared with CarboSil and then impregnated with 15 wt % SNAP provide a controlled NO release over a 14 d period at physiologically relevant fluxes and are shown to significantly reduce long-term (14 day) bacterial biofilm formation against Staphylococcus epidermidis and Pseudonomas aeruginosa in a CDC bioreactor model. After 7 h of catheter implantation in the jugular veins of rabbit, the SNAP CarboSil catheters exhibit a 96% reduction in thrombus area (0.03 ± 0.01 cm2/catheter) compared to the controls (0.84 ± 0.19 cm2/catheter) (n = 3). These results suggest that SNAP impregnated CarboSil can become an attractive new biomaterial for use in preparing intravascular catheters and other implanted medical devices.

Efficient Eradication of Mature Pseudomonas aeruginosa Biofilm via Controlled Delivery of Nitric Oxide Combined with Antimicrobial Peptide and Antibiotics.

Fast eradication of mature biofilms is the 'holy grail' in the clinical management of device-related infections. Endogenous nitric oxide (NO) produced by macrophages plays an important role in host defense against intracellular pathogens, and NO is a promising agent in preventing biofilms formation in vitro. However, the rate of delivery of NO by various NO donors (e.g., diazeniumdiolates, S-nitrosothiols, etc.) is difficult to control, which hinders fundamental studies aimed at understanding the role of NO in biofilm control. In this study, by using a novel precisely controlled electrochemical NO releasing catheter device, we examine the effect of physiological levels of NO on eradicating mature Pseudomonas aeruginosa biofilm (7 days), as well as the potential application of the combination of NO with antimicrobial agents. It is shown that physiological levels of NO exhibit mixed effects of killing bacteria and dispersing ambient biofilm. The overall biofilm-eradicating effect of NO is quite efficient in a dose-dependent manner over a 3 h period of NO treatment. Moreover, NO also greatly enhances the efficacy of antimicrobial agents, including human beta-defensin 2 (BD-2) and several antibiotics, in eradicating biofilm and its detached cells, which otherwise exhibited high recalcitrance to these antimicrobial agents. The electrochemical NO release technology offers a powerful tool in evaluating the role of NO in biofilm control as well as a promising approach when combined with antimicrobial agents to treat biofilm-associated infections in hospital settings, especially infections resulting from intravascular catheters.

CD82 Is a Marker for Prospective Isolation of Human Muscle Satellite Cells and Is Linked to Muscular Dystrophies.

Cell-surface markers for prospective isolation of stem cells from human skeletal muscle have been difficult to identify. Such markers would be powerful tools for studying satellite cell function during homeostasis and in pathogenesis of diseases such as muscular dystrophies. In this study, we show that the tetraspanin KAI/CD82 is an excellent marker for prospectively isolating stem cells from human fetal and adult skeletal muscle. Human CD82+ muscle cells robustly engraft into a mouse model of muscular dystrophy. shRNA knockdown of CD82 in myogenic cells reduces myoblast proliferation, suggesting it is functionally involved in muscle homeostasis. CD82 physically interacts with alpha7beta1 integrin (α7ß1-ITG) and with α-sarcoglycan, a member of the Dystrophin-Associated Glycoprotein Complex (DAPC), both of which have been linked to muscular dystrophies. Consistently, CD82 expression is decreased in Duchenne muscular dystrophy patients. Together, these findings suggest that CD82 function may be important for muscle stem cell function in muscular disorders.

S-Nitroso-N-acetylpenicillamine (SNAP) Impregnated Silicone Foley Catheters: A Potential Biomaterial/Device To Prevent Catheter-Associated Urinary Tract Infections.

Urinary Foley catheters are utilized for management of hospitalized patients and are associated with high rates of urinary tract infections (UTIs). Nitric oxide (NO) potently inhibits microbial biofilm formation, which is the primary cause of catheter associated UTIs (CAUTIs). Herein, commercial silicone Foley catheters are impregnated via a solvent swelling method with S-nitroso-N-acetyl-D-penicillamine (SNAP), a synthetic NO donor that exhibits long-term NO release and stability when incorporated into low water-uptake polymers. The proposed catheters generate NO surface-fluxes >0.7 × 10-10 mol min-1 cm-2 for over one month under physiological conditions, with minimal SNAP leaching. These biomedical devices are demonstrated to significantly decrease formation of biofilm on the surface of the catheter tubings over 3, 7, and 14 day periods by microbial species (Staphylococcus epidermidis and Proteus mirabilis) commonly causing CAUTIs. Toxicity assessment demonstrates that the SNAP-impregnated catheters are fully biocompatible, as extracts of the catheter tubings score 0 on a 3-point grading scale using an accepted mouse fibroblast cell-line toxicity model. Consequently, SNAP-impregnated silicone Foley catheters can likely provide an efficient strategy to greatly reduce the occurrence of nosocomial CAUTIs.

Shared epitope-antagonistic ligands: a new therapeutic strategy in mice with erosive arthritis.

OBJECTIVE: The mechanisms underlying bone damage in rheumatoid arthritis (RA) are incompletely understood. We recently identified the shared epitope (SE), an HLA-DRB1-coded 5-amino acid sequence motif carried by the majority of RA patients as a signal transduction ligand that interacts with cell surface calreticulin and accelerates osteoclast (OC)-mediated bone damage in collagen-induced arthritis (CIA). Given the role of the SE/calreticulin pathway in arthritis-associated bone damage, we sought to determine the therapeutic targetability of calreticulin. METHODS: A library of backbone-cyclized peptidomimetic compounds, all carrying an identical core DKCLA sequence, was synthesized. The ability of these compounds to inhibit SE-activated signaling and OC differentiation was tested in vitro. The effect on disease severity and OC-mediated bone damage was studied by weekly intraperitoneal administration of the compounds to DBA/1 mice with CIA. RESULTS: Two members of the peptidomimetics library were found to have SE-antagonistic effects and antiosteoclast differentiation effects at picomolar concentrations in vitro. The lead mimetic compound, designated HS(4-4)c Trp, potently ameliorated arthritis and bone damage in vivo when administered in picogram doses to mice with CIA. Another mimetic analog, designated HS(3-4)c Trp, was found to lack activity, both in vitro and in vivo. The differential activity of the 2 analogs depended on minor differences in their respective ring sizes and correlated with distinctive geometry when computationally docked to the SE binding site on calreticulin. CONCLUSION: These findings identify calreticulin as a novel therapeutic target in erosive arthritis and provide sound rationale and early structure/activity relationships for future drug design.

Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with S-Nitroso-N-acetyl-D-penicillamine.

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-D-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC-MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer-crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4-4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.

Thromboresistant/anti-biofilm catheters via electrochemically modulated nitric oxide release.

Inexpensive nitric oxide (NO) release strategies to prevent thrombosis and bacterial infections are desirable for implantable medical devices. Herein, we demonstrate the utility of electrochemically modulated NO release from a catheter model using an inner copper wire working electrode and an inorganic nitrite salt solution reservoir. These catheters generate NO surface fluxes of >1.0 × 10(-10)mol min(-1) cm(-2) for more than 60 h. Catheters with an NO flux of 1.1 × 10(-10)mol min(-1) cm(-2) are shown to significantly reduce surface thrombus formation when implanted in rabbit veins for 7h. Further, the ability of these catheters to exhibit anti-biofilm properties against bacterial species commonly causing bloodstream and urinary catheter infections is examined. Catheters releasing NO continuously during the 2d growth of Staphylococcus aureus exhibit a 6 log-unit reduction in viable surface bacteria. We also demonstrate that catheters generating NO for only 3h at a flux of 1.0 × 10(-10)mol min(-1) cm(-2) lower the live bacterial counts of both 2d and 4d pre-formed Escherichia coli biofilms by >99.9%. Overall, the new electrochemical NO-release devices could provide a cost-effective strategy to greatly enhance the biocompatibility and antimicrobial properties of intravascular and urinary catheters, as well as other implantable medical devices.