Precision-porous polyurethane elastomers engineered for application in pro-healing vascular grafts: Synthesis, fabrication and detailed biocompatibility assessment.

Unmet needs for small diameter, non-biologic vascular grafts and the less-than-ideal performance of medium diameter grafts suggest opportunities for major improvements. Biomaterials that are mechanically matched to native blood vessels, reduce the foreign body capsule (FBC) and demonstrate improved integration and healing are expected to improve graft performance. In this study, we developed biostable, crosslinked polyurethane formulations and used them to fabricate scaffolds with precision-engineered 40 µm pores. We matched the scaffold mechanical properties with those of native blood vessels by optimizing the polyurethane compositions. We hypothesized that such scaffolds promote healing and mitigate the FBC. To test our hypothesis, polyurethanes with 40 µm pores, 100 µm pores, and non-porous slabs were implanted subcutaneously in mice for 3 weeks, and then were examined histologically. Our results show that 40 µm porous scaffolds elicit the highest level of angiogenesis, cellularization, and the least severe foreign body capsule (based on a refined assessment method). This study presents the first biomaterial with tuned mechanical properties and a precision engineered porous structure optimized for healing, thus can be ideal for pro-healing vascular grafts and in situ vascular engineering. In addition, these scaffolds may have wide applications in tissue engineering, drug delivery, and implantable device.

Photoreactive Carboxybetaine Copolymers Impart Biocompatibility and Inhibit Plasticizer Leaching on Polyvinyl Chloride.

Protein and cell interactions on implanted, blood-contacting medical device surfaces can lead to adverse biological reactions. Medical-grade poly(vinyl chloride) (PVC) materials have been used for decades, particularly as blood-contacting tubes and containers. However, there are numerous concerns with their performance including platelet activation, complement activation, and thrombin generation and also leaching of plasticizers, particularly in clinical applications. Here, we report a surface modification method that can dramatically prevent blood protein adsorption, human platelet activation, and complement activation on commercial medical-grade PVC materials under various test conditions. The surface modification can be accomplished through simple dip-coating followed by light illumination utilizing biocompatible polymers comprising zwitterionic carboxybetaine (CB) moieties and photosensitive cross-linking moieties. This surface treatment can be manufactured routinely at small or large scales and can impart to commercial PVC materials superhydrophilicity and nonfouling capability. Furthermore, the polymer effectively prevented leaching of plasticizers out from commercial medical-grade PVC materials. This coating technique is readily applicable to many other polymers and medical devices requiring surfaces that will enhance performance in clinical settings.

Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy.

Patients with uremia are subject to greatly increased cardiovascular risk that cannot be completely explained by traditional cardiovascular risk factors. An increase in oxidative stress and inflammation has been proposed as contributory nontraditional uremic cardiovascular risk factors. Oxidative stress reflects the balance between oxidant generation and antioxidant defense mechanisms. Reduction/oxidation (redox) reactions may result in a stochastic process leading to oxidation of neighboring macromolecules. However, in many instances the reactive oxygen species target particular amino acid residues or lipid moieties. This provides a mechanism by which increased oxidative stress and/or alteration of antioxidant mechanisms can alter cell signaling. In individuals with advanced chronic kidney disease, the redox balance is not in equilibrium and is tipped toward oxidation resulting in the dysregulation of cellular process with subsequent vascular and tissue injury. In this review, the major oxidant and antioxidant pathways and the biomarkers to assess redox status in uremia are discussed, as well as the data linking the pathogenesis of oxidative stress, inflammation, cardiovascular events, and the progressive loss of kidney function in chronic kidney disease.

Novel PAradigm to improve Inflammatory burden in end stage Renal disease (rePAIR): study protocol for a randomized controlled trial.

BACKGROUND: Given the importance of inflammation as a predictor of poor outcomes in End Stage Renal Disease (ESRD), reductions in inflammatory biomarkers have been proposed as a critical target in this population. This study targets chronic periodontitis, an oral inflammatory disease of microbial etiology causing persistent inflammation in ESRD. Unlike the previously reported episodic periodontal interventions, we propose to control periodontal inflammation with a continuous maintenance and oral health behavior modifications. We hypothesize that this strategy will improve systemic inflammation and oxidative stress, oral health and quality of life within the 6-month observation period. METHODS: The rePAIR (novel PAradigm to improve Inflammatory burden in ESRD) study is a pilot and feasibility, parallel-arm, and randomized controlled clinical trial that will recruit 72 ESRD subjects with periodontitis in a model of computerized block randomization. This trial aims to compare the effect of standard-of-care vs. repeated non-surgical periodontal therapy on systemic and oral inflammatory burden. This trial will recruit ESRD adult patients with periodontitis older than 21 years old with a minimum of 12 teeth and no history of periodontal treatment within a year. The trial will examine serum C-reactive protein (CRP) (primary outcome) as a biomarker of inflammation as well as interleukin-6 (IL-6), F2 isofurans and F2 isoprostanes (secondary outcomes) and compare their difference between groups from baseline to 6 months. The trial will also compare the difference between groups in patient-centered and clinical oral outcomes from baseline to 6 months. DISCUSSION: The trial follows a rigorous and transparent study design capturing elements such as pre-specified eligibility criteria, pre-specified primary and secondary outcomes, detailed intervention description to allow replication, intervention random allocation and concealment, blinding in outcome assessment, appropriate sample size calculations, explanation of interim analysis, as per CONSORT Guidelines. Further, gender diversity is secured not only at recruitment but also throughout the trial and during the analysis. Therefore, treatment response outcomes will be examined per gender category. In order to manage anticipated problems, the protocol has included alternative approaches. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03241511 . Registered on 7 August 2017.

Periodontitis associated with chronic kidney disease among Mexican Americans.

OBJECTIVE: In comparison to non-Hispanic whites, a number of health-care disparities, including poor oral health, have been identified among Hispanics in general and Mexican Americans in particular. We hypothesized that Mexican Americans with chronic kidney disease (CKD) would have higher prevalence of chronic periodontitis compared with Mexican Americans with normal kidney function, and that the level of kidney function would be inversely related to the prevalence of periodontal disease. METHODS: We examined this hypothesis using the National Health and Nutrition Examination Survey 1988-1994 (NHANES III) data set. We followed the American Academy of Periodontology/Center for Disease Control and Prevention case definition for periodontitis. Glomerular filtration rate was estimated using the CKD-Epidemiology equation for Hispanic populations. The classification to CKD stages was based on the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. RESULTS: Periodontitis prevalence increased across the kidney function groups showing a statistically significant dose-response association (P<0.001). Mexican Americans with reduced kidney function were twofold more likely to have periodontitis compared with Mexican Americans with normal kidney function after adjusting for potential confounders such as smoking, diabetes, and socioeconomic status. Multivariate adjusted odds ratio for periodontitis significantly increased with 1, 5, and 10 mL/minute estimated glomerular filtration rate reduction from the mean. CONCLUSION: This is the first report, to the best our knowledge, that showed an increase of periodontitis prevalence with decreased kidney function in this population.

Toward the optimal dose metric in continuous renal replacement therapy.

PURPOSE: There is no consensus on the optimal method to measure delivered dialysis dose in patients with acute kidney injury (AKI). The use of direct dialysate-side quantification of dose in preference to the use of formal blood-based urea kinetic modeling and simplified blood urea nitrogen (BUN) methods has been recommended for dose assessment in critically-ill patients with AKI. We evaluate six different blood-side and dialysate-side methods for dose quantification. METHODS: We examined data from 52 critically-ill patients with AKI requiring dialysis. All patients were treated with pre-dilution CVVHDF and regional citrate anticoagulation. Delivered dose was calculated using blood-side and dialysis-side kinetics. Filter function was assessed during the entire course of therapy by calculating BUN to dialysis fluid urea nitrogen (FUN) ratios q/12 hours. RESULTS: Median daily treatment time was 1,413 min (1,260-1,440). The median observed effluent volume per treatment was 2,355 mL/h (2,060-2,863) (p<0.001). Urea mass removal rate was 13.0 ± 7.6 mg/min. Both EKR (r²=0.250; p<0.001) and KD (r²=0.409; p<0.001) showed a good correlation with actual solute removal. EKR and KD presented a decline in their values that was related to the decrease in filter function assessed by the FUN/BUN ratio. CONCLUSIONS: Effluent rate (mL/kg/h) can only empirically provide an estimated of dose in CRRT. For clinical practice, we recommend that the delivered dose should be measured and expressed as KD. EKR also constitutes a good method for dose comparisons over time and across modalities.

Effluent volume in continuous renal replacement therapy overestimates the delivered dose of dialysis.

BACKGROUND AND OBJECTIVES: Studies examining dose of continuous renal replacement therapy (CRRT) and outcomes have yielded conflicting results. Most studies considered the prescribed dose as the effluent rate represented by ml/kg per hour and reported this volume as a surrogate of solute removal. Because filter fouling can reduce the efficacy of solute clearance, the actual delivered dose may be substantially lower than the observed effluent rate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were examined from 52 critically ill patients with acute kidney injury (AKI) requiring dialysis. All patients were treated with predilution continuous venovenous hemodiafiltration (CVVHDF) and regional citrate anticoagulation. Filter performance was monitored during the entire course of therapy by measuring blood urea nitrogen (BUN) and dialysis fluid urea nitrogen (FUN) at initiation and every 12 hours. Filter efficacy was assessed by calculating FUN/BUN ratios every 12 hours of filter use. Prescribed urea clearance (K, ml/min) was determined from the effluent rate. Actual delivered urea clearance was determined using dialysis-side measurements. RESULTS: Median daily treatment time was 1413 minutes (1260 to 1440) with a total effluent volume of 46.4 ± 17.4 L and urea mass removal of 13.0 ± 7.6 mg/min. Prescribed clearance overestimated the actual delivered clearance by 23.8%. This gap between prescribed and delivered clearance was related to the decrease in filter function assessed by the FUN/BUN ratio. CONCLUSIONS: Effluent volume significantly overestimates delivered dose of small solutes in CRRT. To assess adequacy of CRRT, solute clearance should be measured rather than estimated by the effluent volume.