The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Antimicrobial efficiency and cytocompatibility of different decontamination methods on titanium and zirconium surfaces.

OBJECTIVES: The purpose of this study was to investigate the efficiency of different implant-decontamination methods regarding biofilm modification and potential cytotoxic effects. Therefore, the amount of biofilm reduction, cytocompatibility, and elementary surface alterations were evaluated after decontamination of titanium and zirconium surfaces. MATERIAL AND METHODS: Titanium and zirconium disks were contaminated with a newly developed high-adherence biofilm consisting of six microbial species. Decontaminations were performed using titanium curette, stainless steel ultrasonic scaler (US), glycine (GPAP) and erythritol (EPAP) powder air-polishing, Er:YAG laser, 1% chlorhexidine (CHX), 10% povidone-iodine (PVI), 14% doxycycline (doxy), and 0.95% NaOCl solution. Microbiologic analysis was done using real-time qPCR. For assessment of cytocompatibility, a multiplex assay for the detection of cytotoxicity, viability, and apoptosis on human gingival fibroblasts was performed. X-ray photoelectron spectroscopy (XPS) was used to evaluate chemical alterations on implant surfaces. RESULTS: Compared with untreated control disks, only GPAP, EPAP, US, and Er:YAG laser significantly reduced rRNA counts (activity) on titanium and zirconium (p < .01), whereas NaOCl decreased rRNA count on titanium (p < .01). Genome count (bacterial presence) was significantly reduced by GPAP, EPAP, and US on zirconium only (p < .05). X-ray photoelectron spectroscopy analyses revealed relevant re-exposure of implant surface elements after GPAP, EPAP, and US treatment on both materials, however, not after Er:YAG laser application. Cytocompatibility was impaired by CHX, PVI, doxy, and NaOCl. CHX and PVI resulted in the lowest viability and doxy in the highest apoptosis. CONCLUSIONS: Within the limits of this in vitro study, air-polishing methods and ultrasonic device resulted in effective biofilm inactivation with surface re-exposure and favorable cytocompatibility on titanium and zirconium. Chemical agents, when applied on implant surfaces, may cause potential cytotoxic effects.

Switching from high-flux dialysis to hemodiafiltration: Cost-consequences for patients, providers, and payers.

Hemodiafiltration (HDF) achieves a more efficient reduction of the uremic toxic load compared to standard high-flux hemodialysis (HF-HD) by virtue of the combined diffusive and convective clearances of a broad spectrum of uremic retention solutes. Clinical trials and registry data suggest that HDF improves patient outcomes. Despite the acknowledged need to improve survival rates of dialysis patients and the survival benefit HDF offers, there is little to no utilization in some countries (such as the US) in prescribing HDF to their patients. In this analysis, we present the healthcare value-based case for HDF (relative to HF-HD) from the patient, provider, and payor perspectives. The improved survival and reduced morbidity observed in studies conducted outside the US, as well as the reduced hospitalization, are attractive for each stakeholder. We also consider the potential barriers to greater utilization of HDF therapies, including unfounded concerns regarding additional costs of HDF, e.g., for the preparation and microbial testing of quality of substitution fluids. Ultrapure fluids are easily attainable and prepared from dialysis fluids using established "online" (OL) technologies. OL-HDF has matured to a level whereby little additional effort is required to safely implement it as all modern machine systems are today equipped with the OL-HDF functionality. Countries already convinced of the advantages of HF-HD are thus well positioned to make the transition to OL-HDF to achieve further clinical and associated economic benefits. Healthcare systems struggling to cope with the increasing demand for HD therapies would therefore, like patients, be beneficiaries in the long term with increased usage of OL-HDF for end stage kidney disease patients.

Demineralization Inhibitory Effects of Highly Concentrated Fluoride Dentifrice and Fluoride Gels/Solutions on Sound Dentin and Artificial Dentin Caries Lesions in vitro.

OBJECTIVES: The aim of this in vitro study was to compare the demineralization inhibitory effect of gels/solutions used in combination with either standard or highly fluoridated dentifrices on sound dentin as well as on artificial dentin caries-like lesions. METHODS: Bovine dentin specimens (n = 240) with two different surfaces each (sound [ST] and artificial caries lesion [DT]) were prepared and randomly allocated to twelve groups. Weekly interventions during pH-cycling (28 days, 6 × 120 min demineralization/day) were: the application of gels/solutions containing amine fluoride/sodium fluoride (12,500 ppm F [ppm]; pH = 4.4; AmF); NaF (12,500 ppm; pH = 6.6; NaF1); NaF (12,500 ppm; pH = 6.3; NaF2); silver diamine fluoride (14,200 ppm; pH = 8.7; SDF); acidulated phosphate fluoride (12,500 ppm; pH = 3.8; APF), and no intervention (standard control; S). Furthermore, half of the specimens in each group were brushed (10 s; twice per day) with dentifrice slurries containing either 1,450 ppm (e.g., AmF1450) or 5,000 ppm (e.g., AmF5000). Differences in integrated mineral loss (ΔΔZ) and lesion depth (ΔLD) were calculated between values before and after pH-cycling using transversal microradiography. RESULTS: After pH-cycling Ss showed significantly increased ΔZDT and LDDT values, indicating further demineralization. In contrast, except for one, all groups including fluoride gels/solutions showed significantly decreased ΔZDT values. Additional use of most fluoride gels/solutions significantly enhanced mineral gain, mainly in the surface area; however, acidic gels/solutions seemed to have negative effects on lesion depths. SIGNIFICANCE: Under the present pH-cycling conditions the highly fluoridated dentifrice significantly reduced caries progression and additional application of nearly all of the fluoride gels/solutions resulted in remineralization. However, there was no difference in the remineralizing capacity of fluoride gels/solutions when used in combination with either standard or highly fluoridated dentifrices.

Hand-held bioprinting for de novo vascular formation applicable to dental pulp regeneration.

Aim of the study: Deep carious lesions may cause irreversible pulpitis and the current endodontic treatment typically removes the whole dental pulp tissue, which finally reduces lifespan of the teeth. Nowadays, the most frequent treatment is based on removing the infected tissue and filling the root canal with inert synthetic materials. Tissue engineering approaches are important alternatives to the current treatment, because they can potentially maintain the biological function of the tooth instead of sacrificing it.Materials and Methods: In this study, we propose a tissue engineering approach based on a hand-held in situ bioprinting strategy. Our approach enabled bioprinting of cell-loaded collagen-based bioinks with suitable rheological, structural and biological properties, which allowed for vasculogenesis in the root canal.Results: The rheological properties of the bioprintable bioink were measured by oscillatory amplitude sweep testing and were corroborated by macroscopic evaluation after in vitro culture, in which printed bioinks maintained their original form without contraction. Moreover, we showed evidence for successful vasculogenesis in bioprintable bioinks with comparable quality and quantity to control fibrin and collagen non-bioprintable hydrogels.Conclusions: We conclude that hand-held bioprinting holds potential for in situ treatment of dental diseases with successful evidence for vascular tube formation, as an asset for maintenance of the biological function of the tooth.

Effects of Dentifrices Differing in Fluoride Content on Remineralization Characteristics of Dentin in vitro.

OBJECTIVES: The aim of this study was to compare the caries preventive effect of highly fluoridated dentifrices and gels on sound dentin as well as on artificial dentin caries-like lesions. METHODS: Bovine dentin specimens (n = 240), with 2 different surfaces each (1 sound surface [sound treatment (ST)] and one caries lesion [demineralized treatment (DT)]), were prepared and randomly allocated to one highly (6 × 120 min demineralization/day [H]) and one lowly cariogenic (6 × 60 min demineralization/day [L]) pH-cycling model. Treatments during pH-cycling (28 days) were: brushing 2×/day with: 0 ppm F [H0/L0], 1,450 ppm F [H1,450/L1,450], 2,800 ppm F [H2,800/L2,800], 5,000 ppm F [H5,000/L5,000], 5,000 ppm F plus TCP [H5,000+TCP/L5,000+TCP], and 12,500 ppm F [H12,500/L12,500] containing dentifrices/gels. Dentifrice/gel slurries were prepared with deionized water (1:2 wt/wt). Differences in integrated mineral loss (∆∆Z) and ∆ lesion depth were calculated between values before and after pH-cycling using transversal microradiography. RESULTS: The correlation between ΔΔZDT and F- was strong for the highly (rH = 0.691; p < 0.001) and moderate (rL = 0.500; p < 0.001) for the lowly cariogenic model, indicating a fluoride dose-response for both. Significant differences for ΔΔZDT and ΔΔZST could be found between H0, H1,450, H5,000, and H12,500 as well as L0, L5,000, and L125,000 (p ≤ 0.046; analysis of covariance [ANCOVA]). Except for 0 ppm F-, no significant difference in ΔΔZST and ΔΔZDT could be found between the highly and lowly cariogenic model (p ≥ 0.056; ANCOVA). CONCLUSION: For both pH-cycling conditions a dose-response for fluoride could be revealed. For elderly people with exposed root surfaces, the use of gels containing 12,500 ppm F instead of regularly (1,450 ppm F) or highly (5,000 ppm F) fluoridated dentifrices should be further investigated, as it offered higher caries-preventive effects in vitro.

Extracellular Vesicles-Loaded Fibrin Gel Supports Rapid Neovascularization for Dental Pulp Regeneration.

Rapid vascularization is required for the regeneration of dental pulp due to the spatially restricted tooth environment. Extracellular vesicles (EVs) released from mesenchymal stromal cells show potent proangiogenic effects. Since EVs suffer from rapid clearance and low accumulation in target tissues, an injectable delivery system capable of maintaining a therapeutic dose of EVs over a longer period would be desirable. We fabricated an EV-fibrin gel composite as an in situ forming delivery system. EVs were isolated from dental pulp stem cells (DPSCs). Their effects on cell proliferation and migration were monitored in monolayers and hydrogels. Thereafter, endothelial cells and DPSCs were co-cultured in EV-fibrin gels and angiogenesis as well as collagen deposition were analyzed by two-photon laser microscopy. Our results showed that EVs enhanced cell growth and migration in 2D and 3D cultures. EV-fibrin gels facilitated vascular-like structure formation in less than seven days by increasing the release of VEGF. The EV-fibrin gel promoted the deposition of collagen I, III, and IV, and readily induced apoptosis during the initial stage of angiogenesis. In conclusion, we confirmed that EVs from DPSCs can promote angiogenesis in an injectable hydrogel in vitro, offering a novel and minimally invasive strategy for regenerative endodontic therapy.

Chronic Kidney Disease: Exploring Value-Based Healthcare as a Potential Viable Solution.

BACKGROUND: Increasing healthcare expenditures have triggered a trend from volume to value by linking patient outcome to costs. This concept first described as value-based healthcare (VBHC) by Michael Porter is especially applicable for chronic conditions. This article aims to explore the applicability of the VBHC framework to the chronic kidney disease (CKD) care area. METHODS: The 4 dimensions of VBHC (measure value; set and communicate value benchmarking; coordinate care; payment to reward value-add) were explored for the CKD care area. Available data was reviewed focusing on CKD initiatives in Europe to assess to what extent each of the 4 dimensions of VBHC have been applied in practice. RESULTS: Translating VBHC into value-based renal care (VBRC) seems to be initiated to a limited extent in European health systems. In most cases not all dimensions of VBHC have been utilized in the renal care initiatives. CONCLUSION: The translation of VBHC into VBRC is possible and even desirable if an optimal treatment pathway for CKD patients could be achieved. This would require an organizational change in health system set up and should include a strategy focusing on full care responsibility. The patient outcome perspective and health economic analysis need to be the centre of attention.

Evaluation of Restorative Materials Containing Preventive Additives in a Secondary Caries Model in vitro.

The incorporation of antibacterial agents into dental restorative materials is a promising strategy for secondary caries prevention. Previously, Carolacton affected Streptococcus mutans biofilm formation on composite materials in vitro. The present study evaluated secondary caries formation adjacent to Carolacton-containing composites and conventional restorative materials using an artificial biofilm model. Standardized cavities were prepared in bovine dentin-enamel samples (n = 175) and restored with various dental materials (Tetric EvoCeram [T], GrandioSo composite without [G] and with Carolacton [GC], Grandio Flow without [F] and with Carolacton [FC], GrandioSo containing sodium fluoride [GNaF], and Ketac Fil [K]). After artificial aging, S. mutans was grown on the samples for 7 days. The investigation of gap sizes and secondary caries formation was performed using confocal laser scanning microscopy and transversal microradiography. Median gap size in enamel was 9.4 µm (interquartile range 7.9-12.7). Compared to all other groups significant differences in gap sizes could be observed for Ketac Fil (p < 0.001; Mann-Whitney test). Only GrandioSo composite containing 30% sodium fluoride and Ketac Fil showed significantly smaller lesion areas in enamel (p < 0.001; Mann-Whitney test) than all other groups which was confirmed by the mineral loss data (p < 0.001; Mann-Whitney test). Based on the present in vitro results, it seems that Carolacton-containing composite in the current formulation within the shown simplified monoculture biofilm model is not able to prevent caries formation compared to fluoride-releasing restorative materials.

Combined Tin-Containing Fluoride Solution and CO2 Laser Treatment Reduces Enamel Erosion in vitro.

The aim of this in vitro study was to evaluate the effect of combined CO2 laser and tin-containing fluoride treatment on the formation and progression of enamel erosive lesions. Ninety-six human enamel samples were obtained, stored in thymol solution and, after surface polishing, randomly divided into 6 different surface treatment groups (n = 16 in each group) as follows: no treatment, control (C); one CO2 laser irradiation (L1); two CO2 laser irradiations (L2); daily application of fluoride solution (F); combined daily fluoride solution + one CO2 laser irradiation (L1F), and combined daily fluoride solution + two CO2 laser irradiations (L2F). Laser irradiation was performed at 0.3 J/cm2 (5 µs/226 Hz/10.6 µm) on day 1 (L1) and day 6 (L2). The fluoride solution contained AmF/NaF (500 ppm F), and SnCl2 (800 ppm Sn) at pH 4.5. After surface treatment the samples were submitted to an erosive cycling over 10 days, including immersion in citric acid (2 min/0.05 M/pH = 2.3) 6 times daily and storage in remineralization solution (≥1 h) between erosive attacks. At the end of each cycling day, the enamel surface loss (micrometers) was measured using a 3D laser profilometer. Data were statistically analyzed by means of a 2-level mixed effects model and linear contrasts (α = 0.05). Group F (-3.3 ± 2.0 µm) showed significantly lower enamel surface loss than groups C (-27.22 ± 4.1 µm), L1 (-18.3 ± 4.4 µm) and L2 (-16.3 ± 5.3 µm) but higher than L1F (-1.0 ± 4.4 µm) and L2F (1.4 ± 3.2 µm, p < 0.05). Under the conditions of this in vitro study, the tin-containing fluoride solution caused 88% reduction of enamel surface loss, while its combination with CO2 laser irradiation at 0.3 J/cm2 hampered erosive loss almost completely.

Differences in degradation behavior of two non-cross-linked collagen barrier membranes: an in vitro and in vivo study.

OBJECTIVES: Collagen barrier membranes are used in guided bone regeneration/guided tissue regeneration because of their excellent bio- and cytocompatibility. However, they are considered to have limitations in clinical outcome because of rapid and unpredictable degradation profiles. The aim of this study was to investigate the degradation behavior of two porcine-based, non-cross-linked collagen membranes in vitro and in vivo. MATERIALS AND METHODS: Remaix™ (RX; Matricel GmbH, Herzogenrath, Germany) and Bio-Gide® (BG; Geistlich Pharma AG, Wolhusen, Switzerland) membranes were characterized by testing mechanical strength, denaturation temperature, enzymatic degradation and hydroxyproline content in vitro (n = 5 up to 16). Thereafter, both membranes were implanted subcutaneously in rats (n = 20) for up to 20 weeks to investigate tissue compatibility with respect to membrane thickness. RESULTS: BG contained a significant higher hydroxyproline content compared with RX, but RX showed a higher stress at break (dry: 11.4 (SD 2.9) vs. 5.5 (SD 1.5) N/mm(2)), higher suture retention (wet: 5.6 (SD 1.3) vs. 2.7 (SD 0.7) N), increased denaturation temperature (55.1 (SD 1) vs. 49.4 (SD 0.6)°C) and an almost twofold reduction in degradation rate (15.6% (SEM 1.3)/h vs. 24.8% (SEM 2.9)/h) in vitro. In the rat model, both membranes showed excellent tissue compatibility without signs of inflammatory reactions. Shortly after implantation, RX and BG showed moderate infiltration of mononuclear cells that appeared not to be influenced by the surface texture of the membranes. In the histomorphometric analysis, both membranes showed significant different thickness over the 20 weeks period (P = 0.0002). Although the thickness remained almost stable during the first 9 weeks after implantation, after 20 weeks, the thickness of RX decreased only slightly, whereas BG showed a thickness loss of around 50% and stronger degradation than RX. Therefore, the higher stability of RX against biodegradation found in vitro was confirmed in the animal study. CONCLUSION: This study shows differences in the biodegradation characteristics of two non-cross-linked collagen membranes in vitro and in vivo. Whether the higher stability of RX is of clinical relevance should be analyzed in future clinical investigations.

Doping of casted silk fibroin membranes with extracellular vesicles for regenerative therapy: a proof of concept.

Bioactive material concepts for targeted therapy have been an important research focus in regenerative medicine for years. The aim of this study was to investigate a proof-of-concept composite structure in the form of a membrane made of natural silk fibroin (SF) and extracellular vesicles (EVs) from gingival fibroblasts. EVs have multiple abilities to act on their target cell and can thus play crucial roles in both physiology and regeneration. This study used pH neutral, degradable SF-based membranes, which have excellent cell- and tissue-specific properties, as the carrier material. The characterization of the vesicles showed a size range between 120 and 180 nm and a high expression of the usual EV markers (e.g. CD9, CD63 and CD81), measured by nanoparticle tracking analysis (NTA) and single-EV flow analysis (IFCM). An initial integration of the EVs into the membrane was analyzed using scanning and transmission electron microscopy (SEM and TEM) and vesicles were successfully detected, even if they were not homogeneously distributed in the membrane. Using direct and indirect tests, the cytocompatibility of the membranes with and without EVs could be proven and showed significant differences compared to the toxic control (p < 0.05). Additionally, proliferation of L929 cells was increased on membranes functionalized with EVs (p > 0.05).

In vitro and in vivo evaluation of biohybrid tissue-engineered vascular grafts with transformative 1H/19F MRI traceable scaffolds.

Biohybrid tissue-engineered vascular grafts (TEVGs) promise long-term durability due to their ability to adapt to hosts' needs. However, the latter calls for sensitive non-invasive imaging approaches to longitudinally monitor their functionality, integrity, and positioning. Here, we present an imaging approach comprising the labeling of non-degradable and degradable TEVGs' components for their in vitro and in vivo monitoring by hybrid 1H/19F MRI. TEVGs (inner diameter 1.5 mm) consisted of biodegradable poly(lactic-co-glycolic acid) (PLGA) fibers passively incorporating superparamagnetic iron oxide nanoparticles (SPIONs), non-degradable polyvinylidene fluoride scaffolds labeled with highly fluorinated thermoplastic polyurethane (19F-TPU) fibers, a smooth muscle cells containing fibrin blend, and endothelial cells. 1H/19F MRI of TEVGs in bioreactors, and after subcutaneous and infrarenal implantation in rats, revealed that PLGA degradation could be faithfully monitored by the decreasing SPIONs signal. The 19F signal of 19F-TPU remained constant over weeks. PLGA degradation was compensated by cells' collagen and α-smooth-muscle-actin deposition. Interestingly, only TEVGs implanted on the abdominal aorta contained elastin. XTT and histology proved that our imaging markers did not influence extracellular matrix deposition and host immune reaction. This concept of non-invasive longitudinal assessment of cardiovascular implants using 1H/19F MRI might be applicable to various biohybrid tissue-engineered implants, facilitating their clinical translation.

Protective effect of CO2 laser (10.6 µm) and fluoride on enamel erosion in vitro.

The aim of this study was to analyze the effect of CO(2) laser (10.6 µm) irradiation with 5-µs pulse width in prevention of enamel erosion due to citric acid exposure in vitro. One hundred forty-four bovine enamel samples were cut into 5 × 5 × 2-mm-size slabs and polished to obtain plane surfaces. Enamel surfaces were covered with acid-resistant varnish, except for a central area of 2.5 mm in diameter. The samples were divided into four groups (n = 12/group/day): C-control, no treatment; L-CO(2) laser irradiation (0.3 J/cm(2), 5 µs, 226 Hz); F-topical fluoride treatment, 1.25%F(-) (AmF/NaF) for 3 min; and FL-fluoride treatment + CO(2) laser. For erosive demineralization, samples were immersed in 40 ml of citric acid (0.05 M, pH 2.3) for 20 min two times per day during 5 days. After 1, 3, and 5 days, surface loss was measured by digital profilometer. According to the repeated measure ANOVA and post hoc comparisons, all the treatments showed statistically significant reduction of enamel loss as compared to control group, in all investigated times (p < 0.0001): L (52%,31%,37%); F (28%,24%,29%); FL (73%,55%,57%). Both CO(2) laser irradiation alone (L) and the combined laser-fluoride treatment (FL) caused less enamel loss than the fluoride group (F) in all days (p < 0.0001 for L in all times; and p < 0.0001, p = 0.0220 and p = 0.0051 for F, respectively, at days 1, 3, and 5). Under the conditions of this study, CO(2) laser irradiation (0.3 J/cm(2), 5 µs, 226 Hz) could effectively reduce enamel surface loss due to citric acid exposure, in vitro. This effect was still observed after 5 days of repeated acid exposures.

A systematic review of the cost-effectiveness of renal replacement therapies, and consequences for decision-making in the end-stage renal disease treatment pathway.

OBJECTIVES: Comparative economic assessments of renal replacement therapies (RRT) are common and often used to inform national policy in the management of end-stage renal disease (ESRD). This study aimed to assess existing cost-effectiveness analyses of dialysis modalities and consider whether the methods applied and results obtained reflect the complexities of the real-world treatment pathway experienced by ESRD patients. METHODS: A systematic literature review (SLR) was conducted to identify cost-effectiveness studies of dialysis modalities from 2005 onward by searching Embase, MEDLINE, EBM reviews, and EconLit. Economic evaluations were included if they compared distinct dialysis modalities (e.g. in-centre haemodialysis [ICHD], home haemodialysis [HHD] and peritoneal dialysis [PD]). RESULTS: In total, 19 cost-effectiveness studies were identified. There was considerable heterogeneity in perspectives, time horizon, discounting, utility values, sources of clinical and economic data, and extent of clinical and economic elements included. The vast majority of studies included an incident dialysis patient population. All studies concluded that home dialysis treatment options were cost-effective interventions. CONCLUSIONS: Despite similar findings across studies, there are a number of uncertainties about which dialysis modalities represent the most cost-effective options for patients at different points in the care pathway. Most studies included an incident patient cohort; however, in clinical practice, patients may switch between different treatment modalities over time according to their clinical need and personal circumstances. Promoting health policies through financial incentives in renal care should reflect the cost-effectiveness of a comprehensive approach that considers different RRTs along the patient pathway; however, no such evidence is currently available.

Long-Term Degradation Assessment of a Polyurethane-Based Surgical Adhesive-Assessment and Critical Consideration of Preclinical In Vitro and In Vivo Testing.

Tissue adhesives constitute a great possibility to improve conventional wound closure. In contrast to sutures, they enable nearly immediate hemostasis and can prevent fluid or air leaks. In the present study, a poly(ester)urethane-based adhesive was investigated which already proved to be suitable for different indications, such as reinforcing vascular anastomosis and sealing liver tissue. Using in vitro and in vivo setups, the degradation of the adhesives was monitored over a period of up to 2 years, to evaluate long-term biocompatibility and determine degradation kinetics. For the first time, the complete degradation of the adhesive was documented. In subcutaneous locations, tissue residues were found after 12 months and in intramuscular locations, tissue degradation was complete after about 6 months. A detailed histological evaluation of the local tissue reaction revealed good biocompatibility throughout the different degradation stages. After full degradation, complete remodeling to physiological tissue was observed at the implant locations. In addition, this study critically discusses common issues related to the assessment of biomaterial degradation kinetics in the context of medical device certification. This work highlighted the importance and encouraged the implementation of biologically relevant in vitro degradation models to replace animal studies or at least reduce the number of animals in preclinical testing prior to clinical studies. Moreover, the suitability of frequently used implantation studies based on ISO 10993-6 at standard locations was critically discussed, especially in light of the associated lack of reliable predictions for degradation kinetics at the clinically relevant site of implantation.

Knockout of bone sialoprotein in cementoblasts cell lines affects specific gene expression in unstimulated and mechanically stimulated conditions.

One of the major components in cementum extracellular matrix is bone sialoprotein (BSP). BSP knockout (Ibsp) mice were reported to have a nonfunctional hypo-mineralized cementum, as well as detachment and disorganization of the periodontal ligament tissue. However, studies investigating the influence of Ibsp in cementoblasts are missing yet. This study investigates the influences of Bsp in three cementoblasts cell lines (OCCM.30-WT,IbspΔNterm, and IbspKAE). The mRNA expression of cementoblast and osteoclast markers (Col1a1, Alpl, Ocn, Runx2, Ctsk, Rankl and Opg) and the cell morphology were compared. Additionally, a functional monocyte adhesion assay was performed. To understand the influence of external stimuli, the effect of Ibsp was investigated under static compressive force, mimicking the compression side of orthodontic tooth movement. Cementoblasts with genotype IbspΔNterm and IbspKAE showed slight differences in cell morphology compared to OCCM.30-WT, as well as different gene expression. Under compressive force, the Ibsp cell lines presented expression pattern markers similar to the OCCM.30-WT cell line. However, Cathepsin K was strongly upregulated in IbspΔNterm cementoblasts under compressive force. This study provides insight into the role of BSP in cementoblasts and explores the influence of BSP on periodontal ligament tissues. BSP markers in cementoblasts seem to be involved in the regulation of cementum organization as an important factor for a functional periodontium. In summary, our findings provide a basis for investigations regarding molecular biology interactions of BSP in cementoblasts, and a supporting input for understanding the periodontal and cellular cementum remodeling.

A polyurethane-based surgical adhesive for sealing blood vessel anastomoses-A feasibility study in pigs.

Peri- and postoperative anastomotic leakage from blood vessel anastomosis is a common and potentially life-threatening complication. As an adjunctive therapy providing an additional layer of safety, a new biodegradable, polyurethane-based adhesive was developed. It consists of two components: an isocyanate-functionalized prepolymer and an amino-based curing agent. The adhesive was investigated in a porcine animal model to seal sutured blood vessel anastomoses of arteries, veins, aortas and prosthetic aortic graft replacements. The material-determined properties of the adhesive like viscosity, processing and polymerization time as well as bonding strength were well suited for this application. The adhesive stopped perioperative suture-line bleedings and stayed on all anastomoses until sacrifice. Hematological and serological inflammation marker assessments were unobtrusive. The histological evaluation showed a mild to moderate local tissue reaction to the adhesive constituting a physiological, non-adverse tissue-biomaterial interaction. The adhesive did not interfere with vascular wound healing. The adhesive demonstrated to be suitable to improve the outcome of cardiovascular surgeries by securing the classical sutured anastomoses in a fast, easy and safe manner. However, further studies are required to quantitatively evaluate efficacy in terms of anastomotic leakage prevention as well as long-term tissue compatibility and degradation.

From In Vitro to Perioperative Vascular Tissue Engineering: Shortening Production Time by Traceable Textile-Reinforcement.

BACKGROUND: The production of tissue-engineered vascular graft (TEVG) usually involves a prolonged bioreactor cultivation period of up to several weeks to achieve maturation of extracellular matrix and sufficient mechanical strength. Therefore, we aimed to substantially shorten this conditioning time by combining a TEVG textile scaffold with a recently developed copolymer reinforced fibrin gel as a cell carrier. We further implemented our grafts with magnetic resonance imaging (MRI) contrast agents to allow the in-vitro monitoring of the TEVG's remodeling process. METHODS: Biodegradable polylactic-co-glycolic acid (PLGA) was electrospun onto a non-degradable polyvinylidene fluoride scaffold and molded along with copolymer-reinforced fibrin hydrogel and human arterial cells. Mechanical tests on the TEVGs were performed both instantly after molding and 4 days of bioreactor conditioning. The non-invasive in vitro monitoring of the PLGA degradation and the novel imaging of fluorinated thermoplastic polyurethane (19F-TPU) were performed using 7T MRI. RESULTS: After 4 days of close loop bioreactor conditioning, 617 ± 85 mmHg of burst pressure was achieved, and advanced maturation of extracellular matrix (ECM) was observed by immunohistology, especially in regards to collagen and smooth muscle actin. The suture retention strength (2.24 ± 0.3 N) and axial tensile strength (2.45 ± 0.58 MPa) of the TEVGs achieved higher values than the native arteries used as control. The contrast agents labeling of the TEVGs allowed the monitorability of the PLGA degradation and enabled the visibility of the non-degradable textile component. CONCLUSION: Here, we present a concept for a novel textile-reinforced TEVG, which is successfully produced in 4 days of bioreactor conditioning, characterized by increased ECM maturation and sufficient mechanical strength. Additionally, the combination of our approach with non-invasive imaging provides further insights into TEVG's clinical application.