Host responses to a strontium releasing high boron glass using a rabbit bilateral femoral defect model.

Borate glasses have shown promising potential as bioactive materials. With recent research demonstrating that glass properties may be modulated by appropriate compositional design. This may provide for indication specific material characteristics and controlled release of therapeutic inorganic ions (i.e., strontium); controlling such release is critical in order to harness the therapeutic potential. Within this sub-chronic pilot study, a rabbit long-bone model was utilized to explore the safety and efficacy of a high borate glass (LB102: 70B2 O3 -20SrO-6Na2 O-4La2 O3 ) particulate (90 - 710 µm) for bone regeneration. Six bilateral full-thickness defects (Ø = 3.5 mm; L = 8 mm) were created in three white New Zealand rabbits. Longitudinal non-decalcified sections of each defect site were produced and stained with Goldner's Trichrome. Histopathological examination revealed that LB102 demonstrated osteoconductive and osseointegrative properties with greater new bone being formed within and surrounding LB102 particles, when compared to the sham control. The inflammatory cell infiltration was observed to be slightly higher in the control when compared to LB102 defect sites, while no significant difference in fibrosis and neovascularization was determined, indicating that healing was occurring in a normal fashion. These data further suggest the possible utility of high borate glasses with appropriate compositional design for medical applications, such as bone augmentation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1818-1827, 2017.

Safety and biocompatibility of a novel self-expanding nitinol carotid stent with hybrid cell design in a porcine model of neointimal hyperplasia.

BACKGROUND: Stent design may influence the outcomes, suggesting that adverse event rates vary according to free cell area and cell design. Open cell design technology of self-expandable stents, dedicated for carotid revascularisation has better deliverability, although closed cell technology is expected to cause fewer thromboembolic events. AIM: To evaluate the feasibility and vascular response of novel, hybrid cell, self-expandable nitinol stents (MER®, Balton, Poland) implanted into porcine carotid arteries. Hybrid cell design combines open and closed cell technology. METHODS: All tested stents were implanted with 10% overstretch into 10 carotid segments of Polish domestic pigs. Control angiography was obtained immediately before and after vascular interventions as well as 28 days after the procedure. Thereafter, animals were sacrificed, and the treated segments were harvested and evaluated in the independent histopathology laboratory. RESULTS: All stents were easily introduced and implanted, showing good angiographic acute outcome. At 28 days, in the angiography, all vessels were patent with no signs of thrombi or excessive neointimal formation, with the late lumen loss of -0.11 ± 0.3 mm and percentage diameter stenosis 10.18 ± 8.1%. There was a 10% increase in the vessel reference diameter when compared to baseline (4.57 ± 0.5 vs. 4.96 ± 0.3 mm, p < 0.01). In the histopathology, mean area stenosis was 17.4% and mean intimal thickness was 0.20 mm. At histopathology, the mean injury, inflammation, and fibrin scores were low. Endothelialisation was complete in all stents, and neointimal tissue appeared moderately mature as shown by the moderate mean neointimal smooth muscle score. Nonetheless, histopathology shows one stent affected by peri-strut granulomas and one stent affected by marked mineralisation. CONCLUSIONS: The novel Polish self-expandable nitinol carotid stent with hybrid cell technology shows optimal biocompatibility and a vascular healing profile, and therefore may be introduced for first-in-man application.

Vascular response and mechanical integrity of the new biodegradable polymer coated sirolimus-eluting PROLIM stent implanted in porcine coronary arteries.

BACKGROUND: Although durable polymer coated drug-eluting stents (DES) are standard care in percutaneous coronary interventions, new stent platforms employing biodegradable polymer based drug delivery are increasingly being used in clinical practice. AIM: To evaluate the short- (28 days) and medium-term (90 days) vascular effects of the new biodegradable polymer coated sirolimus-eluting stent - the PROLIM stent. METHODS: The objectives of the study were evaluated using standard angiographic and histological methods. In addition, the mechanical integrity of tested stents was assessed using Faxitron imaging. A total of 12 PROLIM stents, 11 biodegradable polymer only coated stents (BPCS), and 12 bare metal stents (BMS) were implanted in the coronary arteries of 16 female non-atheroslerotic domestic swine using an overstretch of 1.1:1.0. RESULTS: At 28 days, neointimal proliferation was significantly lower in the PROLIM and BMS stents compared to the BPCS stents (p ≤ 0.05). Interestingly, despite thin neointima found at this time in the PROLIM group, there was a further significant decrease in neointimal formation between 28 and 90 days (p = 0.04). Although a statistically bigger neointima was found in BPCS stents at 28 days compared to the PROLIM and BMS stents, there was a 50% decrease in the neointimal area at 90 days follow-up (p = 0.02) which reached the level seen in other groups. The endothelialisation was completed in all tested stents after 28 days. There was a significant increase of fibrin depositions in the PROLIM treated arteries at 28 days which were resorbed nearly completely at 90 days follow-up. At 28 days, the inflammatory response was found to be numerically higher in the BPCS stents (p = NS) compared to other tested groups. On the contrary, at 90 days follow-up when the degradation process of the polymer had been completed, the inflammatory reaction decreased substantially to the level seen in the PROLIM and BMS stents. Faxitron analysis of the stented arteries revealed no major abnormalities except for isolated strut fractures observed in the mid portions of two BMS stents and one BPCS stent. CONCLUSIONS: The PROLIM - a biodegradable polymer coated sirolimus-eluting stent - demonstrates very good short-term and medium-term angiographic and histological results. The lack of 'catch-up phenomenon', fast endothelialisation process, and minimal inflammatory reaction may contribute to favourable clinical outcomes using PROLIM stents.

RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy.

Overexpression of regulator of G protein signaling 5 (RGS5) in arteries over veins is the most striking difference observed using microarray analysis. The obvious question is what arterial function might require RGS5. Based on functions of homologous proteins in regulating cardiac mass and G-protein-coupled receptor (GPCR) signaling, we proposed that RGS5 and vascular expressed RGS2 and RGS4 could participate in regulating arterial hypertrophy. We used the suprarenal abdominal aorta banding model to induce hypertension and hypertrophy. All 3 RGS messages were expressed in unmanipulated aorta with RGS5 predominating. After 2 days, thoracic aorta lost expression of RGS5, 4, and 2. At 1 week, all three returned to normal, and at 28 days, they increased many fold above normal. Valsartan blockade of angiotensin II (angII)/angII type 1 receptor signaling prevented upregulation of RGS messages but only delayed mass increases, implying wall mass regulation involves both angII-dependent and angII-independent pathways. The abdominal aorta showed less dramatic expression changes in RGS5 and 4, but not 2. Again, those changes were delayed by valsartan treatment with no mass changes. Thoracic aorta contraction to GPCR agonists was examined in aortic explant rings to identify vessel wall physiological changes. In 2-day aorta, the response to Galphaq/i agonists increased above normal, while 28-day aorta had attenuated induced contraction via Galphaq/i agonist, implicating a connection between RGS message levels and changes in GPCR-induced contraction. In vitro overexpression studies showed RGS5 inhibits angII-induced signaling in smooth muscle cells. This study is the first experimental evidence that changes in RGS expression and function correlate with vascular remodeling.

Interdisciplinary shared decision-making: taking shared governance to the next level.

Healthcare organizations have been challenged to make high-quality, safe, and reliable care more affordable, portable, transparent, and efficient. Skillful leadership and contributions from all members of the organization are needed to accomplish these changes. This article describes how one organization, driven by a vision for finding better ways, embarked on a journey to design, implement, and refine their model for interdisciplinary shared decision-making (SDM). The model was based on the principles of accountability, equity, ownership, and partnership, and designed to support staff members in right decision-making at the point of service. The success of SDM depends on leaders who believe in the process and demonstrate their commitment by holding front-line managers accountable for allocating resources and coaching staff. Point-of-service staff, in turn, must accept ownership and accountability for the content of their work and be willing to develop their SDM knowledge, comfort, and skills over time. Preliminary outcomes indicate that these new processes have had a positive effect in helping the organization find better ways to innovate and improve patient care.

Regulation of therapeutic apoptosis: a potential target in controlling hypertensive organ damage.

Cell growth and survival are potential therapeutic targets for the control of complications associated with hypertension. In most cardiovascular disorders, cardiac fibroblasts and large-vessel smooth muscle cells can replicate and thus contribute to the disease. We propose that cardiovascular hyperplasia may be reversed via therapeutic apoptosis induction with drugs that are safe and already used in the clinic. We first reported that, irrespective of the drug class, those drugs that are able to induce regression of cardiovascular hypertrophy are also able to reverse cardiovascular hyperplasia via apoptosis. Drugs active in this regard include inhibitors of the renin-angiotensin system, calcium channel blockers, and beta-blockers. Moreover, the effects of these drugs on cell survival is not merely secondary to blood pressure reduction. Therapeutic apoptosis in the cardiovascular system of the spontaneously hypertensive rat is characterized by a rapid and transient onset following initiation of antihypertensive treatment. Herein, the induction and termination of therapeutic apoptosis during drug treatment of hypertension will be briefly reviewed and supported by novel data suggesting that reversal of cardiovascular hyperplasia is associated with reduced cell growth and a resistance to further induction of therapeutic apoptosis, as shown in spontaneously hypertensive rats receiving an intermittent regime of nifedipine therapy. We propose that the presence of a cell subpopulation with defective cell cycle regulation may determine organ susceptibility to undergo therapeutic apoptosis.

Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development.

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.