Article

Dialdehyde xanthan gum and curcumin synergistically crosslinked bioprosthetic valve leaflets with anti-thrombotic, anti-inflammatory and anti-calcification properties

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Abstract

Currently commercial glutaraldehyde (GA)-crosslinked bioprosthetic valve leaflets (BVLs) suffer from thromboembolic complications, calcification, and limited durability, which are the major stumbling block to wider clinical application of BVLs. Thus, developing new-style BVLs will be an urgent need to enhance the durability of BVLs and alleviate thromboembolic complications. In this study, a quick and effective collaborative strategy of the double crosslinking agents (oxidized polysaccharide and natural active crosslinking agent) was reported to realize enhanced mechanical, and structural stability, excellent hemocompatibility and anti-calcification properties of BVLs. Dialdehyde xanthan gum (AXG) exhibiting excellent stability to heat, acid-base, salt, and enzymatic hydrolysis was first introduced to crosslink decellularized porcine pericardium (D-PP) and then curcumin with good properties of anti-inflammatory, anti-coagulation, anti-liver fibrosis, and anti-atherosclerosis was used to synergistically crosslink and multi-functionalize D-PP to obtain AXG + Cur-PP. A comprehensive evaluation of structural characterization, hemocompatibility, endothelialization potential, mechanical properties and component stability showed that AXG + Cur-PP exhibited better anti-thrombotic properties and endothelialization potential, milder immune responses, excellent anti-calcification properties and enhanced mechanical properties compared with GA-crosslinked PP. Overall, this cooperative crosslinking strategy provides a novel solution to achieve BVLs with enhanced mechanical properties and excellent anti-coagulation, anti-inflammatory, anti-calcification, and the ability to promote endothelial cell proliferation.

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Turmeric (Curcuma longa) is a popular Indian spice that has been used for centuries in herbal medicines for the treatment of a variety of ailments such as rheumatism, diabetic ulcers, anorexia, cough and sinusitis. Curcumin (diferuloylmethane) is the main curcuminoid present in turmeric and responsible for its yellow color. Curcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anticoagulant and anti-infective effects. This review summarizes and discusses recently published papers on the key biomedical applications of curcumin based materials. The highlighted studies in the review provide evidence of the ability of curcumin to show the significant vitro antioxidant, diabetic complication, antimicrobial, neuroprotective, anti-cancer activities and detection of hypochlorous acid, wound healing, treatment of major depression, healing of paracentesis, and treatment of carcinoma and optical detection of pyrrole properties. Hydrophobic nature of this polyphenolic compound along with its rapid metabolism, physicochemical and biological instability contribute to its poor bioavailability. To redress these problems several approaches have been proposed like encapsulation of curcumin in liposomes and polymeric micelles, inclusion complex formation with cyclodextrin, formation of polymer-curcumin conjugates, etc.
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Elastin, a main component of decellularized extracellular matrices and elastin-containing materials, has been used for tissue engineering applications due to their excellent biocompatibility. However, elastin is easy to be calcified, leading to the decrease of life span for elastin-based substitutes. How to inhibit the calcification of elastin-based scaffolds, but maintain their good biocompatibility, still remains significantly challenging. Procyanidins (PC) is a type of natural polyphenols with crosslinking ability. To investigate whether pure elastin could be crosslinked by PC with anti-calcification effect, PC was firstly used to crosslink aortic elastin. The results show that PC can crosslink elastin and effectively inhibit elastin-initiated calcification. Further experiments reveal the possible mechanisms for the anti-calcification of PC crosslinking including (1) inhibiting inflammation cell attachment, and secretion of inflammatory factors such as MMPs and TNF-α, (2) preventing elastin degradation by elastase, (3) direct inhibition of mineral nucleation in elastin. Moreover, the PC-crosslinked aortic elastin maintains natural structure with high pore volume (1111 μL/g), large pore size (10-300 μm) and high porosity (75.1%) which facilitates recellularization of scaffolds in vivo, and displays excellent hemocompatibility, anti-thrombus and anti-inflammatory potential. The advantages of PC-crosslinked porous aortic elastin suggested that it can serve as a promising scaffold for tissue engineering. Copyright © 2015. Published by Elsevier Ltd.
Article
The vulnerability of probiotics at low pH and high temperature has limited their optimal use as nutraceuticals. This study addressed these issues by adopting a physicochemical driven approach of incorporating Lactobacillus plantarum LAB12 into chitosan (Ch) coated alginate–xanthan gum (Alg–XG) beads. Characterisation of Alg–XG–Ch, which elicited little effect on bead size and polydispersity, demonstrated good miscibility with improved bead surface smoothness and L. plantarum LAB12 entrapment when compared to Alg, Alg–Ch and Alg–XG. Sequential incubation of Alg–XG–Ch in simulated gastric juice and intestinal fluid yielded high survival rate of L. plantarum LAB12 (95%) at pH 1.8 which in turn facilitated sufficient release of probiotics (>7 log CFU/g) at pH 6.8 in both time- and pH-dependent manner. Whilst minimising viability loss at 75 and 90 °C, Alg–XG–Ch improved storage durability of L. plantarum LAB12 at 4 °C. The present results implied the possible use of L. plantarum LAB12 incorporated in Alg–XG–Ch as new functional food ingredient with health claims.
Article
The earliest description of calcific aortic stenosis is attributed to the French physician Lazare Riviere who, in 1663, reported the necropsy findings from a patient with palpitations, progressive dyspnea, and loss of peripheral pulses. He noted left ventricular enlargement and identified large caruncle-like masses obstructing the left ventricular outflow to the aorta.1 Although other reports followed, the debate about the etiology of aortic valve calcification (AVC) did not begin until much later.1 Although calcification was originally attributed to endocarditis, in 1846, Hasse challenged this theory by suggesting that a degenerative process occurred within the valve itself to initiate ossification.1 In 1904, Moenckeburg authored the first detailed description of AVC in which he reported that this pathology likely occurred as a result of calcium deposition on valve cusps that had become sclerotic. He described 2 mechanisms to explain this phenomenon: degeneration within the layers of the valve leaflets nearest the sinuses of Valsalva that propagated toward the tips of the cusps or sclerotic changes of the aorta that extended to involve the valve cusps.1 Within the past 20 years, there has been a tremendous resurgence in interest in advancing these early hypotheses to identify the cellular and molecular mechanisms that initiate AVC owing to the high prevalence of this disease, its associated morbidity and mortality, and the emerging idea that therapies that target these processes could increase the durability of surgically implanted and transcatheter bioprosthetic valves. Recent estimates indicate that aortic valve disease is common in the US adult population and contributes to >28000 deaths and 48000 hospitalizations annually.2 Worldwide, population-based studies have revealed that aortic valve disease is the most frequently observed valve pathology and is present in up to 43% of patients presenting with valvular heart disease.3 In individuals ≥65 years of age, …
Article
Patients who require aortic valve replacement are increasingly receiving biologic valves to avoid long-term anticoagulation. The thromboembolic risk of bioprosthetic valves is reportedly low. The study objective was to review the incidence of early valve thrombosis requiring reoperation in patients who received a bioprosthetic valve in the aortic position. We reviewed all adult patients who had a biologic valve implanted in the aortic position at Mayo Clinic between January 1993 and July 2009. Records were reviewed for all cases of reoperation that occurred less than 2 years postoperatively. Incidences of valve thrombosis were calculated including 95% Poisson confidence intervals. During the study interval, 4568 patients received biologic valves for aortic valve replacement. We identified 8 patients who underwent reoperation to replace the aortic prosthesis because of thrombus that resulted in functional aortic stenosis. The median age of patients at the time of reoperation was 77 years (range, 52-86), and the median time to reoperation was 398 days (range, 106-626). All patients with valve thrombosis received a stented porcine valve: St Jude Biocor (St Jude Medical, Inc, St Paul, Minn) in 4 patients, Medtronic Mosaic (Medtronic Inc, Minneapolis, Minn) in 2 patients, and Medtronic Hancock (Medtronic Inc) in 2 patients. The calculated incidence of valve thrombosis was 1.26% (confidence interval, 0.56-1.96) for the Biocor valve, 0.37% (confidence interval, 0.19-0.56) for the Mosaic valve, and 0.84% (confidence interval, 0.42-1.25) for the Hancock valve (P = .34). There were no cases of valve thrombosis in patients who received a pericardial valve (5923 patient-years) or stentless valve (172 patient-years). The incidence of early thrombosis of porcine aortic bioprostheses requiring reoperation was not insignificant. Potential causes and mechanisms for such thrombosis are unknown. Recognition of this unanticipated problem and reoperation resulted in a satisfactory outcome for patients.
Article
Turmeric (Curcuma longa), a herbal remedy and culinary spice, has been used in traditional Indian culture for millennia. An active ingredient found in turmeric is curcumin (diferuloylmethane). In the current study, we investigated the antiplatelet properties of this naturally occurring compound. Curcumin inhibited human platelet aggregation and dense granule secretion induced by GPVI agonist convulxin in a concentration-dependent manner. At 50 microM, it effectively inhibited the maximal extent of aggregation and dense granule secretion to as much as 75%. It also dramatically inhibited the activation-dependent tyrosine phosphorylation of Y753 and Y759 on PLCgamma2, but did not affect the phosphorylation of Y145 residue on the cytosolic adaptor protein SLP-76. Interestingly, curcumin had no significant effect on the phosphorylation of Y525/Y526 present on the activation loop of Syk (spleen tyrosine kinase), but had a significant inhibitory effect on in vitro Syk kinase activity. Moreover, the inhibitory action of curcumin is not due to an inhibition of thromboxane generation because all our studies were performed using aspirin-treated platelets. We conclude that curcumin inhibits platelet activation induced by GPVI agonists through interfering with the kinase activity of Syk and the subsequent activation of PLCgamma2.
Article
Glutaraldehyde-treated porcine aortic valve xenografts frequently fail due to calcification. Calcification in the prostheses begins intracellularly. In a previous study, various types of cell injury to canine valvular fibroblasts, including glutaraldehyde treatment, led to calcification. An influx of extracellular Ca2+ into the phosphate-rich cytosol was theorized to be the mechanism of calcification. To test the Ca2+ influx theory, cytosolic Ca2+ and Pi concentrations were assessed in glutaraldehyde-treated porcine aortic valve fibroblasts, and their relationship to a subsequent calcification was studied. Glutaraldehyde caused an immediate and sustained massive cytosolic Ca2+ increase that was dose dependent and a several-fold increase in Pi. Calcification of cells followed within a week. The earliest calcification was observed in blebs formed on glutaraldehyde-treated cells. Live control cells or cells fixed with glutaraldehyde in Ca2+-free solution did not calcify under the same conditions. Concomitant increases in Ca2+ and Pi in glutaraldehyde-treated cells appear to underlie the mechanism of calcification, and the presence of extracellular Ca2+ during glutaraldehyde fixation promotes calcification.
Article
Prevention of calcification in glutaraldehyde (GA) treated porcine aortic valve fibroblasts and rat aorta with Ca2+ channel blockers (Ca(2+)-CBs). GA causes a massive increase in [Ca2+]i and a many fold increase in [Pi]i followed by calcification of porcine aortic valve fibroblasts. The influx of extracellular Ca2+ into [Pi]i rich cells apparently underlies the mechanism of calcification. Inhibition of Ca2+ influx is likely to prevent calcification in GA-treated cells. [Ca2+]i in GA-treated cells was measured by fluorescence image analysis. [Ca2+]i increase in fibroblasts treated with various Ca(2+)-CBs was compared with the untreated control. To study the role of Ca2+ influx in calcification and to find out the portals of Ca2+ entry, porcine aortic valve fibroblasts and freshly removed rat aorta were treated with verapamil + ryanodine, or verapamil + econazole, fixed with GA and incubated in Hank's balanced salt solution with 2.5 mmol/L calcium. The progress of calcification was monitored by the rate of Ca and Pi depletions from the supernatant. Calcified cells and tissues were identified by calcein fluorescence. Verapamil + ryanodine or econazole inhibited the GA-induced Ca2+ influx and prevented calcification of the cells and rat aorta. The effect of verapamil was additive to that of ryanodine and econazole. Findings further support the influx theory of calcification. Ca2+ enters GA-treated cells mainly through the store operated and the L-type Ca2+ channels. Ca(2+)-CBs may be useful for prevention of calcification in GA-treated vascular bioprostheses. Cell culture serves as a convenient model for screening drug effects on calcification.
Article
The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain. To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to alpha-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1beta, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not alpha-actin or desmin, cells in myxomatous valves contained both vimentin and alpha-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1beta, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves. Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.
Article
Elastin degeneration and calcification occur in many cardiovascular diseases, including medial arterial elastocalcinosis, atherosclerosis, and bioprosthetic heart valve mineralization. In the present study, we tested the hypothesis that the onset and progression of elastin-oriented calcification is associated with matrix remodeling and elastin degradation events. We studied whether aluminum ions inhibit elastin calcification by reducing elastin degradation and altering remodeling events. Subdermal implantation of pure elastin in juvenile rats resulted in a time-dependent calcification of elastin, reaching high levels 21 days after implantation. In situ hybridization showed that elastin calcification was associated with an up-regulation of matrix metalloproteinase (MMP) mRNA expression, specifically MMP-9 and MMP-2. Gelatin zymography demonstrated increased MMP-9 and MMP-2 enzyme activities in early stages of elastin calcification. Calcified elastin displayed a time-dependent pattern of tenascin-C (TN-C) and alkaline phosphatase (AP) expression. Pretreatment of pure elastin with aluminum ions prior to implantation resulted in complete inhibition of elastin calcification. Aluminum ion binding to elastin was found to protect elastin against MMP-mediated degradation in vitro. Noncalcified, explanted aluminum-pretreated elastin exhibited reduced activities of MMPs. TN-C expression in elastin implants exhibited a time-dependent pattern that was also affected by pretreatment of elastin with aluminum ions. In conclusion, elastin calcification is accompanied by matrix remodeling events, and the efficacy of aluminum pretreatment in inhibiting elastin calcification may be related in part to its effects on elastin remodeling.
Article
Glutaraldehyde fixation of bioprosthetic tissue has been used successfully for almost 40 years. However, it is generally recognized that glutaraldehyde fixation of bioprostheses is associated with the occurrence of calcification. Accordingly, many efforts have been undertaken to develop techniques for the fixation of bioprostheses, which will not lead to calcification. Here we describe a new improved carbodiimide based cross-linking method. Rather than cross-linking the tissue through its free primary amine groups, these groups were first blocked with butanal and the tissue was then cross-linked by means of carbodiimide activation of tissue carboxylic acid groups followed by a reaction with a poly(propylene glycol)bis 2-(aminopropyl) ether, (Jeffamine trade mark ). It was demonstrated that cross-linked porcine leaflets had a calcification of less than 1mg/g tissue after 8 weeks sub-dermal implantion in rats. Furthermore, aortic wall calcification was reduced to 50mg/g, compared to standard glutaraldehyde fixed tissue, which showed 120mg/g tissue calcification in the 8 weeks calcification model used.
Article
Progressive degeneration and calcification of glutaraldehyde (Glut) fixed tissues used in cardiovascular surgery restrict their long-term clinical performance. This limited biological stability may be attributable to the inability of Glut to adequately protect certain tissue components such as elastin from enzymatic attack. The aim of our studies was to develop novel tissue-processing techniques targeted specifically at elastin stabilization by using tannic acid (TA), a plant polyphenol capable of protecting elastin from digestion by specific enzymes. In present studies we demonstrated that Glut does not adequately protect porcine aorta from elastase-mediated degradation in vitro. The addition of TA to the Glut fixation process increased the stability of Glut-fixed aorta to elastase digestion by 15-fold and also decreased calcification in the rat subdermal model by 66%. TA was found to be chemically compatible with Glut fixation and did not hinder collagen crosslinking as shown by minor changes in thermal denaturation temperatures, resistance to collagenase and mechanical properties. In vitro and in vivo studies also revealed that TA binding to aortic wall was stable over an extended period of time. TA-mediated elastin stabilization in Glut-fixed cardiovascular implants may significantly extend the clinical durability of these tissue replacements.
Article
Heart valve diseases have a significant high mortality, and the valve replacement using glutaraldehyde crosslinked porcine heart valves is one of the main curing techniques. But its application is limited due to poor durability, calcification of the valves and immunogenic reactions. The aim of this study was to evaluate the crosslinking effect of procyanidins on porcine heart valve matrix. After crosslinking of the decellularized porcine aortic heart valves by procyanidins, the tensile strength, the in vitro enzymatic degradation resistance, procyanidins release from the crosslinked materials and the cytotoxicity of procyanidins to heart valvular interstitial cells were examined. The results showed that the tensile strength of procyanidins crosslinked valve matrix was higher than that of glutaraldehyde crosslinked valve matrix. Valve matrix crosslinked by 10 mg/ml procyanidins could be stored in D-Hanks solution for at least 45 days without any decline in ultimate tensile strength and maintained the elasticity as the fresh valves. Furthermore, procyanidins was found to release when the crosslinked tissue stored in D-Hanks solution. The release rate was high during the first 4 days and then dramatically decreased thereafter. During releasing phase, the concentration of procyanidins was no toxicity to heart valve interstitial cells. In vitro enzymatic degradation revealed that crosslinked matrix could resist the enzymatic hydrolysis, and the resistant capacity was approximately the same as glutaraldehyde crosslinked valve matrix. This study shows that procyanidins can crosslink porcine heart valves effectively without toxicity. Our results suggested that this method might be a useful approach for preparation of bioprosthetic heart valve.
Article
Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification. Ascending aortas/valves (from rats [syngeneic] or guinea pigs [xenogeneic]) were transplanted (fresh or after 48 hour of G-F) into the infrarenal aortas of young rat recipients for 20 days. A xenogeneic group was also treated with steroids until graft harvest. The valves and media/adventitia were scored blindly for inflammation (0 to 4). Percent graft infiltration by T cells/macrophages was determined (immunohistochemistry), and rat IgG ELISAs were performed. There was >3 times more valve inflammation, >10 times more valve T-cell/macrophage infiltrate, and >3 times antibody rise in the G-F xenogeneic groups compared with the fresh syngeneic or the G-F syngeneic groups (P<0.05). There was >2 times more adventitial inflammation and T-cell/macrophage infiltrate in the xenogeneic groups (P<0.05). Steroid treatment decreased inflammation and antibody rise in the xenogeneic groups (P<0.05). Correlation analysis revealed media/adventitia inflammation (P=0.02) and percent macrophage (P=0.01) infiltration to be predictors of calcification. G-F xenografts have cellular/humoral rejection and calcify secondarily.
Aortic bioprosthetic valve durability: Incidence, mechanisms, predictors, and management of surgical and transcatheter valve degeneration
  • Rodriguez-Gabella