Papers by Narendra Vyavahare
Journal of Membrane Science, 1990
ABSTRACT
Biochemical and Biophysical Research Communications, 2014
Abdominal aortic aneurysms (AAA) are progressive dilatations of infra-renal aorta causing structu... more Abdominal aortic aneurysms (AAA) are progressive dilatations of infra-renal aorta causing structural weakening rendering the aorta prone to rupture. AAA can be potentially stabilized by inhibiting inflammatory enzymes such as matrix metalloproteinases (MMP); however, active regression of AAA is not possible without new elastic fiber regeneration. Here we report the elastogenic benefit of direct delivery of polyphenols such as pentagalloyl glucose (PGG), epigallocatechin gallate (EGCG), and catechin, to smooth muscle cells obtained either from healthy or from aneurysmal rat aorta. Addition of 10 μg/ml PGG and ECGC induce elastin synthesis, organization, and crosslinking while catechin does not. Our results indicate that polyphenols bind to monomeric tropoelastin and enhance coacervation, aid in crosslinking of elastin by increasing lysyl oxidase (LOX) synthesis, and by blocking MMP-2 activity. Thus, polyphenol treatments leads to increased mature elastin fibers synthesis without increasing the production of intracellular tropoelastin.
Biotechnology and Bioengineering, 2004
We have developed a method for fabricating bacterial colony arrays and complex patterns using com... more We have developed a method for fabricating bacterial colony arrays and complex patterns using commercially available ink-jet printers. Bacterial colony arrays with a density of 100 colonies/cm2 were obtained by directly ejecting Escherichia coli (E. coli) onto agar-coated substrates at a rapid arraying speed of 880 spots per second. Adjusting the concentration of bacterial suspensions allowed single colonies of viable bacteria to be obtained. In addition, complex patterns of viable bacteria as well as bacteria density gradients were constructed using desktop printers controlled by a simple software program. © 2003 Wiley Periodicals, Inc.
Gene Therapy, 2001
Gene therapy with viral vectors has progressed to clinical trials. However, the localization of v... more Gene therapy with viral vectors has progressed to clinical trials. However, the localization of viral vector delivery to diseased target sites remains a challenge. We tested the hypothesis that an adenoviral vector could be successfully delivered by complexation with a specific antibody that is bound to a biodegradable matrix designed for achieving localized gene transduction. We report the first successful delivery system based upon antibody immobilization of virions in a type I collagen-avidin gel using a polyclonal biotinylated IgG specific for the adenovirus hexon. In vitro stability studies demonstrated retention of viral vector activity with antibody-complexed adenovirus collagen gel preparations, in comparison to loss of vector activity from collagen gels prepared with nonspecific biotinylated IgG. Cell culture investigations using this antibody-controlled release system for adenoviral vector transduction of rat aortic smooth muscle cells (A10) demonstrated a significantly more localized reporter expression (beta-galactosidase) compared with non-antibody-complexed controls. Herpes simplex thymidine kinase (HSVtk) adenoviral vectors were immobilized on avidin-collagen gels via this antibody-complexation approach, and ganciclovir was added to rat smooth muscle cells (A10) in culture with the gels. With complexed HSVtk adenovirus, only cells either in contact with the virus-containing gel or within 50 microm were killed. By comparison, at the same adenovirus and ganciclovir dose, non-antibody-complexed HSVtk adenoviral delivery with ganciclovir resulted in the death of virtually all cells. Myocardial gene transfer studies in pigs demonstrated significantly more efficient right ventricular adenoviral GFP expression with anti-hexon antibody-complexed matrix injections, compared with direct vector injections. Thus, our results show that matrix formulations based on antibody-complexation delivery of adenovirus resulted in site-specific localization of transgene expression that enhances the efficiency of therapeutic vector strategies and provides a potent means for localization, to avoid distal side-effects. This approach has therapeutic potential as an implantable preparation that through the means of antibody-complexation, can localize and optimize viral vector gene therapy.
Journal of Controlled Release, 1995
Cardiovascular controlled release, utilizing drug-polymer composites implanted in direct contact ... more Cardiovascular controlled release, utilizing drug-polymer composites implanted in direct contact with the heart, has recently come into clinical use with a dexamethasone eluting cardiac pacemaker lead tip. Furthermore, cardiovascular controlled release systems are under active investigation in a number of other areas of possible application. The general working hypothesis of this approach is that regionally administered drug delivered directly to the heart or a blood vessel will more efficiently and effectively treat localized disease processes of interest, while avoiding systemic side effects. Successful experimental examples illustrating the validity of this hypothesis have involved investigations into cardiovascular calcification, therapy of cardiac arrhythmias, and treatment of arterial restenosis following angioplasty. Efficacious results in each of these areas, with some limitations, have been noted, and are discussed in detail in this paper. An ideal cardiovascular controlled release system will consist of a feedback responsive implant in which drug release kinetics could be varied according to disease activity, or other considerations such as side effects of the therapeutic agent. Furthermore, cardiovascular drug delivery should be ideally extremely long acting and this may be possible through the use of therapeutic agents in a refillable reservoir configuration, or local gene therapy with long standing expression of the gene of interest. 747-3270 1995 Elsevier Science B.V. SSDI 0168-3659 ( 95 ) 00045-3 surgical and cardiac catheter interventions have greatly benefited many patients through relieving, by either surgery, ablation, or angioplasty, various localized cardiovascular disease processes. As a result of this, cardiac catheterization has become the most common surgical procedure in the United States and coronary artery bypass surgery is now the most frequently performed surgical operation in the United States requiring general anesthesia. Catheter mediated interventional procedures for relieving various obstructive sites in the coronary artery vascular bed have also come into widespread use. Initially, balloon tip catheters were used for
American Journal of Pathology, 1999
Elastin , an abundant structural protein present in the arterial wall , is prone to calcification... more Elastin , an abundant structural protein present in the arterial wall , is prone to calcification in a number of disease processes including porcine bioprosthetic heart valve calcification and atherosclerosis. The mechanisms of elastin calcification are not completely elucidated. In the present work , we demonstrated calcification of purified elastin in rat subdermal implants (Ca 2؉ ؍ 89.73 ؎ 9.84 g/mg after 21 days versus control , unimplanted Ca 2؉ ؍ 0.16 ؎ 0.04 g/mg). X-ray diffraction analysis along with resolution enhanced FTIR spectroscopy demonstrated the mineral phase to be a poorly crystalline hydroxyapatite. We investigated the time course of calcification, the effect of glutaraldehyde crosslinking on calcification , and mechanisms of inhibition of elastin calcification by pretreatment with aluminum chloride (AlCl 3 ). Glutaraldehyde pretreatment did not affect calcification (Ca 2؉ ؍ 89.06 ؎ 17.93 g/mg for glutaraldehyde crosslinked elastin versus Ca 2؉ ؍ 89.73 ؎ 9.84 g/mg for uncrosslinked elastin). This may be explained by radioactive ( 3 H) glutaraldehyde studies showing very low reactivity between glutaraldehyde and elastin. Our results further demonstrated that AlCl 3 pretreatment of elastin led to complete inhibition of elastin calcification using 21day rat subdermal implants , irrespective of glutaraldehyde crosslinking (Ca 2؉ ؍ 0.73-2.15 g/mg for AlCl 3 pretreated elastin versus 89.73 ؎ 9.84 for untreated elastin). The AlCl 3 pretreatment caused irreversible binding of aluminum ions to elastin , as assessed by atomic emission spectroscopy. Moreover, aluminum ion binding altered the spatial configuration of elastin as shown by circular dichroism (CD), Fourier transform infrared (FTIR) , and 13 C nuclear magnetic resonance (NMR) spectroscopy studies, suggesting a net structural change including a reduction in the extent of  sheet structures and an increase in coil-turn conformations. Thus , it is concluded that purified elastin calcifies in rat subdermal implants, and that the AlCl 3 -pretreated elastin completely re-
Elastin , an abundant structural protein present in the arterial wall , is prone to calcification... more Elastin , an abundant structural protein present in the arterial wall , is prone to calcification in a number of disease processes including porcine bioprosthetic heart valve calcification and atherosclerosis. The mechanisms of elastin calcification are not completely elucidated. In the present work , we demonstrated calcification of purified elastin in rat subdermal implants (Ca 2؉ ؍ 89.73 ؎ 9.84 g/mg after 21 days versus control , unimplanted Ca 2؉ ؍ 0.16 ؎ 0.04 g/mg). X-ray diffraction analysis along with resolution enhanced FTIR spectroscopy demonstrated the mineral phase to be a poorly crystalline hydroxyapatite. We investigated the time course of calcification, the effect of glutaraldehyde crosslinking on calcification , and mechanisms of inhibition of elastin calcification by pretreatment with aluminum chloride (AlCl 3 ). Glutaraldehyde pretreatment did not affect calcification (Ca 2؉ ؍ 89.06 ؎ 17.93 g/mg for glutaraldehyde crosslinked elastin versus Ca 2؉ ؍ 89.73 ؎ 9.84 g/mg for uncrosslinked elastin). This may be explained by radioactive ( 3 H) glutaraldehyde studies showing very low reactivity between glutaraldehyde and elastin. Our results further demonstrated that AlCl 3 pretreatment of elastin led to complete inhibition of elastin calcification using 21day rat subdermal implants , irrespective of glutaraldehyde crosslinking (Ca 2؉ ؍ 0.73-2.15 g/mg for AlCl 3 pretreated elastin versus 89.73 ؎ 9.84 for untreated elastin). The AlCl 3 pretreatment caused irreversible binding of aluminum ions to elastin , as assessed by atomic emission spectroscopy. Moreover, aluminum ion binding altered the spatial configuration of elastin as shown by circular dichroism (CD), Fourier transform infrared (FTIR) , and 13 C nuclear magnetic resonance (NMR) spectroscopy studies, suggesting a net structural change including a reduction in the extent of  sheet structures and an increase in coil-turn conformations. Thus , it is concluded that purified elastin calcifies in rat subdermal implants, and that the AlCl 3 -pretreated elastin completely re-
Journal of Biomedical Materials Research, 1999
Bioprosthetic heart valve (BPHV) degeneration, characterized by extracellular matrix deterioratio... more Bioprosthetic heart valve (BPHV) degeneration, characterized by extracellular matrix deterioration, remodeling, and calcification, is an important clinical problem accounting for thousands of surgeries annually. Here we report for the first time, in a series of in vitro accelerated fatigue studies (5-500 million cycles) with glutaraldehyde fixed porcine aortic valve bioprostheses, that the mechanical function of cardiac valve cusps caused progressive damage to the molecular structure of type I collagen as assessed by Fourier transform IR spectroscopy (FTIR). The cyclic fatigue caused a progressive loss of helicity of the bioprosthetic cuspal collagen, which was evident from FTIR spectral changes in the amide I carbonyl stretching region. Furthermore, cardiac valve fatigue in these studies also led to loss of glycosaminoglycans (GAGs) from the cuspal extracellular matrix. The GAG levels in glutaraldehyde crosslinked porcine aortic valve cusps were 65.2 ± 8.66 g uronic acid/10 mg of dry weight for control and 7.91 ± 1.1 g uronic acid/10 mg of dry weight for 10-300 million cycled cusps. Together, these molecular changes contribute to a significant gradual decrease in cuspal bending strength as documented in a biomechanical bending assay measuring three point deformation. We conclude that fatigue-induced damage to type I collagen and loss of GAGs are major contributing factors to material degeneration in bioprosthetic cardiac valve deterioration.
Journal of Biomedical Materials Research, 1998
Clinical usage of bioprosthetic heart valves (BPHVs) fabricated from glutaraldehyde-pretreated po... more Clinical usage of bioprosthetic heart valves (BPHVs) fabricated from glutaraldehyde-pretreated porcine aortic valves is restricted due to calcification-related failure. We previously reported a highly efficacious ethanol pretreatment of BPHVs for the prevention of cuspal calcification. The aim of the present study is to extend our understanding of the material changes brought about by ethanol and the relationship of these material effects to the ethanol pretreatment anticalcification mechanism. Glutaraldehydecrosslinked porcine aortic valve cusps (control and ethanolpretreated) were studied for the effects of ethanol on tissue water content and for spin-lattice relaxation times (T1) using solid state proton NMR. Cusp samples were studied for protein conformational changes due to ethanol by ATR-FTIR spectroscopy. The changes in cuspal tissue-cholesterol (in vitro) interactions also were studied. Cusp material stability was assessed in terms of residual glutaraldehyde content and collagenase degradation. Water content of the cusp samples was decreased significantly due to ethanol pretreatment. The cuspal collagen conformational changes (per infrared spectroscopy) brought about by ethanol pretreatment were persistent even after rat subdermal implantation of cusp samples for 7 days. In vitro cholesterol uptake by cusps was greatly reduced as a result of ethanol pretreatment. Ethanol pretreatment of cusps also resulted in increased resistance to collagenase digestion. Cuspal glutaraldehyde content was not changed by ethanol pretreatment. We conclude that ethanol pretreatment of bioprosthetic heart valve cusps causes multi-component effects on the tissue/material and macromolecular characteristics, which partly may explain the ethanol-pretreatment anticalcification mechanism.
Journal of Biomedical Materials Research, 1998
The effectiveness of ethanol pretreatment on preventing calcification of glutaraldehyde-fixed por... more The effectiveness of ethanol pretreatment on preventing calcification of glutaraldehyde-fixed porcine aortic bioprosthetic heart valve (BPHV) cusps was previously demonstrated, and the mechanism of action of ethanol was attributed in part to both lipid removal and a specific collagen conformational change. In the present work, the effect of ethanol pretreatment on BPHV aortic wall calcification was investigated using both rat subdermal and sheep circulatory implants. Ethanol pretreatment significantly inhibited calcification of BPHV aortic wall, but with less than complete inhibition. The maximum inhibition of calcification of BPHV aortic wall was achieved using an 80% ethanol pretreatment; calcium levels were 71.80 ± 8.45 g/mg with 80% ethanol pretreatment compared to the control calcium level of 129.90 ± 7.24 g/mg (p = 0.001). Increasing the duration of ethanol exposure did not significantly improve the inhibitory effect of ethanol on aortic wall calcification. In the sheep circulatory implants, ethanol pretreatment partly prevented BPHV aortic wall calcification with a calcium level of 28.02 ± 4.42 g/mg compared to the control calcium level of 56.35 ± 6.14 g/mg (p = 0.004). Infrared spectroscopy (ATR-FTIR) studies of ethanol-pretreated BPHV aortic wall (vs. control) demonstrated a significant change in protein structure due to ethanol pretreatment. The water content of the aortic wall tissue and the spin-lattice relaxation times (T 1 ) as assessed by proton nuclear magnetic resonance spectroscopy did not change significantly owing to ethanol pretreatment. The optimum condition of 80% ethanol pretreatment almost completely extracted both phospholipids and cholesterol from the aortic wall; despite this, significant calcification occurred. In conclusion, these results clearly demonstrate that ethanol pretreatment is significantly but only partially effective for inhibition of calcification of BPHV aortic wall and this effect may be due in part to lipid extraction and protein structure changes caused by ethanol. It is hypothesized that ethanol pretreatment may be of benefit for preventing bioprosthetic aortic wall calcification only in synergistic combination with another agent.
Biomaterials, 2001
Calcification of polyurethane cardiovascular implants is an important disease process that has th... more Calcification of polyurethane cardiovascular implants is an important disease process that has the potential to compromise the long-term function of devices such as polymer heart valves and ventricular assist systems. In this study we report the successful formulation and characterization of bisphosphonate-derivatized polyurethanes, hypothesized to resist implant calcification based on the pharmacologic activity of the immobilized bisphosphonate. Fully polymerized polyurethanes (a polyurea-polyurethane and a polycarbonate polyurethane) were modified (post-polymerization) with bromoalkylation of the hard segments followed by attachment of a bisphosphonate group at the bromine site. These bisphosphonate-polyurethanes resisted calcification in rat 60 day subdermal implants compared to nonmodified control polyurethane implants, that calcify. Bisphosphonates-modified polyurethanes were also studied in circulatory implants using a pulmonary valve cusp replacement model in sheep. Polyurethane cusps modified with bisphosphonate did not calcify in 90 day implants, compared to control polyurethane cusps implants, that demonstrated nodular surface oriented calcific deposits. It is concluded that bisphosphonate modified polyurethanes resist calcification both in subdermal implants and in the circulation. This novel biomaterial approach offers great promise for long-term blood stream implantation with calcification resistance. #
Macromolecules, 1992
Water-soluble poly(ether urethanes) (M, up to 170 000) have been prepared by the copolymerization... more Water-soluble poly(ether urethanes) (M, up to 170 000) have been prepared by the copolymerization of bis(succinimidy1) carbonate derivatives of poly(ethy1ene glycol) (PEG) with L-lysine (Lys) in a strictly alternating fashion. The resulting copolymers have physical properties similar to those of PEG while the carboxylic acid groups of L-lysine provide multiple pendent groups along the polymer backbone for further functionalization. By using PEG chains of different molecular weights, a homologous series of PEGLys copolymers was prepared containing one lysine unit every 1000, 2000,4000, and 8000 Da. The pendent carboxylic acid groups were utilized in cross-linking reactions leading to amide cross-links, new acyl semicarbazide cross-links, and hydroxyethyl acrylate and hydroxyethyl methacrylate derived cross-links. The resulting hydrogels formed transparent, highly swollen films. At an equilibrium water content of about 80%, these films exhibited a relatively high degree of tensile strength ranging from 0.26 to 1.09 MPa. Due to their favorable physicomechanical properties and the nontoxicity of the components, PEGLys-derived hydrogels may find applications as biomaterials.
Journal of Polymer Science Part A-polymer Chemistry, 1994
A group of new, water-soluble poly(ether-urethane)s, derived from poly(ethylene glycol) and the a... more A group of new, water-soluble poly(ether-urethane)s, derived from poly(ethylene glycol) and the amino acid L-lysine, provide pendent carboxylic acid groups along the polymer backbone at regular intervals. The carboxylic acid groups were utilized for the attachment of acrylate and methacrylate pendent chains (hydroxyethyl acrylate, hydroxyethyl methacrylate, aminoethyl methacrylate, and aminoethyl methacrylamide), leading to functionalized polymers. The pendent chains were attached via ester and/or amide bonds having different degrees of hydrolytic stability. The attachment reactions proceeded with high yields (up to 95%). The functionalized polymers were subsequently photopolymerized (UV irradiation) to obtain crosslinked hydrogels. Crosslinked membranes with the highest degree of mechanical strength were obtained when the crosslinking reaction was performed in dioxane with benzoin methyl ether (0.1 wt %) as the initiator. the crystallinity, thermomechanical properties, and hydrolytic stability of the crosslinked membranes were studied. All membranes were transparent and highly swellable (equilibrium water content: 64–88%). The tensile strength in the swollen state ranged from 0.15 to 1.09 MPa. Under physiological conditions (phosphate buffered water, 0.1M, pH 7.4, 37°C) the hydrolytic stability of the hydrogels varied depending on the bonds used in the attachment of the acrylate pendent chains: Hydrogels with hydroxyethyl acrylate pendent chains dissolved within 30 days, while hydrogels containing aminoethyl methacrylamide pendent chains remained unchanged throughout a 30 day period. Using high molecular weight FITC-dextrans as model compounds, complete release from the swollen hydrogels required between 60 and 150 h. Overall, the evaluation of poly(ethylene glycol)-lysine derived, photocrosslinked hydrogels indicated that these materials provide a range of potentially useful properties. © 1994 John Wiley & Sons, Inc.
Journal of Controlled Release, 1995
Controlled release delivery implants based on ethylene-vinyl acetate (EVA) copolymer were studied... more Controlled release delivery implants based on ethylene-vinyl acetate (EVA) copolymer were studied for prevention of calcification of aortic wall in an intracirculatory rat allograft model. The calcium salt of ethanehydroxybisphosphonate (CaEHBP) and ferric chloride (FeC13) were used as anti-calcification drugs either in combination or separately in solvent-cast EVA films. These matrices were characterized in vitro for their drug release at 37°C at pH 7.4 (0.05 M HEPES buffer). Inulin was included in the single drug loaded systems as an inert filler to obtain comparable loadings. The films released the drugs in vitro continuously over 60 days without any rapid burst phase. For rat allograft studies controlled release matrices or non-drug EVA films were sutured periadventitially to the aortic wall allografts to study the anticalcification efficacy for 30 days. The calcium and phosphorous levels of the explanted allografts were quantified. Controlled release films releasing both the drugs (CaEHBP and FeC13) together synergistically inhibited calcification of the aortic walls. CaEHBP alone releasing from EVA polymer was partially effective, and EVA films releasing only FeC13 did not inhibit calcification at all. Overall, no adverse effects on somatic growth or recipient bone morphology were noted following controlled release drug administration.
Cardiovascular Pathology, 1996
Bioprosthetic heart valve calcification, which is a very frequent failure mode for this type of c... more Bioprosthetic heart valve calcification, which is a very frequent failure mode for this type of cardiac valve prosthesis, occurs through an interaction of host, implant, and mechanical factors. However, anticalcification strategies in general have not been based on these major mechanistic considerations. Rather, many anticalcification strategies are empirical in nature with poorly understood mechanisms of action. This paper will present a review of the previous successful experimental approaches to calcification inhibition, including the relevance of animal models, and differences between results obtained with in vitro studies, subdermal implants, and circulatory implants in large animals. Principles will be considered concerning extending experimental results to proposals for clinical use, as well as interpreting clinical data over time. General principles for further development of anticalcification strategies also will be considered from the point of view of material-molecular factors, interactions with the biologic environment, and tissue engineering.
Journal of Biomedical Materials Research, 2001
Bioprosthetic heart valves (BPHVs) derived from glutaraldehyde-crosslinked porcine aortic valves ... more Bioprosthetic heart valves (BPHVs) derived from glutaraldehyde-crosslinked porcine aortic valves are frequently used in heart valve replacement surgeries. However, the majority of bioprostheses fail clinically because of calcification and degeneration. We have recently shown that glycosaminoglycan (GAG) loss may be in part responsible for degeneration of glutaraldehyde-crosslinked bioprostheses. In the present studies, we used a mild reaction of periodate-mediated crosslinking to stabilize glycosaminoglycans in the bioprosthetic tissue. We demonstrate the feasibility of periodate reaction by crosslinking major components of extracellular matrix of bioprosthetic heart valve tissue, namely type I collagen and hyaluronic acid (HA). Uronic acid assay of periodate-fixed HA-collagen matrices showed 48% of HA disaccharides were bound to collagen. Furthermore, we show that such reactions are also feasible to fix glycosaminoglycans present in the middle spongiosa layer of bioprosthetic heart valves. The periodate reactions were compatible with conventional glutaraldehyde crosslinking and showed adequate stabilization of extracellular matrix as demonstrated by thermal denaturation temperature and collagenase assays. Moreover, uronic acid assays of periodate-fixed BPHV cusps showed 36% reduction in the amount of unbound GAG disaccharides as compared with glutaraldehyde-crosslinked cusps. We also demonstrate that calcification of BPHV cusps was significantly reduced in the periodate-fixed group as compared with the glutaraldehyde-fixed group in 21-day rat subdermal calcification studies (periodate-fixed tissue Ca 72.01 +/- 5.97 microg/mg, glutaraldehyde-fixed tissue Ca 107.25 +/- 6.56 microg/mg). We conclude that periodate-mediated GAG fixation could reduce structural degeneration of BPHVs and may therefore increase the useful lifetime of these devices.
American Journal of Pathology, 2000
Elastin , a major extracellular matrix protein present in arterial walls provides elastic recoil ... more Elastin , a major extracellular matrix protein present in arterial walls provides elastic recoil and resilience to arteries. Elastin is prone to calcification in a number of cardiovascular diseases including atherosclerosis and bioprosthetic heart valve mineralization. We have recently shown that purified elastin when implanted subdermally in rats undergoes severe calcification. In the present study , we used this elastin implant model to investigate the molecular mechanisms underlying elastin calcification. Intense matrix metalloproteinase (MMP-2) and tenascin-C (TN-C) expression were seen in the proximity of the initial calcific deposits at 7 days. Gelatin zymography studies showed both MMP-2 (latent and active form) and MMP-9 expression within the implants. To investigate the role of MMPs in calcification, rats were administered a MMP inhibitor, (2S-allyl-N-hydroxy-3R-isobutyl-N-(1S-methylcarbamoyl-2-phenylethyl)-succinamide (BB-1101) by daily injection , either systemically or at the implant site. The site-specific BB-1101 administration almost completely suppressed TN-C expression, as shown by immunohistochemical staining , within the implants. The systemic BB-1101 injections also significantly reduced TN-C expression within the elastin implants. Moreover , calcification of elastin implants was significantly reduced in the site-specific administration group (5.43 ؎ 1.03 g/mg Ca for BB-1101 group versus 21.71 ؎ 1.19 for control group, P < 0.001). Alizarin Red staining clearly showed that the elastin fibers were heavily calcified in the control group, whereas in BB-1101 group the calcification was scarce with few fibers showing initial calcification deposits. The systemic administration of BB-1101 also significantly reduced elastin calcification (28.07 ؎ 5.81 control versus 16.92 ؎ 2.56 in the BB-1101 group, P < 0.05) , although less than the site-specific administration. Thus , the present studies indicate that MMPs and TN-C play a role in elastin-oriented calcification.
Biomaterials, 2006
Glycosaminoglycans (GAGs) are important structural and functional components in native aortic hea... more Glycosaminoglycans (GAGs) are important structural and functional components in native aortic heart valves and in glutaraldehyde (Glut)-fixed bioprosthetic heart valves (BHVs). However, very little is known about the fate of GAGs within the extracellular matrix of BHVs and their contribution to BHV longevity. BHVs used in heart valve replacement surgery have limited durability due to mechanical failure and pathologic calcification. In the present study we bring evidence for the dramatic loss of GAGs from within the BHV cusp structure during storage in saline and both shortand long-term Glut fixation. In order to gain insight into role of GAGs, we compared properties of fresh and Glut-fixed porcine heart valve cusps before and after complete GAG removal. GAG removal resulted in significant morphological and functional tissue alterations, including decreases in cuspal thickness, reduction of water content and diminution of rehydration capacity. By virtue of this diminished hydration, loss of GAGs also greatly increased the ''with-curvature'' flexural rigidity of cuspal tissue. However, removal of GAGs did not alter calcification potential of BHV cups when implanted in the rat subdermal model. Controlling the extent of pre-implantation GAG degradation in BHVs and development of improved GAG crosslinking techniques are expected to improve the mechanical durability of future cardiovascular bioprostheses.
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Papers by Narendra Vyavahare