Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

Effects of Aspirin on Endothelial Function and Hypertension

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. SUMMARY: Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations

Decellularized ECM-derived bioinks: Prospects for the future

Decellularization aims to remove cells from tissue ultrastructure while preserving the mechanical and biological properties, which makes the decellularized extracellular matrix (dECM)an appropriate scaffold for tissue engineering applications. Three-dimensional (3D)bioprinting technology as a reproducible and accurate method can print the combination of ECM and autologous cells layer by layer to fabricate patient based cell-laden structures representing the intrinsic cues of natural ECM. This review defines ECM, classifies decellularization agents and techniques, and explains different sources of ECM. Then, bioprinting techniques, bioink concept, applications of dECM bioinks, and finally the future perspectives of 3d bioprinting technology are discussed. © 2019 Elsevier Inc

Decellularized ECM-derived bioinks: Prospects for the future

Decellularization aims to remove cells from tissue ultrastructure while preserving the mechanical and biological properties, which makes the decellularized extracellular matrix (dECM) an appropriate scaffold for tissue engineering applications. Three-dimensional (3D) bioprinting technology as a reproducible and accurate method can print the combination of ECM and autologous cells layer by layer to fabricate patient based cell-laden structures representing the intrinsic cues of natural ECM. This review defines ECM, classifies decellularization agents and techniques, and explains different sources of ECM. Then, bioprinting techniques, bioink concept, applications of dECM bioinks, and finally the future perspectives of 3d bioprinting technology are discussed. © 2019 Elsevier Inc

Nitric oxide-releasing vascular grafts: A therapeutic strategy to promote angiogenic activity and endothelium regeneration

Small-diameter vascular grafts (SDVGs) are associated with a high incidence of failure due to infection and obstruction. Although several vascular grafts are commercially available, specific anatomical differences of defect sites require patient-based design and fabrication. Design and fabrication of such custom-tailored grafts are possible with 3d-printing technology. The aim of this study is to develop 3d-printed SDVGs with a nitric oxide (NO)-releasing coating to improve the success rate of implantation. The SDVGs were printed from polylactic acid and coated with blending of 10 wt S-nitroso-N-acetyl-D-penicillamine into the polymeric substrate consisting of poly (ethylene glycol) and polycaprolactone. Our results show that NO is released in the physiological range (0.5�4 � 10�10 mol·cm�2·min�1) for 14 days and NO-releasing coating showed significant antibacterial potential against Gram-positive and Gram-negative strains. It was shown that both NO-releasing and control grafts are biocompatible in-vitro and in-vivo. Interestingly, the NO-releasing SDVGs dramatically enhanced ECs proliferation and significantly enhanced ECs migration in-vitro compared to control grafts. In addition, the NO-releasing SDVGs showed angiogenic potential in-vivo which can further prove the results of our in-vitro study. These findings are expected to facilitate tissue regeneration and integration of custom-made vascular implants with enhanced clinical success. Statement of significance: A series of 3d-printed small-diameter vascular grafts (SDVGs, <6 mm) with controlled release of nitric oxide (NO) were prepared to combine the advantages of 3D printing technology and NO-releasing systems. The resulting NO-releasing grafts were promisingly showing sustained NO release in the physiological range over a two weeks period. In addition to the evaluation of endothelial cell migration in-vitro, we implanted for the first time the NO-releasing vascular grafts in a chick chorioallantoic membrane (CAM) to investigate the effect of the prepared grafts on the angiogenesis in-vivo. The fabricated grafts also exhibited bactericidal properties which prevent the formation of a biofilm layer and can thereby enhance the chance of endothelialization on the surface. Taken together, the innovative combination of rapid and highly accurate 3d-printing technology as a patient-specific fabrication method with NO-releasing coating represents a promising approach to develop bactericidal SDVGs with improved endothelialization. © 2019 Acta Materialia Inc

Additive Manufacturing of Biomaterials � The Evolution of Rapid Prototyping

Biomaterials rapid prototyping (RP), recently known as additive manufacturing (AM), has appeared as a revolutionary technology, promising to transform research into medical therapeutics. RP is a layer by layer manufacturing process which directly translates computer data such as Computer Aided Design (CAD), Computer Tomography (CT), and Magnetic Resonance Imaging (MRI) into three-dimensional (3D) objects. RP technologies play a significant role in biomedical industry such as anatomical models for surgery training/planning, rehabilitation, dentistry, customized implants, drug delivery devices, tissue engineering, and organ printing. The integration of biomaterials and rapid prototyping technologies is an exciting route in developing biomaterial implants for the past decade. This review describes and classifies the RP systems into three categories of liquid-based, solid-based, and powder-based according to the initial form of their feed materials. Then, discusses possible benefits, drawbacks, and applications of each process in the field of biomaterials science and engineering. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

Additively manufactured small-diameter vascular grafts with improved tissue healing using a novel SNAP impregnation method

The vascular network has a complex architecture such as branches, curvatures, and bifurcations which is even more complicated in view of individual patients' defect anatomy requiring custom-specifically designed vascular implants. In this work, 3D printing is used to overcome these challenges and a new shorter impregnation method was developed to incorporate S-nitroso-N-acetyl-d-penicillamine (SNAP) as a nitric oxide (NO) donor to printed grafts. The 3D-printed small-diameter vascular grafts (SDVGs) were impregnated with SNAP solution during SNAP synthesis (S1) or with SNAP dissolved in methanol (S2). The advantage of the newly developed S1 impregnation method is the elimination of the synthesis step by direct impregnation inside the S1 solution. Scanning electron microscopy imaging reveals the successful crystal formation in both methods. The results demonstrate that both S1- and S2-impregnated grafts, after covering with polycaprolactone topcoat, can release NO in a controlled manner and in the physiological range (0.5�4.0 � 10�10 mol cm�2 min�1) over a 15 days period. The created grafts with a NO-releasing surface have also shown bactericidal effect while the healing properties of the implant were improved by promoting migration and proliferation of endothelial cells (ECs). These results suggest that incorporation of 3D printing technology with the newly developed S1 impregnation of SNAP can optimize and shorten the manufacturing process of the next generation of patient-based antibacterial SDVGs with a higher attraction for ECs. © 2019 Wiley Periodicals, Inc

Controlled NO-Release from 3D-Printed Small-Diameter Vascular Grafts Prevents Platelet Activation and Bacterial Infectivity

Thrombogenicity and bacterial infectiveness are the most common complications for foreign blood contacting surfaces associated with functional failure of small-diameter vascular grafts (SDVGs). In this work, novel bactericidal and nonthrombogenic SDVGs were manufactured via 3D-printing technology, thus producing a controlled nitric oxide (NO) release coating. S-Nitroso-N-acetyl-D-penicillamine (SNAP) was synthesized as an NO-donor, and three biomedical grade composite matrixes of poly(ethylene glycol) (PEG)-SNAP, polycaprolactone (PCL)-SNAP, and PEG-PCL-SNAP were validated for water uptake and NO-release kinetics. To optimize and extend the NO releasing profile, a PCL top-coat (tc) was deposited over the NO-releasing layer. The PEG-PCL-SNAP-tc was selected for biological tests as its NO-release profile was prolonged and well-controlled. Coating the 3D-printed SDVG with PEG-PCL-SNAP-tc resulted in quantitative antibacterial features against both Gram-positive and Gram-negative bacteria and in NO-mediated inhibition of platelet activation and aggregation. Antibacterial and antithrombogenic properties in plasma are expected to be as effective as in PBS, since NO release in plasma was not significantly different from that in PBS. Overall, application of the inexpensive, rapid, and reproducible 3D-printing technology as a custom-based production method, in combination with a well-controlled NO release system, is promising for the production of innovative bactericidal and hemocompatible SDVGs. © 2019 American Chemical Society