Current clinical treatment strategies for the bypassing of small diameter (<6 mm) blood vessels in the management of cardiovascular disease frequently fail due to a lack of suitable autologous ...grafts, as well as infection, thrombosis, and intimal hyperplasia associated with synthetic grafts. The rapid advancement of 3D printing and regenerative medicine technologies enabling the manufacture of biological, tissue-engineered vascular grafts (TEVGs) with the ability to integrate, remodel, and repair in vivo, promises a paradigm shift in cardiovascular disease management. This review comprehensively covers current state-of-the-art biofabrication technologies for the development of biomimetic TEVGs. Various scaffold based additive manufacturing methods used in vascular tissue engineering, including 3D printing, bioprinting, electrospinning and melt electrowriting, are discussed and assessed against the biomechanical and functional requirements of human vasculature, while the efficacy of decellularization protocols currently applied to engineered and native vessels are evaluated. Further, we provide interdisciplinary insight into the outlook of regenerative medicine for the development of vascular grafts, exploring key considerations and perspectives for the successful clinical integration of evolving technologies. It is expected that continued advancements in microscale additive manufacturing, biofabrication, tissue engineering and decellularization will culminate in the development of clinically viable, off-the-shelf TEVGs for small diameter applications in the near future.
Current clinical strategies for the management of cardiovascular disease using small diameter vessel bypassing procedures are inadequate, with up to 75% of synthetic grafts failing within 3 years of implantation. It is this critically important clinical problem that researchers in the field of vascular tissue engineering and regenerative medicine aim to alleviate using biofabrication methods combining additive manufacturing, biomaterials science and advanced cellular biology. While many approaches facilitate the development of bioengineered constructs which mimic the structure and function of native blood vessels, several challenges must still be overcome for clinical translation of the next generation of tissue-engineered vascular grafts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Polycaprolactone surface modification can use various acid or base treatments.•Acid causes bulk degradation, molecular weight loss and limited surface change.•Acid appears akin to ...physiological degradation, base causes superficial degradation.•Base causes increased surface charge, morphological changes, protein adsorption.•Stable mineral apatite formation with both but superior with base treatment.
Poly(ε-caprolactone) (PCL) chain cleavage results in the formation of polar terminal species, comprising hydroxy and carboxyl groups that enhance surface hydrophilicity and enable subsequent biofunctionalization. However, the direct effects of various acidic and basic treatments on 3D printed PCL scaffolds have not been studied from a functional perspective. In this study, we comprehensively assessed the influence of acid (hydrochloric, HCl) and base (sodium hydroxide, NaOH) catalyzed hydrolysis across different conditions on various properties of 3D printed PCL scaffolds. Analyses included testing of physiochemical and mechanical properties, and assessment of rate and stability of surface-nucleating bioactive apatite-like minerals. HCl exposure resulted in pronounced bulk degradation, as observed through limited increase in surface charge, pronounced mechanical weakening, and clear decrease in molecular weight. Conversely, NaOH treatment resulted in a more superficial degradation, with a dramatic increase in surface charge, much lower mechanical degradation, and little change in molecular weight. Indeed, the characteristics observed under acidic catalysis appeared more representative of physiological degradation. The apatite-like coating on the base-treated surface was found to be superior. Our results demonstrate the range of surface and bulk properties achievable through these accessible treatments, and support such techniques for the functionalization of PCL scaffolds for biomedical applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Refractory cardiogenic shock (CS) often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO) to sustain end-organ perfusion. Current animal models result in heterogenous cardiac ...injury and frequent episodes of refractory ventricular fibrillation. Thus, we aimed to develop an innovative, clinically relevant, and titratable model of severe cardiopulmonary failure. Six sheep (60 ± 6 kg) were anaesthetized and mechanically ventilated. VA-ECMO was commenced and CS was induced through intramyocardial injections of ethanol. Then, hypoxemic/hypercapnic pulmonary failure was achieved, through substantial decrease in ventilatory support. Echocardiography was used to compute left ventricular fractional area change (LVFAC) and cardiac Troponin I (cTnI) was quantified. After 5 h, the animals were euthanised and the heart was retrieved for histological evaluations. Ethanol (58 ± 23 mL) successfully induced CS in all animals. cTnI levels increased near 5000-fold. CS was confirmed by a drop in systolic blood pressure to 67 ± 14 mmHg, while lactate increased to 4.7 ± 0.9 mmol/L and LVFAC decreased to 16 ± 7%. Myocardial samples corroborated extensive cellular necrosis and inflammatory infiltrates. In conclusion, we present an innovative ovine model of severe cardiopulmonary failure in animals on VA-ECMO. This model could be essential to further characterize CS and develop future treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background and purpose - Constant fixator stiffness for the duration of healing may not provide suitable mechanical conditions for all stages of bone repair. We therefore investigated the influence ...of stiffening fixation on callus stiffness and morphology in a rat diaphyseal osteotomy model to determine whether healing time was shortened and callus stiffness increased through modulation of fixation from flexible to stiff.
Material and methods - An external unilateral fixator was applied to the osteotomized femur and stiffened by decreasing the offset of the inner fixator bar at 3, 7, 14, and 21 days after operation. After 5 weeks, the rats were killed and healing was evaluated with mechanical, histological, and microcomputed tomography methods. Constant fixation stiffness control groups with either stiff or flexible fixation were included for comparison.
Results - The callus stiffness of the stiff group and all 4 experimental groups was greater than in the flexible group. The callus of the flexible group was larger but contained a higher proportion of unmineralized tissue and cartilage. The stiff and modulated groups (3, 7, 14, and 21 days) all showed bony bridging at 5 weeks, as well as signs of callus remodeling. Stiffening fixation at 7 and 14 days after osteotomy produced the highest degree of callus bridging. Bone mineral density in the fracture gap was highest in animals in which the fixation was stiffened after 14 days.
Interpretation - The predicted benefit of a large robust callus formed through early flexible fixation could not be shown, but the benefits of stabilizing a flexible construct to achieve timely healing were demonstrated at all time points.
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DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background
Extracorporeal membrane oxygenation (ECMO), an invasive mechanical therapy, provides cardio-respiratory support to critically ill patients when maximal conventional support has failed. ...ECMO is delivered via large-bore cannulae which must be effectively secured to avoid complications including cannula migration, dislodgement and accidental decannulation. Growing evidence suggests tissue adhesive (TA) may be a practical and safe method to secure vascular access devices, but little evidence exists pertaining to securement of ECMO cannulae. The aim of this study was to determine the safety and efficacy of two TA formulations (2-octyl cyanoacrylate and
n
-butyl-2-octyl cyanoacrylate) for use in peripherally inserted ECMO cannula securement, and compare TA securement to ‘standard’ securement methods.
Methods
This in vitro project assessed: (1) the tensile strength and flexibility of TA formulations compared to ‘standard’ ECMO cannula securement using a porcine skin model, and (2) the chemical resistance of the polyurethane ECMO cannulae to TA. An Instron 5567 Universal Testing System was used for strength testing in both experiments.
Results
Securement with sutures and
n
-butyl-2-octyl cyanoacrylate both significantly increased the force required to dislodge the cannula compared to a transparent polyurethane dressing (
p
= 0.006 and
p
= 0.003, respectively) and 2-octyl cyanoacrylate (
p
= 0.023 and
p
= 0.013, respectively). Suture securement provided increased flexibility compared to TA securement (
p
< 0.0001), and there was no statistically significant difference in flexibility between 2-octyl cyanoacrylate and
n
-butyl-2-octyl cyanoacrylate (
p
= 0.774). The resistance strength of cannula polyurethane was not weakened after exposure to either TA formulation after 60 min compared to control.
Conclusions
Tissue adhesive appears to be a promising adjunct method of ECMO cannula insertion site securement. Tissue adhesive securement with
n
-butyl-2-octyl cyanoacrylate may provide comparable securement strength to a single polypropylene drain stitch, and, when used as an adjunct securement method, may minimise the risks associated with suture securement. However, further clinical research is still needed in this area.
Extracorporeal life support (ECLS) has extensive applications in managing patients with acute cardiac and pulmonary failure. Two primary modalities of ECLS, cardiopulmonary bypass (CPB) and ...extracorporeal membrane oxygenation (ECMO), include several similarities in their composition, complications, and patient outcomes. Both CPB and ECMO pose a high risk of thrombus formation and platelet activation due to the large surface area of the devices and bleeding due to system anticoagulation. Therefore, novel methods of anticoagulation are needed to reduce the morbidity and mortality associated with extracorporeal support. Nitric oxide has potent antiplatelet properties and presents a promising alternative or addition to anticoagulation with heparin during extracorporeal support.
We developed two ex-vivo models of CPB and ECMO to investigate nitric oxide (NO) effects on anticoagulation and inflammation in these systems.
Sole addition of NO as an anticoagulant was not successful in preventing thrombus formation in the ex vivo setups, therefore a combination of low level heparin with NO was used. Antiplatelet effects were observed in the ex vivo ECMO model when nitric oxide was delivered at 80 PPM. Platelet count was preserved after 480 minutes when nitric oxide was delivered at 30 PPM.
Combined delivery of nitric oxide and heparin did not improve haemocompatibility in either ex vivo model of CPB and ECMO. Anti-inflammatory effects of NO in ECMO systems have to be evaluated further.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Extracorporeal membrane oxygenation (ECMO) is used in critical care to manage patients with severe respiratory and cardiac failure. ECMO brings blood from a critically ill patient into contact with a ...non-endothelialized circuit which can cause clotting and bleeding simultaneously in this population. Continuous systemic anticoagulation is needed during ECMO. The membrane oxygenator, which is a critical component of the extracorporeal circuit, is prone to significant thrombus formation due to its large surface area and areas of low, turbulent, and stagnant flow. Various surface coatings, including but not limited to heparin, albumin, poly(ethylene glycol), phosphorylcholine, and poly(2-methoxyethyl acrylate), have been developed to reduce thrombus formation during ECMO. The present work provides an up-to-date overview of anti-thrombogenic surface coatings for ECMO, including both commercial coatings and those under development. The focus is placed on the coatings being developed for oxygenators. Overall, zwitterionic polymer coatings, nitric oxide (NO)-releasing coatings, and lubricant-infused coatings have attracted more attention than other coatings and showed some improvement in in vitro and in vivo anti-thrombogenic effects. However, most studies lacked standard hemocompatibility assessment and comparison studies with current clinically used coatings, either heparin coatings or nonheparin coatings. Moreover, this review identifies that further investigation on the thrombo-resistance, stability and durability of coatings under rated flow conditions and the effects of coatings on the function of oxygenators (pressure drop and gas transfer) are needed. Therefore, extensive further development is required before these new coatings can be used in the clinic.
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IJS, KILJ, NUK, PNG, UL, UM
Differential hypoxaemia (DH) is common in patients supported by femoral veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and can cause cerebral hypoxaemia. To date, no models have studied ...the direct impact of flow on cerebral damage. We investigated the impact of V-A ECMO flow on brain injury in an ovine model of DH. After inducing severe cardiorespiratory failure and providing ECMO support, we randomised six sheep into two groups: low flow (LF) in which ECMO was set at 2.5 L min
ensuring that the brain was entirely perfused by the native heart and lungs, and high flow (HF) in which ECMO was set at 4.5 L min
ensuring that the brain was at least partially perfused by ECMO. We used invasive (oxygenation tension-PbTO
, and cerebral microdialysis) and non-invasive (near infrared spectroscopy-NIRS) neuromonitoring, and euthanised animals after five hours for histological analysis. Cerebral oxygenation was significantly improved in the HF group as shown by higher PbTO
levels (+ 215% vs - 58%, p = 0.043) and NIRS (67 ± 5% vs 49 ± 4%, p = 0.003). The HF group showed significantly less severe brain injury than the LF group in terms of neuronal shrinkage, congestion and perivascular oedema (p < 0.0001). Cerebral microdialysis values in the LF group all reached the pathological thresholds, even though no statistical difference was found between the two groups. Differential hypoxaemia can lead to cerebral damage after only a few hours and mandates a thorough neuromonitoring of patients. An increase in ECMO flow was an effective strategy to reduce such damages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
9.
Hurdles to Cardioprotection in the Critically Ill See Hoe, Louise E; Bartnikowski, Nicole; Wells, Matthew A ...
International journal of molecular sciences,
08/2019, Volume:
20, Issue:
15
Journal Article
Peer reviewed
Open access
Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation ...(HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of ...endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage
can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused
models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current
models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field.
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