Has Extracorporeal Gas Exchange Performance Reached Its Peak?

Extracorporeal gas exchange therapies evolved considerably within the first three-four decades of their appearance, and have since reached a mature stage, where minor alterations and discrete fine-tuning might offer some incremental improvement. A different approach is introduced here, making use of modern, purely diffusive membrane materials, and taking advantage of the elevated concentration gradient ensuing from gas pressure buildup in the gas chamber of the oxygenator. An assortment of silicone membrane gas exchangers were tested in vitro as per a modified protocol in pursuance of assessing their gas exchange efficiency under both regular and high-pressure aeration conditions. The findings point to a stark performance gain when pressurization of the gas compartment is involved; a 40% rise above atmospheric pressure elevates oxygen transfer rate (OTR) by nearly 30%. Carbon dioxide transfer rate (CTR) does not benefit as much from this principle, yet it retains a competitive edge when higher gas flow/blood flow ratios are employed. Moreover, implementation of purely diffusive membranes warrants a bubble-free circulation. Further optimization of the introduced method ought to pave the way for in vivo animal trials, which in turn may potentially unveil new realms of gas exchange performance for therapies associated with extracorporeal circulation.

A new approach towards extracorporeal gas exchange and first in vitro results.

OBJECTIVES: Extracorporeal life support (ECLS) pertains to therapeutic and prophylactic techniques utilized in a wide range of medical applications, with severe pulmonary diseases being the most prominent cases. Over the past decades, little progress has been made in advancing the basic principles and properties of gas exchangers. Here, in an unconventional approach, dialysis hollow fibers are handled with silicone to create a purely diffusive coating that prevents plasma leakage and promotes gas exchange. METHODS: Commercial dialyzers of varying surface area and fiber diameter have been coated with silicone, to determine the impact of each parameter on performance. The impermeability of the silicone layer has been validated by pressurization and imaging methods. SEM images have revealed a homogeneous silicone film coating the lumen of the capillaries, while fluid dynamic investigations have confirmed its purely diffusive nature. RESULTS: The hemodynamic behavior and the gas exchange efficiency of the silicone-coated prototypes have been investigated in vitro with porcine blood under various operating conditions. Their performance has been found to be similar to that of a commercial PMP oxygenator. CONCLUSIONS: This novel class of gas exchangers is characterized by high versatility and expeditious manufacturing. Intraoperability between conventional ECLS systems and dialysis machines broadens the range of application infinitely. Ultimately, long-term clinical applicability ought to be determined over in vivo animal investigations.

In vitro evaluation of the performance of an oxygenator depending on the non-standard gas content of the inlet blood with special regard on CO2 elimination.

INTRODUCTION: The performance of an oxygenator, as found in literature, is evaluated according to protocols that define standard values of the gas content in the inlet blood. However, when dealing with simulations of lung insufficiency, a more extensive evaluation is needed. This work aims to investigate and assess the gas exchange performance of an oxygenator for different input values of gas content in blood. METHODS: Three commercially available oxygenators with different membrane surfaces were investigated in a mock loop for three blood flow rates (0.5l/min, 1l/min, and 5l/min) and two gas-to-blood ratios (1:1, and 15:1). The initial CO2 and O2 partial pressures (pCO2 and pO2) in blood were set to ≥ 100 mmHg and ≤10 mmHg, respectively. For each ratio, the efficiency, defined as the ratio between the difference of pressure inlet and outlet and the inlet pCO2 (pCO2(i)), was calculated. RESULTS: The CO2 elimination in an oxygenator was higher for higher pCO2(i). While for a pCO2(i) of 100 mmHg, an oxygenator eliminated 80 mmHg, the same oxygenator at the same conditions eliminated 5 mmHg CO2 when pCO2(i) was 10 mmHg. The efficiency of the oxygenator decreased from 76,9% to 49,5%. For simulation reasons, the relation between the pCO2(i) and outlet (pCO2(o)) for each oxygenator at different blood and gas flows, was described as an exponential formula. CONCLUSION: The performance of an oxygenator in terms of CO2 elimination depends not only on the blood and gas flow, but also on the initial pCO2 value. This dependence is crucial for simulation studies in the future.

Oxygenation performance assessment of an artificial lung in different central anatomic configurations.

OBJECTIVES: Aim of this work was to characterize possible central anatomical configurations in which a future artificial lung (AL) could be connected, in terms of oxygenation performance. METHODS: Pulmonary and systemic circulations were simulated using a numerical and an in vitro approach. The in vitro simulation was carried out in a mock loop in three phases: (1) normal lung, (2) pulmonary shunt (50% and 100%), and (3) oxygenator support in three anatomical configurations: right atrium-pulmonary artery (RA-PA), pulmonary artery-left atrium (PA-LA), and aorta-left atrium (Ao-LA). The numerical simulation was performed for the oxygenator support phase. The oxygen saturation (SO2) of the arterial blood was plotted over time for two percentages of pulmonary shunt and three blood flow rates through the oxygenator. RESULTS: During the pulmonary shunt phase, SO2 reached a steady state value (of 68% for a 50% shunt and of nearly 0% for a 100% shunt) 20 min after the shunt was set. During the oxygenator support phase, physiological values of SO2 were reached for RA-PA and PA-LA, in case of a 50% pulmonary shunt. For the same conditions, Ao-LA could reach a maximum SO2 of nearly 60%. Numerical results were congruous to the in vitro simulation ones. CONCLUSIONS: Both in vitro and numerical simulations were able to properly characterize oxygenation properties of a future AL depending on its placement. Different anatomical configurations perform differently in terms of oxygenation. Right to right and right to left connections perform better than left to left ones.

Phenomenological characterization of blood's intermediate shear rate: a new concept for hemorheology.

The phenomena of aggregation, breakdown, and disaggregation of the rouleaux of red blood cells (RBCs) in addition to deformability affect the human blood viscosity at different shear rates. In this study, the intermediate shear rate is introduced and defined when the effect of aggregation on the change of blood viscosity is diminished; and afterwards, the alteration in the blood viscosity is dominantly affected by the deformation of RBCs. With this respect, modeling the effective parameters on the blood shear-thinning behavior including hematocrit and plasma viscosity was performed for the two different shear regions discriminated by the proposed intermediate shear rates. The presented rheological model reflects a phenomenological approach to assess the human blood viscosity with an average error of ± 5% compared to experimental data for hematocrits between 0.299 and 0.702, subjected to various shear rates from 0.2 to 680 1/s. The temperature changes as well as biochemical effects on whole blood viscosity are characterized by the introduced plasma viscosity-dependent model. The presented comprehensive model could be used for better understanding of blood flow hemodynamics and analyzing the shear dependence of aggregation and deformability behaviors of RBCs.

Quantification of dissolved H2 and continuous monitoring of hydrogen-rich water for haemodialysis applications: An experimental study.

The prevalence of oxidative and inflammatory stress in end-stage renal disease (ESRD) patients has often been associated with chronic haemodialysis therapies. Over the past decades, several reports have shown the potential of hydrogen molecule as an antioxidant in the treatment of various medical conditions in animal models, as well as in pilot studies with human patients. Recently, a hydrogen-enriched dialysate solution has been introduced, holding promise in reducing the oxidative and/or inflammatory complications arising during haemodialysis. To this end, a standardised measuring method to determine the levels of hydrogen in dialysate and subsequently in blood is required. This study explores the possibility of quantifying hydrogen concentration using a novel contactless sensor that detects dissolved hydrogen in liquids. An experimental circuit is assembled to validate the sensitivity and accuracy of the hydrogen monitoring system (Pureron Japan Co., Ltd) through in vitro investigations with physiological solutions. Measurements of dissolved molecular hydrogen concentration are corroborated by an established oxygen sensor providing continuous partial pressure readings. The relationship between the applied H2 content in the gaseous mixture and the H2 concentration value at equilibrium is linear. At the same time, the hydrogen monitoring system has a rather long response time, and its readings seem to slightly diverge from sensor to sensor as well as at different temperatures. For this reason, a sensor recalibration might be necessary, which could become part of the product's ongoing development. Nevertheless, the aforementioned minor deficiencies can be mostly considered negligible in applications such as haemodialysis.

Development of Hormonal Intravaginal Rings: Technology and Challenges.

Intravaginal rings (IVRs) are minimally invasive polymeric devices specifically designed to be used for the sustained and prolonged release of various type of drugs such as hormones. One of the benefits of using topical drug delivery systems (e.g., IVRs) is the fact that systemic drug delivery may cause drug resistance due to elevated drug levels. Topical drug delivery also provides higher concentrations of the drug to the target site and has fewer side effects. In addition, when a drug is administered vaginally, the hepatic first-pass effect is avoided, resulting in higher absorption. Contraception and treatments for specific diseases such as endometriosis and hormone deficiencies can be improved by the administration of hormones via an IVR. This article aims to classify and compare various designs of commercially available and non-commercial hormonal IVRs and to analyze their performance. Current challenges affecting the development of IVRs are investigated, and proposed solutions are discussed. A comprehensive search of publications in MEDLINE/PubMed and of commercial product data of IVRs was performed, and the materials, designs, performance, and applications (e.g., contraception, endometriosis, estrogen deficiency and urogenital atrophy) of hormonal IVRs were thoroughly evaluated. Most hormonal IVRs administer female sex hormones, i.e., estrogen and progestogens. In terms of material, IVRs are divided into 3 main groups: silicone, polyurethane, and polyethylene-co-vinyl acetate IVRs. As regards their design, there are 4 major designs for IVRs which strongly affect their performance and the timing and rate of hormone release. Important challenges include reducing the burst release and maintaining the bioavailability of hormones at their site of action over a prolonged period of administration as well as lowering production costs. Hormonal IVRs are a promising method which could be used to facilitate combination therapies by administering multiple drugs in a single IVR while eliminating the side effects of conventional drug administration methods. IVRs could considerably improve women's quality of life all over the world within a short period of time.

ECMO Assistance during Mechanical Ventilation: Effects Induced on Energetic and Haemodynamic Variables.

BACKGROUND AND OBJECTIVE: Simulation in cardiovascular medicine may help clinicians understand the important events occurring during mechanical ventilation and circulatory support. During the COVID-19 pandemic, a significant number of patients have required hospital admission to tertiary referral centres for concomitant mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Nevertheless, the management of ventilated patients on circulatory support can be quite challenging. Therefore, we sought to review the management of these patients based on the analysis of haemodynamic and energetic parameters using numerical simulations generated by a software package named CARDIOSIM©. METHODS: New modules of the systemic circulation and ECMO were implemented in CARDIOSIM© platform. This is a modular software simulator of the cardiovascular system used in research, clinical and e-learning environment. The new structure of the developed modules is based on the concept of lumped (0-D) numerical modelling. Different ECMO configurations have been connected to the cardiovascular network to reproduce Veno-Arterial (VA) and Veno-Venous (VV) ECMO assistance. The advantages and limitations of different ECMO cannulation strategies have been considered. We have used literature data to validate the effects of a combined ventilation and ECMO support strategy. RESULTS: The results have shown that our simulations reproduced the typical effects induced during mechanical ventilation and ECMO assistance. We focused our attention on ECMO with triple cannulation such as Veno-Ventricular-Arterial (VV-A) and Veno-Atrial-Arterial (VA-A) configurations to improve the hemodynamic and energetic conditions of a virtual patient. Simulations of VV-A and VA-A assistance with and without mechanical ventilation have generated specific effects on cardiac output, coupling of arterial and ventricular elastance for both ventricles, mean pulmonary pressure, external work and pressure volume area. CONCLUSION: The new modules of the systemic circulation and ECMO support allowed the study of the effects induced by concomitant mechanical ventilation and circulatory support. Based on our clinical experience during the COVID-19 pandemic, numerical simulations may help clinicians with data analysis and treatment optimisation of patients requiring both mechanical ventilation and circulatory support.

Arteriovenous access in hemodialysis: A multidisciplinary perspective for future solutions.

In hemodialysis, vascular access is a key issue. The preferred access is an arteriovenous fistula on the non-dominant lower arm. If the natural vessels are insufficient for such access, the insertion of a synthetic vascular graft between artery and vein is an option to construct an arteriovenous shunt for punctures. In emergency situations and especially in elderly with narrow and atherosclerotic vessels, a cuffed double-lumen catheter is placed in a larger vein for chronic use. The latter option constitutes a greater risk for infections while arteriovenous fistula and arteriovenous shunt can fail due to stenosis, thrombosis, or infections. This review will recapitulate the vast and interdisciplinary scenario that characterizes hemodialysis vascular access creation and function, since adequate access management must be based on knowledge of the state of the art and on future perspectives. We also discuss recent developments to improve arteriovenous fistula creation and patency, the blood compatibility of arteriovenous shunt, needs to avoid infections, and potential development of tissue engineering applications in hemodialysis vascular access. The ultimate goal is to spread more knowledge in a critical area of medicine that is importantly affecting medical costs of renal replacement therapies and patients' quality of life.

The course of hematocrit value along the length of a dialyzer's fiber: Hemoconcentration modeling and validation methods.

OBJECTIVES: Contemporary therapies for chronic kidney disease patients encompass a wide range of hemodialysis treatments, most of which rely greatly on dialyzers and hemofilters. The filtration process taking place in these devices with respect to the hemodynamic characteristics of the flow, has not yet been fully investigated. This study aims at improving the understanding of hemodynamics in a dialyzer by employing experimental methods and mathematical models. METHODS: A semiempirical model has been formulated based on the principles of hemodynamics, considering the dominant phenomena of filtration-backfiltration and the corresponding driving forces. An in vitro hemodialysis circuit was accordingly assembled for experimental data acquisition, and subsequently for model validation. The circuit consisted of two dialyzers arranged in sequential order, in pursuance of increasing the number of sampling points. Fresh, heparinized porcine blood was used throughout the course of this study. Pressure and flow data obtained from in vitro investigations with the hemodialysis circuit were used as an input for the semiempirical model. FINDINGS: The model predicted a substantial divergence in the course of hematocrit value along the length of the hollow fibers, which is corroborated by the experimental data. Particularly in certain operational conditions, hematocrit rose from 25% at the inlet to 65% halfway along the dialyzers' length, to end at 30% at the outlet. CONCLUSION: Validation of the model's predictions with experimental data demonstrated a very good agreement, confirming the model's accuracy. Potential implementation of the model in clinical practice in the future might contribute greatly to an improved hemodialysis experience.

An experimental study of shear-dependent human platelet adhesion and underlying protein-binding mechanisms in a cylindrical Couette system.

Undesirable thrombotic reactions count among the most frequent and serious complications for patients who rely on the use of medical devices. To improve the design of medical devices, it is essential to develop a more precise understanding of platelet reactions. Clinical studies and experiments have shown a strong dependence of platelet deposition behavior on the flow. However, today the influence of hemodynamic parameters such as the shear rate on thrombotic reactions is not well understood. For the study of the shear-dependent mechanisms leading to the activation, adhesion and aggregation of platelets, a Couette flow system was used to investigate thrombocyte behavior with regard to well-defined flow conditions at shear-rate values between γ˙=400 $\dot \gamma = {\rm{400}}$ and 1400 1/s. Results were calculated for physiological temperature. It could be shown that the platelet adhesion density increased with increasing shear rates up to γ˙=800 1/s $\dot \gamma = {\rm{800 1/s}}$ and the adhesion pattern was homogeneous. At γ˙=800 1/s, $\dot \gamma = {\rm{800 1/s}},$ a sudden drop in platelet adhesion density occurred and platelets adhered in filaments. Fluorescence microscopy results of von Willebrand factor (vWF) confirm that a shear rate of γ˙=800 1/s $\dot \gamma = {\rm{800 1/s}}$ represents the threshold where a switch of the platelet-binding mechanism from fibrinogen-mediated to vWF-mediated platelet adhesion takes place.

A new approach for semiempirical modeling of mechanical blood trauma.

PURPOSE: Two semi-empirical models were recently published, both making use of existing literature data, but each taking into account different physical phenomena that trigger hemolysis. In the first model, hemoglobin (Hb) release is described as a permeation procedure across the membrane, assuming a shear stress-dependent process (sublethal model). The second model only accounts for hemoglobin release that is caused by cell membrane breakdown, which occurs when red blood cells (RBC) undergo mechanically induced shearing for a period longer than the threshold time (nonuniform threshold model). In this paper, we introduce a model that considers the hemolysis generated by both these possible phenomena. METHODS: Since hemolysis can possibly be caused by permeation of hemoglobin through the RBC functional membrane as well as by release of hemoglobin from RBC membrane breakdown, our proposed model combines both these models. An experimental setup consisting of a Couette device was utilized for validation of our proposed model. RESULTS: A comparison is presented between the damage index (DI) predicted by the proposed model vs. the sublethal model vs. the nonthreshold model and experimental datasets. This comparison covers a wide range of shear stress for both human and porcine blood. An appropriate agreement between the measured DI and the DI predicted by the present model was obtained. CONCLUSIONS: The semiempirical hemolysis model introduced in this paper aims for significantly enhanced conformity with experimental data. Two phenomenological outcomes become possible with the proposed approach: an estimation of the average time after which cell membrane breakdown occurs under the applied conditions, and a prediction of the ratio between the phenomena involved in hemolysis.

Surface modification of silicone tubes by functional carboxyl and amine, but not peroxide groups followed by collagen immobilization improves endothelial cell stability and functionality.

Surface modification by functional groups promotes endothelialization in biohybrid artificial lungs, but whether it affects endothelial cell stability under fluid shear stress, and the release of anti-thrombotic factors, e.g. nitric oxide (NO), is unknown. We aimed to test whether surface-modified silicone tubes containing different functional groups, but similar wettability, improve collagen immobilization, endothelialization, cell stability and cell-mediated NO-release. Peroxide, carboxyl, and amine-groups increased collagen immobilization (41-76%). Only amine-groups increased ultimate tensile strength (2-fold). Peroxide and amine enhanced (1.5-2.5 fold), but carboxyl-groups decreased (2.9-fold) endothelial cell number after 6 d. After collagen immobilization, cell numbers were enhanced by all group-modifications (2.8-3.8 fold). Cells were stable under 1 h-fluid shear stress on amine, but not carboxyl or peroxide-group-modified silicone (>50% cell detachment), while cells were also stable on carboxyl-group-modified silicone with immobilized collagen. NO-release was increased by peroxide and amine (1.1-1.7 fold), but decreased by carboxyl-group-modification (9.8-fold), while it increased by all group-modifications after collagen immobilization (1.8-2.8 fold). Only the amine-group-modification changed silicone stiffness and transparency. In conclusion, silicone-surface modification of blood-contacting parts of artificial lungs with carboxyl and amine, but not peroxide-groups followed by collagen immobilization allows the formation of a stable functional endothelial cell layer. Amine-group-modification seems undesirable since it affected silicone's physical properties.

Simulation of blood oxygenation in capillary membrane oxygenators using modified sulfite solution.

Blood oxygenation is the main performance characteristic of capillary membrane oxygenators (CMOs). Handling of natural blood in in vitro investigations of CMOs is quite complex and time-consuming. Since the conventional blood analog fluids (e.g. water/glycerol) lack a substance with an affinity to capture oxygen comparable to hemoglobin's affinity, in this study a novel approach using modified sulfite solution is proposed to address this challenge. The solution comprises sodium sulfite as a component, simulating the role of hemoglobin in blood oxygenation. This approach is validated by OTR (oxygen transfer rate) measured using native porcine blood, in two types of commercially available CMOs. Consequently, the number of complicated natural blood investigations in the evolution procedure of newly developed oxygenators would considerably decrease. Moreover, the reassessing of failed devices, in clinics, would be performed more precisely using a modified sulfite solution than simple water/glycerol testing.

Engineering parameters in bioreactor's design: a critical aspect in tissue engineering.

Bioreactors are important inevitable part of any tissue engineering (TE) strategy as they aid the construction of three-dimensional functional tissues. Since the ultimate aim of a bioreactor is to create a biological product, the engineering parameters, for example, internal and external mass transfer, fluid velocity, shear stress, electrical current distribution, and so forth, are worth to be thoroughly investigated. The effects of such engineering parameters on biological cultures have been addressed in only a few preceding studies. Furthermore, it would be highly inefficient to determine the optimal engineering parameters by trial and error method. A solution is provided by emerging modeling and computational tools and by analyzing oxygen, carbon dioxide, and nutrient and metabolism waste material transports, which can simulate and predict the experimental results. Discovering the optimal engineering parameters is crucial not only to reduce the cost and time of experiments, but also to enhance efficacy and functionality of the tissue construct. This review intends to provide an inclusive package of the engineering parameters together with their calculation procedure in addition to the modeling techniques in TE bioreactors.

Science versus design; comparable, contrastive or conducive?

Science and design are two completely separated areas of expertise with their own specialists. Science analyses the existing world to create new knowledge, design uses existing knowledge to create a new world. This tunnel-vision mentality and narrow-minded approach is dangerous for problem solving, where a broad view on potential solutions is required to realise a high-quality answer on the defined problem. We state that design benefits from scientific methods, resulting in a more effective design process and in better products, while science benefits from a design approach, resulting in more efficient and effective results. Our philosophy is illustrated using examples from the field of biomedical engineering. Both methods can benefit tremendously from each other. By applying scientific methods, superior choices will be made in the design process. With design, more accurate, effective and efficient science will be performed.

Novel concept for pure diffusive capillary membrane oxygenators: silicone hollow sphere (SiHSp) fibers.

The preeminent limitation of silicone membrane oxygenators is the poor gas permeability compared with microporous hollow fiber oxygenators (MHFO). However, the imponderability of plasma leakage, foam formation, and brittleness are all hazards that result in blood trauma formation, hereby limiting the application of MHFO during long-term oxygenation therapies. Here, we introduce a novel type of pure diffusive capillary-form silicone membrane called silicone hollow sphere. Silicone hollow sphere walls embed hollow microspheres into the core. The lodging of such microspheres promotes a higher gas exchange performance (as a result of the reduction of dense material) without altering the total thickness of capillary walls; thereby the demanded mechanical strength for handling is nevertheless conserved. Out of the same silicone material, seven SiHSp fibers with six different design specifications and a control were constructed to define experimentally the appropriate configuration for subsequent production. Each fiber was used in a miniaturized module oxygenator of a constant effective membrane surface area (Amem = 0.02 m) and length (L =183 mm) for a fair evaluation. Modules were investigated in vitro with porcine blood. O2 and CO2 transfer rates weighed 12.6 mlO2/min and 10.4 mlCO2/min, respectively, for one type of SiHSp, comparable with microporous polypropylene (OXYPHAN) exhibiting 14.1 mlO2/min and 13.2 mlCO2/min, respectively, at a maximum blood flow rate (Qmax = 200 ml/min). Silicone hollow sphere fibers show a promising competency to MHFs. They also show an evident dominancy over the conventional silicone fibers, evaluated by the control module, which emphasizes the advantage of this design.

A theoretical model for evaluation of the design of a hollow-fiber membrane oxygenator.

Geometric data are fundamental to the design of a contactor. The efficiency of a membrane contactor is mainly defined by its mass-transfer coefficient. However, design modifications also have significant effects on the performance of membrane contactors. In a hollow-fiber membrane oxygenator (HFMO), properties such as priming volume and effective membrane surface area (referred to as design specifications) can be determined. In this study, an extensive theoretical model for calculation of geometric data and configuration properties, and, consequently, optimization of the design of an HFMO, is presented. Calculations were performed for Oxyphan(®) hollow-fiber micro-porous membranes, which are frequently used in current HFMOs because of their high gas exchange performance. The results reveal how to regulate both the transverse and longitudinal pitches of fiber bundles to obtain a lower rand width and a greater number of windings. Such modifications assist optimization of module design and, consequently, substantially increase the efficiency of an HFMO. On the basis of these considerations, three values, called efficiency factors, are proposed for evaluation of the design specifications of an HFMO with regard with its performance characteristics (i.e. oxygen-transfer rate and blood pressure drop). Moreover, the performance characteristics of six different commercial HFMOs were measured experimentally, in vitro, under the same standard conditions. Comparison of calculated efficiency factors reveals Quadrox(®) is the oxygenator with the most efficient design with regard with its performance among the oxygenators tested.

Hemocompatibility of high strength oxide ceramic materials: an in vitro study.

High strength oxide ceramic materials like alumina and zirconia are frequently used for artificial joints because of their biocompatibility and high wear resistance. Their suitability as materials for implants and biomedical devices with direct blood contact, such as cardiovascular implants or components for blood pumps and dialyzers, has not been confirmed to date. The objective of this study was to investigate whether oxide ceramics show sufficient hemocompatibility. Dense specimens were made out of alumina, zirconia, titanium oxide, and aluminum titanate. Polyvinylchloride and silicone were additionally tested as reference materials. Interactions of human blood with the surfaces were studied by investigating partial thromboplastin time (PTT), thrombin antithrombin III complex (TAT), free plasma hemoglobin concentration, complete blood count, complement factor 5a, and protein adsorption. The results from the PTT and TAT tests clearly indicated higher blood activation by the ceramic materials when compared to the two polymer materials. However, alumina and zirconia showed lower C5a concentrations and less protein adsorption than the reference materials. Our results revealed that oxide ceramic materials alone cannot be used for implants in direct blood contact without modification of the ceramic surface, for example, by made-to-measure inert nanocoatings.

Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces.

In vitro studies with miniaturized rotating circuits and heparinized human blood, as well as long-term extracorporeal membrane oxygenation with either heparin coated (HBS) or uncoated surfaces connected to adult sheep, were performed comparing the impact on complement activation in blood and on surfaces. Analysis of surface bound complement proteins revealed significantly reduced binding of activated C3 and C5b-9 to HBS in vitro, compared with uncoated surfaces, which was probably due to more HBS bound complement inhibitors (C1-Inhibitor, factor H) being present. This was reflected by significantly reduced activation of the alternative pathway (C3bBbP) and terminal complex (SC5b-9) by HBS but slightly increased levels of classic pathway complex (C1rs-C1-inhibitor). These results were confirmed during in vivo study by analysis of hemolytic complement function, activation specific C3 derived split products, and surface bound complement proteins. Increased binding of complement regulators to HBS appears to effectively reduce complement activation by biomaterials, leading to improved long-term biocompatibility.