Biocompatibility: bioengineering aspects.

Bioengineers have contributed to biocompatibility research. Many materials have been designed, synthesized and characterized by use of various analytical instruments. The blood compatibility of materials has been studied by focusing on the blood-material interfacial reactions. Although much information has been accumulated regarding such local reactions, understanding of biocompatibility is still limited. A more global approach to study is needed. A new approach to understanding biocompatibility is proposed and discussed. Three points are stressed: interaction within body's defense system and its effect on blood-material reactions; induction of a systemic reaction by a local reaction, which then affects the blood-material interaction; the time sequence of such interactions between local and systemic reactions. To establish a logical approach to study biocompatibility is most important at this moment for the future progress in biocompatibility research.

Introductory tests to in vivo evaluation: magnetic coupling influence in motor controller.

An implantable centrifugal blood pump has been developed with original features for a ventricle assist device (VAD). This pump is part of a multicenter and international study with objective to offer simple, affordable, and reliable devices to developing countries. Previous computational fluid dynamics investigations were performed followed by prototyping and in vitro tests. Also, previous blood tests for assessment of hemolysis showed mean normalized index of hemolysis (NIH) results of 0.0054 ± 2.46 × 10⁻³ mg/100 L (at 5 L/min and 100 mm Hg). To precede in vivo evaluation, measurements of magnetic coupling interference and enhancements of actuator control were necessary. Methodology was based on the study of two different work situations (1 and 2) studied with two different types of motors (A and B). Situation 1 is when the rotor of pump is closest to the motor and situation 2 its opposite. Torque and mechanical power were collected with a dynamometer (80 g/cm) and then plotted and compared for two situations and both motors. The results showed that motor A has better mechanical behavior and less influence of coupling. Results for situation 1 showed that it is more often under magnetic coupling influence than situation 2. The studies lead to the conclusion that motor A is the best option for in vivo studies as it has less influence of magnetic coupling in both situations.

Preliminary studies for the development of a second generation granulocytapheresis (G-CAP) column. Part II: in vitro and ex vivo studies.

Our previous studies concluded Egyptian cotton was the most appropriate material for making a second generation granulocytapheresis (G-CAP) column as structural dimensions of the cotton fibers are able to attract granulocytes. Unfortunately, it is considered to be blood incompatible as its fibers are of non-synthetic origins. In this study we examined the alteration of the removal rates of blood cells with different surface modifications of Egyptian cotton to enhance its blood compatibility. The surface-modified cotton fibers were compared after three kinds of combination treatments. There were no differences in the removal rates of white blood cells (WBCs) and particularly neutrophils with the use of three kinds of biolized cottons. Next, an ex vivo animal study with a healthy dog was performed with the prototype of the G-CAP column. The dog's blood pressure (BP) decreased to approximately 80% of the initial values of BP at 20 min after the start of the extracorporeal circulation. The decrease in BP gradually reverted to normal. WBCs and particularly neutrophils decreased significantly at 15 min after the start of the extracorporeal circulation and remained low during the extracorporeal circulation. The ability of this column to remove WBCs was maintained during extracorporeal circulation. Especially, neutrophils at the inlet of the column were thoroughly removed for 1 h. Based upon these results, a second generation G-CAP column could be fabricated with Egyptian cotton and applied for clinical use on the condition that the biocompatibility of the Egyptian cotton needs to be improved by the appropriate biolization method.

Molecular surgery for the treatment of malignant tumors: bioincompatible material apheresis for cancer therapy?

Controlled immunological shock, induced by bioincompatible material apheresis for cancer (BIC MAC) therapy, produces an immunoactive status in experimental subjects. However, in order to provide a safe, painless, effective, and reproducible BIC MAC therapy, it is mandatory to provide general anesthesia with endotracheal intubation not only during apheresis procedures of 1-h duration but also for an additional 5 h. Using this procedure, there was no mortality experienced during animal experiments. Also, there were no procedurally related physical or sensory abnormalities demonstrated. This general anesthesia of 6 h covered not only the initial 30 min of the hypotension and hypoxic stages but also the recovery stages to hemodynamically normalize the experimental animals. After 6 h, the accumulated leukocytes in the lung are released back to the systemic circulation. In general, granulocytes decreased almost 100% while lymphocytes decreased only 40-50%. During these 6 h, increases of cytokines (tumor necrosis factor-α, interleukin-6, etc.) sometimes up to 1000 times occurred. After the 6-h procedure, leukocytes returned nearly to preoperative levels but tended to be continuously increased. After the fourth day, leukocyte counts more than doubled. These cellular and humoral activations were normalized after 2 weeks. These studies were conducted on six normal mongrel dogs. Currently, similar studies are planned to be conducted on tumor-bearing experimental animals. This procedurally induced immunoactivation by apheresis may be able to produce effective apoptosis in malignant tumor cells.

The need to change our objective for artificial heart development: from totally implantable permanent ventricular assist devices to wearable therapeutic ventricular assist devices.

As a therapeutic VAD to be combined with drugs, apheresis, and cellular implants, it is advisable to develop a wearable VAD for less than 6 months of application. Such an example was shown by describing the therapeutic BCM Gyro centrifugal VAD.

Evaluation of systemic external microwave hyperthermia for treatment of pleural metastasis in orthotopic lung cancer model.

External microwave (EMW) hyperthermia system (2.45 GHz wave frequency) was evaluated by in vitro studies and in vivo pleural metastasis animal model. Three different non-small-cell lung cancer cells and normal fibroblast cells (control) were treated once a day for 3 days with the prototype EMW system applying mild (39 degrees C), moderate (43 degrees C), and severe (47 degrees C) hyperthermia. On Day-4, tested cells were retrieved and examined by apoptosis assay kit and Western blot analysis. Cancer cells treated with moderate hyperthermia showed significant apoptosis; yet no major damage was observed to normal fibroblast cells. Western blot analysis indicated cleavage on caspase-3, -9 and PARP. Also in the cell cycle analysis, increase of sub G0-G1 population was identified. After optimization of the heating intensity for in vivo environment, we created pleural metastatic animal model in 24 immune deficiency mice (male nu/nu mice) to evaluate inhibitory effect of systemic EMW hyperthermia for disseminated tumor growth. Out of 24 mice, 8 received mild and 8 received moderate hyperthermia, and remaining 8 were the no treatment control. Whole chest area of the experimental animals was irradiated 3 times a week for 2 weeks (total of 6 time irradiations). No significant adverse event was observed including abnormal weight loss, skin burn, ulceration, and death. Metastasized tumors around the pleura and chest cavity were 75% reduced in size and weight compared to non-treated control group. Harvested tumors were stained and TUNEL assay demonstrated significant apoptosis in a moderate hyperthermia group. The EMW hyperthermia system may be possible alternative tool as a systemic hyperthermia therapy in severely advanced lung cancer patients. Further study is necessary to determine device safeness, efficacy, and synergistic effect to other possible combination therapies.

Preliminary studies for the development of a second generation granulocytapheresis (G-CAP) column.

The preliminary studies for developing a second generation granulocytapheresis (G-CAP) column were made. In the past, the G-CAP column has been used for the treatment of ulcerative colitis and rheumatoid arthritis. However, recent clinical studies have revealed that the therapeutic effects of the G-CAP column are not significant compared with those of the sham column. These results were considered to be due to insufficient reduction of granulocytes. Thus, development of a better granulocyte removal column was attempted. Realizing that white cells adhered on small-diameter synthetic fibers of 1-2 microm, small diameter cotton fibers were subjected to the studies of their granulocyte-removing capabilities. Three types of cotton, Pakistani, Australian and Egyptian cottons, were evaluated using normal human blood in vitro. Miniature columns were made of each fiber, and CBC and WBC differentiation was compared between pre- and post-filtered blood. The Egyptian cotton removed leukocytes, especially granulocytes, the most efficiently of the three types of cotton. The Egyptian cotton's granulocyte adhesion properties were not altered after different chemical treatments. A 4-ml column of packaged Egyptian cotton with a density of more than 0.125 g/ml could remove granulocytes effectively up to 80 ml of blood passages. Based upon these studies, second generation G-CAP could be carried out with Egyptian cotton fibers as a scaled-up clinical module.

A new transcutaneous energy transmission system with hybrid energy coils for driving an implantable biventricular assist device.

We have developed a new transcutaneous energy transmission (TET) system for a totally implantable biventricular assist device (BVAD) system in the New Energy and Industrial Development Organization (NEDO) artificial heart project. The TET system mainly consists of an energy transmitter, a hybrid energy coil unit, an energy receiver, an internal battery system, and an optical telemetry system. The hybrid energy coil unit consists of an air-core energy transmission coil and an energy-receiving coil having a ferrite core. Internal units of the TET system are encapsulated in a titanium alloy casing, which has a size of 111 mm in width, 73 mm in length, and 25 mm in height. In in vitro experiments, the TET system can transmit a maximum electric energy of 60 Watts, and it has a maximum transmission efficiency of 87.3%. A maximum surface temperature of 46.1 degrees C was measured at the ferrite core of the energy-receiving coil during an energy transmission of 20 Watts in air. The long-term performance test shows that the TET system has been able to operate stably for over 4 years with a decrease of energy-transmission efficiency from 85% to 80%. In conclusion, the TET system with the hybrid energy coil can overcome the drawback of previously reported TET systems, and it promises to be the highest performance TET system in the world.

Experimental evaluation of a new antithrombogenic stent using ion beam surface modification.

A new antithrombogenic stent using ion beam surface modification nanotechnology was evaluated. The ion stent is being developed to inhibit acute and chronic stent-related thrombosis. Thirty self-expanding mesh stents were fabricated from Ti-Ni metal wires with a dimension of 4 mm (diameter) x 25 mm (length) x 0.15 mm (thickness). Twenty stents were coated with type I collagen and irradiated with a He(+) ion beam at an energy of 150 keV with fluences of 1 x 10(14) ions/cm(2) (ion stent group). Ten stents had no treatment (non-ion stent group). The self-expanding stents were implanted into the right and left peripheral femoral arteries of 15 beagle dogs (vessel diameter approximately 3 mm) via a 6Fr catheter under fluoroscopic guidance. Heparin (100 units/kg) was administered intravenously before implantation. Following stent implantation, no antiplatelet or anticoagulant drugs were administered. The 1-month patency rate for the non-ion stent group was 10% (1/10), and for the ion stent group it was 80% (16/20) with no anticoagulant or antiplatelet drugs given after stent implantation (P = 0.0004 by Fisher's exact test). Ten stents remain patent after 2 years in vivo with no anticoagulant or antiplatelet drugs. These results indicate that He(+) ion-implanted collagen-coated Ti-Ni self-expanding stents have excellent antithrombogenicity and biocompatibility. This ion stent is promising for coronary and cerebral stent applications.

Direct measurement of proximal isovelocity surface area by real-time three-dimensional color Doppler for quantitation of aortic regurgitant volume: an in vitro validation.

OBJECTIVE: The proximal isovelocity surface area (PISA) method is useful in the quantitation of aortic regurgitation (AR). We hypothesized that actual measurement of PISA provided with real-time 3-dimensional (3D) color Doppler yields more accurate regurgitant volumes than those estimated by 2-dimensional (2D) color Doppler PISA. METHODS: We developed a pulsatile flow model for AR with an imaging chamber in which interchangeable regurgitant orifices with defined shapes and areas were incorporated. An ultrasonic flow meter was used to calculate the reference regurgitant volumes. A total of 29 different flow conditions for 5 orifices with different shapes were tested at a rate of 72 beats/min. 2D PISA was calculated as 2pi r(2), and 3D PISA was measured from 8 equidistant radial planes of the 3D PISA. Regurgitant volume was derived as PISA x aliasing velocity x time velocity integral of AR/peak AR velocity. RESULTS: Regurgitant volumes by flow meter ranged between 12.6 and 30.6 mL/beat (mean 21.4 +/- 5.5 mL/beat). Regurgitant volumes estimated by 2D PISA correlated well with volumes measured by flow meter (r = 0.69); however, a significant underestimation was observed (y = 0.5x + 0.6). Correlation with flow meter volumes was stronger for 3D PISA-derived regurgitant volumes (r = 0.83); significantly less underestimation of regurgitant volumes was seen, with a regression line close to identity (y = 0.9x + 3.9). CONCLUSION: Direct measurement of PISA is feasible, without geometric assumptions, using real-time 3D color Doppler. Calculation of aortic regurgitant volumes with 3D color Doppler using this methodology is more accurate than conventional 2D method with hemispheric PISA assumption.