Virtual Collection

Terumo Corporation

Contact information

Address: 2-44-1 Hatagaya, Shibuya-ku, Tokyo, 151-0072 Japan

About

The Terumo Blood Oxygenator (Capiox) Collection is stored at Terumo Corporation, Tokyo, Japan.

The Terumo Blood Oxygenator Collection includes the following historical oxygenators:

• The world’s first microporous hollow fiber membrane oxygenator (Capiox-Ⅱ) commercialized in 1982.
• An external perfusion type hollow fiber membrane oxygenator (Capiox-E), 1988.

The disadvantage of high-pressure loss in an internal perfusion type oxygenator was improved. Gravity drainage was usable as previous “air-bubble” style oxygenators.

• Blood-compatible hollow fiber membrane oxygenators, Capiox-SX (HP), 1996 and Capiox-RX, 2000

To improve biocompatibility, a unique coating (Xcoating), that utilizes both hydrophobic and hydrophilic characteristics, was developed.

• Oxygenator with integrated arterial filter and biocompatible surface coating, Capiox-FX, 2008

The integrated arterial filter is effective for prevention of gaseous emboli. Gaseous emboli automatically enter the inner lumen of the microporous hollow fiber (self-vent mechanism).

The world’s first microporous hollow fiber membrane oxygenator (Capiox- Ⅱ), 1982.

Figure 1 Capiox-Ⅱ oxygenator

Terumo commercialized oxygenators using microporous hollow fiber membranes made of polypropylene (PP) in 1982. Since then, gas exchange membranes used in membrane oxygenators have mainly been porous polypropylene (PP) membranes since then.

 

Background of the development of a microporous hollow fiber membrane oxygenator

The development of artificial lungs that perform gas exchange functions began in 1939 when Gibon succeeded in extracorporeal circulation in animals by combining a film-type oxygenator that formed a thin layer of blood and brought it into contact with oxygen and a roller pump. Clinical success was achieved in 1953.

Since then, the film-type oxygenator has been improved to a rotating disk-type oxygenator, but there were issues including the difficulty in making it disposable, the large priming volume, and the need for improvements in gas exchange performance.

In the 1960s, advances in anti-foaming technology using silicone led to the commercialization of bubble oxygenators, which added oxygen by blowing oxygen bubbles directly into blood.

On the other hand, the development of a membrane oxygenator that mimics the structure of a living lung began in 1944, when Kolff et al. demonstrated that it was possible to oxygenate blood using an artificial kidney with cellophane tubes.

In 1969, the artificial lung (Lande-Edwards), which consisted of stacked flat membranes of polydimethylsiloxane (silicone), became the first membrane lung to be put into practical use. However, there were problems with improving performance, miniaturization, and manufacturing costs. Although it was a more physiological oxygenator than the bubble type, it did not become widely used.

Next, with the advent of porous hydrophobic membranes, the gas permeability problem of membranes was solved and miniaturization was expected, but laminated flat membranes still had various problems such as blood channeling, condensation on the gas side, and membrane strength.

In these circumstances, Terumo in collaboration with Mitsubishi Rayon Co., Ltd. developed the world’s first oxygenator, Capiox-II (Figure l), that uses a hollow fiber microporous membrane made of polypropylene (PP). It was commercialized in 1982.

 

Development site for Capiox (around 1980)

A part of a warehouse was the development site of the Capiox oxygenator. In the beginning, there were only four or five of members in the development team, and they came up with the development process and methodology by themselves. They did not have a large budget available, so they had to make their own substitutes for the expensive measuring instruments required for development.

 

Structure of the membrane and method for manufacturing the membrane

The structure of the oxygenator is an internal perfusion type in which blood flows inside the hollow fiber and gas flows outside. The specifications of the hollow fiber membrane were determined by considering various factors such as pressure resistance, blood priming volume, gas exchange performance, and pressure loss. The mean pore radius was set to 0.07 μm, the porosity was ~50%, the inner diameter was 200 μm, and the outer diameter was 250 μm.

This polypropylene membrane had sufficient mechanical strength and gas exchange performance, but as clinical use cases accumulated, durability became a problem due to various issues such as leakage of plasma leaked from the pores (plasma leak) during long-term use. The membrane was produced by using a stretching method that created fine pores by making cracks between the crystals by highly orienting PP and stretching it, so the pore diameter varied widely and straight pores were formed (Figure 2). This made it easier for blood to leak, and when the fiber would easily tear when it was pulled.

Figure 2 Methods for manufacturing the membrane: stretching method (left) and phase separation method (right).

At Terumo, a method to suppress plasma leakage was devised by using a phase separation method to create a three-dimensional mesh-like pore structure with a high curvature ratio (Figure 2). This manufacturing method utilizes the fact that liquid paraffin (LP) acts as a solvent for PP in its molten state and separates into layers from PP when solidified by cooling. A homogeneous mixture of PP and LP is melt-spun and solidified by cooling. This manufacturing method results in the formation of uniform pores by subsequently extracting and removing the LP. Oxygenators that were manufactured by using the phase separation method showed clear plasma leak resistance compared to that of oxygenators manufactured by using the stretching method. This effort led to the successful development of a hollow fiber that was stronger and had lower risk of blood leakage due to net-shaped pores.

Gravity drainage external perfusion type hollow fiber membrane oxygenator (Capiox-E), 1988

Figure 3 Capiox-E oxygenator

Capiox II had the disadvantage of high-pressure loss. The same circulation systems as previous “air-bubble” style oxygenators are not usable. The next goal was to make a product that could utilize the external perfusion method for blood flow, which would make it usable with gravity drainage. However, adopting this style posed a technology challenge: Blood could not be circulated under pressure to the oxygenator, so blood would not come into contact evenly with the fibers, leading to reduced gas exchange performance.

One technology that helped to solve this problem was to give the fibers slight “waves” through a method called “crimping.” When those fibers were placed inside the oxygenator housing, they would naturally spread out and maintain an optimal distance without clumping together, enabling them to come into maximal contact with blood. This oxygenator that used external perfusion (Figure 4), in which blood randomly flowed across fibers to oxygenate blood, achieved a gas exchange performance level that was six-times higher than that of the previous product that used internal perfusion.

Figure 4 Gas exchange using external perfusion

Blood-compatible hollow fiber membrane oxygenators, Capiox-SX (HP), 1996 and Capiox-RX, 2000

Figure 5 Capiox -SX (HP) oxygenator

Figure 6 Capiox -RX oxygenator

Another problem with oxygenator membranes is that when blood comes into contact with non-biological materials (artificial lung membranes), plasma proteins are adsorbed on the material surface, and the denaturation of these proteins causes various biological reactions. Reactions can cause complications such as abnormal bleeding after surgery and decreased lung function. That is why it is important to minimize the surface area of the circulation path that comes into contact with blood and to improve the blood compatibility of device materials. Therefore, the technological challenges of oxygenators are to improve blood compatibility of materials and to improve gas exchange efficiency (exchange enough gas with the least surface contact). To improve the blood compatibility of the membrane, a method of coating the surface of the oxygenator membrane with heparin, an anticoagulant, has been put into practical use clinically. Terumo’s heparin-coated oxygenator Capiox SX (HP) is shown in Figure 5. Attempts have also been made to achieve similar effects by coating with polymers. Terumo increased blood compatibility by coating the material surface with a polymer called X-coating that inhibits protein adsorption, reduces platelet adhesion and minimizes platelet activation. Terumo has commercialized the artificial lungs Capiox-SX18, SX25 and Capiox-RX (Figure 6).

Oxygenator with integrated arterial filter and biocompatible surface coating, Capiox-FX, 2008

Figure 7 Capiox-FX

Terumo Capiox-FX (Figure 7) was developed with an integrated arterial filter to reduce the priming volume and eliminate a separate arterial filter in the cardiopulmonary bypass circuit. The oxygenator with an integrated arterial filter is expected to be more beneficial for patients with low body weight and when using a minimized extracorporeal circulation system.

The Capiox-FX oxygenator with a built-in arterial filter is effective for prevention of gaseous emboli. A 32-μm screen filter surrounds the fiber layer of the oxygenator. Particulate micro-emboli that may be present in the blood are trapped in the filter mesh, while gaseous emboli remain inside the oxygenator and in contact with the hollow fibers. Driven by the pressure difference, gaseous emboli enter the inner lumen of the microporous hollow fiber and are eliminated via the gas outlet (self-venting technology).