**1. Introduction**

When functions of the living kidney decrease down to under survival level, patients are required to be treated with a system that supports kidney functions. There are several such treatment modalities available, including peritoneal dialysis (PD), hemodialysis (HD), hemofiltration (HF), hemodiafiltration (HDF), hemoadsorption (HA), and their advanced derivatives, among which the most popular treatment system is HD. The artificial kidney device used in HD is called "hemodialyzer" or more simply "dialyzer" that includes membrane to separate the waste products and excess water from blood.

Artificial kidney is also expected to correct pH that is usually acidic before treatment by balancing electrolytes in addition to removing waste products and excess water. All these functions are dependent upon the permeability of the membrane used in a dialyzer and since the quality of treatment is strongly dependent on the performance of the dialyzer, many materials have been proposed as a candidate of the membrane. We have currently several commercial materials available, including natural polymers and synthetic polymer‐ ic ones.

In this chapter, dialysis membrane and its materials are extensively discussed from the physicochemical points of view, including microscopic views taken by scanning electron microscope (SEM), mathematical expressions of membrane transport, fundamental *in vitro* experiments as well as *in vivo* trials or clinical experiences.

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. Basic principles and history of dialysis membrane**

#### **2.1. Law of diffusion**

Dialysis is a phenomenon at which two different fluids (usually liquids) are separating flowing on either side of the membrane (usually counter-currently) and the solute of interest in higher concentration transports across the membrane due to concentration gradient in accordance with the Fick's 1-st law of diffusion, i.e.,

$$J\_{\rm Ax} = -D\_{\rm Ax} \frac{\partial \mathcal{L}\_{\rm A}}{\partial x} \tag{1}$$

where *x* is the co-ordinate in the diffusion direction [m], *J* <sup>A</sup>*<sup>x</sup>* is the mass flux of solute A in *x* direction [kg/(s m2 )], *D* <sup>A</sup>*<sup>x</sup>* is the diffusion coefficient of A in *x* direction [m2 /s], and *C* A is the concentration of A [kg/m3 ]. Dialysis, therefore, is one of separation techniques of the solute of interest by using the membrane and is applied elsewhere in many industrial as well as laboratory situations. Letting *C* A0 and *C* AL to be the concentrations of A at *x*=0 and *x*=*L*, respectively (Figure 1), Eq.(1) is integrated in a straight-forward manner to get,

$$\mathcal{J}\_{\rm Ax} = \begin{pmatrix} \frac{D\_{\rm Ax}}{L} \end{pmatrix} \begin{pmatrix} \mathbf{C}\_{\rm A0} \ \mathbf{-} \ \mathbf{C}\_{\rm AL} \end{pmatrix} = k\_{\rm M} \times \begin{Bmatrix} \mathbf{C}\_{\rm A0} \ \mathbf{-} \ \mathbf{C}\_{\rm AL} \end{Bmatrix} \tag{2}$$

where *k* M is the membrane permeability [m/s] defined by (*D* <sup>A</sup>*<sup>x</sup>*/*L*). From Eq.(2), one would alternately mention that the rate of diffusion is proportional to the concentration difference between either side of the membrane. The value of *k* M is discussed in section 4.

Figure 1-1 Diffusion across a piece of membrane assuming no existence of boundary film adjacent to either side of the membrane **Figure 1.** Diffusion across a piece of membrane assuming no existence of boundary film adjacent to either side of the membrane.

#### **2.2. Dawn of hemodialysis**

**2. Basic principles and history of dialysis membrane**

Dialysis is a phenomenon at which two different fluids (usually liquids) are separating flowing on either side of the membrane (usually counter-currently) and the solute of interest in higher concentration transports across the membrane due to concentration gradient in accordance

∂*C*<sup>A</sup>

where *x* is the co-ordinate in the diffusion direction [m], *J* <sup>A</sup>*<sup>x</sup>* is the mass flux of solute A in *x*

interest by using the membrane and is applied elsewhere in many industrial as well as laboratory situations. Letting *C* A0 and *C* AL to be the concentrations of A at *x*=0 and *x*=*L*,

where *k* M is the membrane permeability [m/s] defined by (*D* <sup>A</sup>*<sup>x</sup>*/*L*). From Eq.(2), one would alternately mention that the rate of diffusion is proportional to the concentration difference

> Figure 1-1 Diffusion across a piece of membrane assuming no existence of boundary film adjacent to either side of the membrane

**Figure 1.** Diffusion across a piece of membrane assuming no existence of boundary film adjacent to either side of the

*x* **= 0** *x* **=** *L*

*x x+x*

)], *D* <sup>A</sup>*<sup>x</sup>* is the diffusion coefficient of A in *x* direction [m2

]. Dialysis, therefore, is one of separation techniques of the solute of

*<sup>L</sup>* )(*C*A0 - *C*AL) ≡ *k*<sup>M</sup> ×(*C*A0 - *C*AL) (2)

Fluid with lower concentration, *CAL*

<sup>∂</sup> *<sup>x</sup>* (1)

/s], and *C* A is the

*J*A*<sup>x</sup>* = - *D*A*<sup>x</sup>*

respectively (Figure 1), Eq.(1) is integrated in a straight-forward manner to get,

between either side of the membrane. The value of *k* M is discussed in section 4.

*JAx*

*<sup>J</sup>* <sup>A</sup>*<sup>x</sup>* = ( *<sup>D</sup>*A*<sup>x</sup>*

Fluid with higher concentration, *CA0*

**2.1. Law of diffusion**

164 Updates in Hemodialysis

direction [kg/(s m2

membrane.

concentration of A [kg/m3

with the Fick's 1-st law of diffusion, i.e.,

Application of dialysis to blood purification, hemodialysis (HD), was first performed for canines reported by Abel *et al.* in 1914 [1]. A chemical substance (sodium salicylate) was added to the subject as a marker prior to the experiment, mimicking the clinical situation of kidney failure in which waste products accumulate in the human body. Then the marker substance was removed by the dialyzer that included the membrane made of collodion. The dialyzer included 16 collodion tubes whose length was 40 cm that is 1.5 times longer than a currently available normal commercial model and the diameter was about 8 mm that is approximately 40 times larger than a popular hollow fiber membrane currently utilized worldwide. Since the collodion was too fragile to perform dialysis experiments, many other membranes cast from natural materials were examined whether or not they were suited as a separation membrane. Finally collodion was replaced by cellophane, and the first clinical trial was performed by Kolff *et al.* in 1943 with a rotating drum dialyzer, designed and assembled by themselves [2]. Separation performance of these dialysis membranes, however, was not discussed extensively at that time because mechanical strength of the materials was more important for performing experiments or treatments than the permeability of the membrane.

#### **2.3. Development of commercial dialysis membranes**

Cuprophan® is a registered name of the membrane made of cuprammonium rayon made from cellulose dissolved in cuprammonium solution, produced by Enka Co. in West Germany, later Membrana in Polypore Co., Germany. Another cuprammonium rayon membrane with nearly the same chemical and physical structures was developed by Asahi-Kasei Co. (Tokyo, Japan) termed Bemberg®, followed by Terumo (Tokyo, Japan). These membranes were also called regenerated cellulosic (RC) membrane since they were cast from cellulose or cotton fibers. Chemical modifications were made for RC membranes mostly because of improving their biocompatibility by replacing their hydroxyl group(s) with acetate group(s). They are called cellulose acetate (CA), cellulose diacetate (CDA), and cellulose triacetate (CTA) in accordance with the number of introduction of acetate groups to the cellulose backbone. Although RC membranes are no longer commercially available, CA, CDA, and CTA membranes still have fairly good market share since they have much higher solute and hydraulic permeabilities as well as better biocompatibility than original RC membranes.

The first synthetic polymeric membrane was developed in 1969 by Rhône-Poulenc (France) and was named AN-69®, since the main material of the membrane was acrylonitrile (AN). The brand name of the dialyzer assembled with a flat sheet AN-69® membrane was RP-6® and it was also the first dialyzer sterilized by the gamma-ray irradiation. Although the production company of AN-69® membrane has been changed over time from Rhône-Poulenc to Hospal, Gambro, and Baxter, dialyzers with AN-69® membrane are still available worldwide, espe‐ cially in the field of acute kidney injury (AKI) therapy since it has strong adsorption charac‐ teristic to specific substances such as inflammatory cytokines.

The first dialyzer with a cellulosic hollow fiber membrane was developed by chemical engineers, Stuart and Lipps in 1967 [3] in Massachusetts Institute of Technology (Boston, MA, U.S.A.), and the commercial product was available in 1972 from Cordis-Dow Co. (Miami, FL, U.S.A.). The basic structure of the hollow-fiber dialyzer is the same as the one of multi-tube heat exchanger that is compact and has large surface area. Because of these advantages, dialyzers with hollow fiber membrane have been become widely used. The first dialyzer with a synthetic polymeric hollow fiber membrane sterilized by gamma-ray was introduced by Toray Co. (Tokyo, Japan), in which polymethylmethacrylate (PMMA) was used as a main material of the membrane [4].

In order to improve solute and hydraulic permeabilities as well as biocompatibilities, many synthetic polymeric membranes have been introduced to the market since early 1980's, and currently these membranes are the main stream. Among them, polysulfone (PSf) and the like (including polyethersulfone (PES), polyarylethersulfone (PAES), etc.) have the highest market share over the world. Since these membranes are made from petroleum, they are hydrophobic in nature. Then most of these membranes include so-called hydrophilic agent that also plays a role of pore-forming agent when cast. The role of the hydrophilic agent is discussed later from the chemical (section 3), mass transport (section 4), and biological (section 5) points of view.
