Bio-Medical Materials and Engineering 23 (2013) 129–142 129

DOI 10.3233/BME-120738
IOS Press

Biocompatibility: Bioengineering aspects 1

Shun Murabayashi ∗ and Yukihiko Nose
Department of Artificial Organs, The Cleveland Clinic Foundation, Cleveland, OH, USA

Received 2 July 2012

Accepted 27 July 2012

Abstract. 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, un-
derstanding 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 inter-
action; 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.
Keywords: Biocompatibility, blood–material interactions, local reactions, systemic reactions, body defense system

1. Introduction for reprint

Dr. Nose had made a great impact in various areas of research and development on artificial organs
technologies. Many materials were used for various devices. Biocompatibility of the materials used for
these devices had been his great concern. I had an opportunity to make a presentation with respect to the
issue of biocompatibility at the Fifth World Congress of the International Society for Artificial Organs,
October 5–8, 1985, Chicago, IL, USA. The presentation was made based upon Dr. Nose’s conception on
biocompatibility. The presentation was arranged into a paper and published in Artificial Organs, Vol. 10
(1986), pp. 114–121. The paper is reprinted here with permission.

2. Introduction

In any device used in contact with blood, a blood-compatible material is essential. The demand for
such materials has been best shown in the development of cardiac prostheses such as the total artificial
heart and the left ventricular assist devices. It may be said that their development is also the history of
human efforts to develop thromboresistant materials. After almost three decades of such efforts, there are
1
This article is reprinted with permission from Artificial Organs (Shun Murabayashi and Yukihiko Nose, Biocompatibility:
bioengineering aspects, Artificial Organs 10(2) (1986), 114–121).
*
Address for correspondence: Shun Murabayashi, Division of Bioengineering and Bioinformatics, Graduate School of
Information Science and Technology, University of Hokkaido, N-14, W-9, Kita-ku, Sapporo, 006-0814 Japan. Tel./Fax: +81 11
706 6789; E-mail: shun@bme.ist.hokudai.ac.jp.

0959-2989/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
130 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

now clinically acceptable devices. However, materials currently available are still not ideal. Patients with
a total artificial heart often suffer from strokes. Moreover, it has been shown in animals that after long-
term implantation, calcified deposition or pannus is formed, which is crucial for device performance
[1,2].
While clotting and thrombosis are the most obvious evidence of incompatibility, they represent only
one aspect of blood compatibility. Materials can affect plasma proteins, immunological factors and cel-
lular components as well as coagulation factors and platelets. Complement activation during extracorpo-
real circulation, such as hemodialysis [3,4], cardiopulmonary bypass [5], and membrane plasmapheresis
[6], has been well documented and possible adverse effects caused by this reaction have been discussed.
The necessity for biocompatibility of the materials is now more recognized than ever. However, un-
derstanding of blood compatibility is still limited, and efforts continue to understand blood–material
interactions and to develop more blood compatible materials.
Bioengineers have contributed to such research by designing and synthesizing materials. After careful
characterization of the material using sophisticated analytical instruments, studies have been conducted
that reveal blood–material interfacial reactions. Although much information has been accumulated, none
of the in vitro tests can predict the in vivo performance of the materials. Probably, this approach focusing
on the interfacial reactions may not be sufficient to take a full view of blood–material interaction. There is
need for a more global approach to studying material-body interaction to understand biocompatibility. In
this article, a new approach will be discussed, because it is believed that establishing a logical approach
to studying biocompatibility is most important for the future progress of biocompatibility research.

3. Global understanding of body–material interaction

When biocompatibility is studied in artificial organs, the following three aspects must be considered.
First, many systems in the body’s defense system are not independent. The coagulation, fibrinolytic,
kallikrein–kinin and complement systems are all interrelated and also interact with cellular components
such as polymorphonuclear granulocytes, lymphocytes, macrophages and platelets. Second, local in-
terfacial blood–material reactions will induce systemic reactions and changes. Therefore, the blood or
body will be changed by blood–material interactions. The systemic changes induced by a local reaction
can then affect the interfacial blood–material interactions. Third, it is important to recognize the time
sequences of such interaction between local and systemic reactions.

3.1. Interactions within the body’s defense system in response to the implant

The body is constantly being challenged by a multiplicity of noxious stimuli that require a well devel-
oped defense mechanism to ensure survival. The coagulation system guards against unnecessary blood
loss after trauma; the fibrinolytic system protects against thrombosis; the kallikrein–kinin system pro-
vides leukotactic and vasoactive components; the complement system provides vasoactive, chemotactic,
phagocytosis-promoting and lytic activities of great importance in infectious and immune diseases. Each
mechanism is in principle a cascade of reactions that consist mainly of proenzyme-enzyme activations.
The cascade system allows amplification and provides several possible points of control, by both positive
and negative feedback mechanisms and inhibitors or inactivators.
Until recently, research on these mechanisms has proceeded separately. A breakthrough in this situa-
tion came with the discovery by Margolis [7] that factor XI1 is necessary not only for intrinsic activation
of blood coagulation, but also for kinin generation. Shortly after, Niewiarowski and Prou-Wartelle [8]
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 131

Fig. 1. Interaction of coagulation, complement, fibrinolytic and kinin system (from Kokichi Kikuchi (Ed.), Medical Immunol-
ogy, Tokyo, 1980, p. 109).

showed that factor XI1 is also involved in the intrinsic activation of plasminogen to plasmin. Finally,
Donaldson [9] provided evidence that factor XI1 is involved in activation of the complement system.
Since these early observations, evidence has been accumulated (Fig. 1) that shows the links among the
coagulation, fibrinolytic, kallikrein–kinin and complement systems. More detailed information on such
interactions can be obtained in recent review articles [10,11]. Some of these interactions are believed
unphysiological in the fluid phase of blood in vivo, and indeed require a large excess of enzyme for
an extended period of time to process enzymatic reactions. However, it is also known that activities of
the proteases of the complement, coagulation and fibrinolytic system are significantly modified in the
presence of cofactors and biologic surfaces [11]. Therefore, there is also the possibility that these inter-
actions will be promoted on the biomaterial surfaces. Such interactions probably contribute enormously
to the complexity and difficulty in understanding blood–material reactions.
The difficulty of a biocompatibility study is enhanced by the participation of cellular components
such as platelets, leukocytes and macrophages. The role of platelets in the hemostatic mechanism is
132 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

well established, but they are also involved in immunological and inflammatory reactions [12]. Recent
studies indicate a number of different mechanisms by which platelets interact with the complement sys-
tem [12]. They include activation of platelets by complement components and activation of complement
components by platelets. It is important to take into account the species differences in complement–
platelet interaction. Species of animals fall into clearly defined groups. Those with C3b receptors on
their platelets include rabbits and dogs, and those without include human, baboon and cattle [13]. This
difference may be partially responsible for the species difference of platelet reactions on the biomaterial
surface. Grabowski et al. [14] studied platelet adhesion on various materials in vitro using heparinized
whole blood and compared the animal species. They observed that dog or rabbit platelet levels on Cupro-
phan were two to three orders of magnitude greater than those of human or calf platelets. However, dog
platelet adherence to fluorinated ethylcellulose was significantly less than to Cuprophan and the number
of dog platelets was similar to that of human platelets. This result may be explained if the complement
system is taken into account. The Cuprophan membrane is well known to induce complement activa-
tion [4]. C3b will be deposited on the Cuprophan surface after exposure to blood [15], which makes
the membrane susceptible to dog platelet adhesion but not to human platelets owing to the lack of C3b
receptor. Fluorination and ethoxylation of the cellulose membrane, on the other hand, probably decrease
its complement activation capability by reducing the hydroxyl group; therefore, similar platelet adhesion
behavior was observed in both species.
The effect of the complement system on platelets was also suggested during membrane plasmapheresis
on a dog (S. Matsubara et al., unpublished data). It is known that transient thrombocytopenia, reduction
of circulating platelets, occurs during extracorporeal circulation in dogs. It has been found that this
phenomenon is related to the anticoagulants used. When citrate was used instead of heparin, reduction of
platelet counts was much less. This result can also be explained by the complement effect. Complement
can be activated in heparinized blood, but the activation is inhibited in citrated blood, probably owing to
the chelation of Ca2+ and Mg2+ by citrate, which are necessary for complement cascade reactions [16].
Although it is not yet clear whether the platelet reduction was caused by the direct effect of C3b binding
on the dog platelets or the secondary effect of leukocytes, which induce platelet-activating factors, this
study demonstrated that transient thrombopenia is related to complement activation.
It is well known that activation of complement affects cellular functions in the defense system [17],
shown in Table 1. Briefly, polymorphonuclear leukocytes are aggregated by C5a, which is considered a
cause of transient leukopenia during extracorporeal circulation such as hemodialysis [18]. Leukocytes
also show chemotactic and opsonic response and release hydrolytic enzyme, tissue factor, which may
promote coagulation [19] and platelet-activating factors [20]. The macrophage also shows chemotactic
and opsonic response [21] and interleukin-1 secretion [22].
As described, both the humoral and the cellular components of the body’s defense system are inter-
related and complex. But, knowledge of the interactions of these systems is at an early stage. It seems
to be very difficult or almost impossible to reveal those interactions of the blood–material reactions.
Therefore, the investigators have been studying biocompatibility by focusing on one humoral system
or one cellular component to elucidate specific reactions with the biomaterial surface. This approach
is, of course, necessary and important; however, progress in the understanding of blood–material in-
teractions might be limited unless complicated and significant interactions among defense systems are
taken into consideration. If the complexities of such interactions that occur on the biomaterial surface
are challenged, the blood–material interactions will be understood more clearly and also fundamental
information will be obtained on the body’s defense mechanism itself.
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 133

Table 1
Effect of complement system on cellular functions
Type of cell Response to complement activation
Polymorphonuclear leukocyte Aggregation (C5a)
Chemotactic response (C5a)
Opsonic response (C3b)
Hydrolytic enzyme release (C5a)
Tissue factor release (C5a)
Platelet-activating factor
release (C5a)
Macrophage Chemotactic response (CSa)
Opsonic response (C3b)
Interleukin-I secretion (C5a)
Platelet Serotonin release (pig: C3a, C5a)
Aggregation (rabbit:C3b);
(human: alternative pathway + fibrinogen)
Thrombocytopenia (dog)

3.2. Local reactions and systemic reactions

Bioengineers regularly assess the biocompatibility of a material by examining the interfacial reactions
(local reactions) between blood and the material surface. It is the authors’ opinion, however, that this
may not be enough and that investigators must look beyond that interface, because the local reaction can
modify the recipient to such an extent that it changes the blood–surface interaction, and because the local
reaction cannot always predict such systemic reactions and changes in the body. Therefore, one has to
observe the systemic reactions and changes very carefully as well as the local reactions. The importance
of this concept was clearly shown in recent biocompatibility studies in the authors’ laboratory. Therefore,
these studies are briefly described.
3.2.1. Effect of membrane on complement activation and leukocytes during plasma exchange
A 38-year-old male patient with primary sclerosing cholangitis was chosen for the study [6]. His clin-
ical condition had improved after 162 plasma exchange treatments. Only one patient was subjected to
the study to eliminate the individual response difference in complement reaction. The patient’s hemato-
logical and biochemical data were stable during the study. Four different types of plasma separator were
evaluated in terms of hematological parameters: CH50 , C3, C5, C3a and C5a. The membrane materials
were polymethylmethacrylate (PMMA), polyvinylalcohol (PVA), polyethylene (PE) and cellulose ac-
etate (CA). The plasma exchange procedure was the same in every case. An initial intravenous injection
of 5000 U of heparin was given as a bolus 5 min prior to the start of blood pumping and a maintenance
dose of 3400 U/h continuously during the perfusion. The blood flow was set at 100 ml/min. The plasma
flow was set in the range of 30–35 ml/min. Samples were drawn from the inlet blood before the module
and the outlet blood from the module. Therefore, the inlet blood is the systemic blood and the outlet
blood reflects the local reactions induced by blood–membrane interactions.
The effect of membrane on white blood cell (WBC) counts and C3a in the systemic blood is shown in
Fig. 2. Transient reduction of WBC counts as observed in the early phase of perfusion with the maximum
reduction at 15–30 min. There was no difference in WBC counts between the inlet and outlet blood
samples for any of the modules. CA membrane showed a more profound reduction of WBC counts than
134 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

Fig. 2. White blood cell (WBC) and C3a changes in inlet blood (systemic blood) during membrane plasamapheresis. (a) Poly-
methylmethacrylate (PMMA). (b) Polyvinylalcohol (PVA). (c) Polyethylene (PE). (d) Cellulose acetate (CA).
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 135

PMMA. The systemic changes of C3a measured by radioimmunoassay showed a relatively good inverse
correlation with the systemic WBC changes. These results are quite similar to those in hemodialysis [4,
23]. One may think that CA induced the highest complement activation, which led to the most profound
WBC reduction.
However, when the C3a level was compared between the inlet and outlet blood, the situation of com-
plement activation was quite different, as shown in Fig. 3. In the local reaction, PVA showed the highest
complement activation with the maximum C3a production at 15 min. The C3a production by CA in-
creased gradually to reach the same level as PVA at 30 min. PMMA showed a similar tendency as CA
with less degree of complement activation. PE showed a constant production of C3a. Interestingly, the
time sequence of the complement activation differed with each membrane. The most important result
indicated in this study is that the local reaction does not relate to the systemic situation. Since the oper-
ational condition of the plasma exchange is the same, the dilution effect of C3a in the systemic blood is
expected to be same. Therefore, the systemic C3a level should reflect the local C3a production. However,
CA showed a more systemic C3a level than PVA at 30 min, although local C3a production at 15 min
was less than that induced by PVA. PMMA showed little complement activation in the local blood at
5 min, but showed a certain level of C3a in the systemic blood at 15 min. Therefore, the local C3a level
does not directly relate to the C3a in the systemic blood.
It has been demonstrated in hemodialysis that complement activation leads to leukocyte sequestration
in the pulmonary vasculature, which results in the reduction of circulating WBC count [3,24]. WBC
changes during plasma exchange correlated well with the concentration of systemic C3a, raising the
following questions: Why did local complement activation not directly affect the leukocyte behavior?
Was there any reaction to prevent C5a binding to the leukocyte receptor, such as adsorption of C5a on
the PVA membrane? Why did the degree of C3a change in the systemic blood depend on the membrane
used? Does the kinetics of clearance of C3a depend on the material used? Or, does complement activation
occur in the body, not only at the material interface? In case of PMMA, complement activation most
likely occurred in the body, although the device was free from endotoxin. This study revealed many
questions, but the most important evidence suggests that the local reaction does not relate to the systemic
reaction or changes in the body. Therefore, one has to observe both the local and the systemic reactions.
3.2.2. Effect of oxygenation on plasma proteins during and after cardiopulmonary bypass
Eight patients with a membrane oxygenator and 12 patients with a bubble oxygenator were subjected
to this study [25]. Plasma proteins absorbed on the membrane were analyzed and comprised mainly
albumin, fibrinogen, and immunoglobulin. These proteins were aggregated and could not be separated
by gel filtration, which suggests that they were denatured. The denaturation of plasma proteins was
not limited to the membrane surface. It was found that in all cases, regardless of the oxygenator type,
cryoprecipitates were formed in the defibrinated plasma obtained from the perfused blood. Immuno-
electropheresis analysis revealed that albumin, fibrinogen, immunoglobulin G and immunoglobulin M
were major components of these cryoprecipitates. It was also shown that rheumatoid factor was positive
in 50% of 14 cases tested, indicating that immunoglobulins were aggregated and/or denatured. Further
evidence of the aggregation or denaturation of immunoglobulins shows that these cryoprecipitates ag-
gregated platelets in 86.7% of the cases. This study clearly demonstrated that the nature of the blood
was changed by the oxygenation procedure, which suggested that the local reaction or membrane-blood
or air-blood interactions induced systemic changes.
It was also shown that acute-phase reactants such as α1 -antitrypsin, α1 -acid glycoprotein, α1 -
antichymotrypsin, and complement component increased by the seventh postoperative day and returned
136 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

Fig. 3. C3a changes in inlet and outlet blood during plasma exchange. See the legend to Fig. 2 for abbreviations.

to the normal levels after 1 month. Although postoperative changes in such protein Components re-
flect largely the surgical insult and resultant inflammatory reaction of the body, one has to observe such
systemic reactions and changes carefully.

3.3. Time sequence of interactions between local and systemic reactions

In the previous section, the authors have noted that the investigator should not consider only local
interfacial reactions. It is important to understand systemic reaction and change, because such changes of
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 137

Fig. 4. Time-varying interactions between local and systemic reactions.

blood will then affect the blood–material interfacial reactions. Therefore, investigators have to consider
the time sequence of the interactions between the local and the systemic impact on the recipient. It is
the authors’ opinion that such interactions may be differentiated into three stages, namely, super-acute
stage, acute stage and chronic stage, as shown in Fig. 4.
3.3.1. Super-acute stage
The super-acute stage shown in Fig. 5 involves the initial events of blood–material interactions. Once
blood comes into contact with a material, activation of the humoral defense system is induced as well
as cellular reactions. At the same time, the surface characteristics of the material are changed owing
to the blood constituent depositions and the rearrangement of the surface segment of the material [26].
Therefore, the surface becomes different from the original surface and may be called a super-acute
surface.
It seems appropriate to recognize that the superacute stage continues for the first 2 h, which is sug-
gested by the following evidence: (a) The pseudoneointima (PNI) on the textured surface of the blood
pump reaches a plateau thickness after 2 h [27]. (b) Complement activation decreases within 2 h dur-
138 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

Fig. 5. Super-acute stage time-varying interaction between local and systemic reactions.

ing hemodialysis [4,23] or membrane plasmapheresis [6]. (c) Lelah et al. [28] studied platelet adhesion
kinetics on various materials in an arteriovenous shunt experiment on the dog. They found platelet adhe-
sion was transient and the number of adhered platelets reached a stable stage after 1.5–2 h. (d) Fibrino-
gen adsorption on a material surface from plasma or blood reaches a steady state within 1–2 h [28–30].
Therefore, the initial events of blood–material interaction may cease within the first 2 h.
3.3.2. Acute stage
After 2 h, the acute-stage interaction starts (Fig. 6). The success or failure of the implant is dependent
on both the surface characteristics of the super-acute surface and the nature of blood that has been
changed by the super-acute reactions. Such changes in blood are induced primarily by the direct effect
of blood–material interactions such as denaturation or alteration of blood constituents and/or generation
of biologically active substances by activation of the defense system, and secondarily by the body’s
response to return to the normal condition that had been perturbed by the superacute reactions.
Probably, the acute stage continues for up to 2 weeks. The PNI on the textured surface of the blood
pump is different after 2 weeks, when precursors of endothelial-like cells appear on the surface [31–33].
Moreover, it is well known that the period of 2 weeks is the turning point of the body’s defense reactions
such as antibody formation or acute-phase reactions. Therefore, it seems to be appropriate to set the time
period of acute-stage interaction at 2 weeks.
3.3.3. Chronic stage
The acute stage is followed by the chronic stage, where different events of blood–material interaction
proceed (Figs 7 and 8). If a benign transformation takes place, it will be a healed PNI surface [31–33]
or a non-PNI “passivation” surface [34]. If a malignant transformation occurs, calcification or pannus
formation develops, which are major problems associated with the long-term implantation of cardiac
prostheses.
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 139

Fig. 6. Acute-stage time-varying interaction between local and systemic reactions.

Little is know about the chronic impact on the recipient. It is known, however, that long-term
hemodialysis patients show a high incidence of atherosclerosis, infection, and malignant tumor [35,
36]. Even though each treatment of hemodialysis is just for several hours, patients are treated repeatedly.
Therefore, the effect of blood–membrane interactions may be regarded as chronic ones. It is important
to consider this chronic impact on patients. Utilization of biocompatible hemodialysis membrane will
contribute to the patient’s well being. It is known that patients treated by reused dialyzers show lower
mortality and morbidity [37,38]. A reused dialyzer is known to activate complement to a much smaller
extent than new cellulosic membranes.
As already mentioned, calcification and pannus formation are major problems of the chronic surface
in cardiac prostheses. Long-term hemodialysis patients have a high incidence of atherosclerosis and
malignant tumors. These phenomena are considered to be completely different at this time; however, we
may find some common explanation.

4. Concluding remarks

The necessity of a global approach in biocompatibility study has been proposed. In the past, investiga-
tors have been trying to understand blood–material interactions by focusing on the interfacial reactions.
This approach may not be enough, and the investigator must consider beyond the interface. The lo-
cal interfacial reaction can induce systemic reactions and changes to such an extent that they affect
the blood–material interactions. Biocompatibility of the material cannot be discussed from the local re-
action point of view. The interactions between local and systemic reaction must be understood. Such
140 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects

Fig. 7. Chronic stage of the time-varying interaction between local and systemic reactions.

Fig. 8. Chronic interactions stage between local and systemic reactions. PNI, pseudoneointima.

interactions may be classified into three stages, namely, super-acute, acute and chronic. In each stage,
the biocompatibility aspect that must be dealt with is different. Much information regarding the local
 S. Murabayashi and Y. Nose / Biocompatibility: Bioengineering aspects 141

reactions has been accumulated; however, understanding of systemic reactions and their effect on the
local reaction is limited. By studying such interactions, blood–material interactions may be understood
more clearly.
In cardiac prostheses such as the total artificial heart, research emphasis is placed on the hemostatic
system. In hemodialysis, complement reactions are studied as the biocompatibility aspect. If it is re-
membered that the body’s defense systems are all interrelated, future study should not he limited to one
humoral system or cellular component.
Biological reactions are so complex and complicated that it seems very difficult to determine blood–
material interactions. However, if this problem is studied according to the global approach as described,
biocompatibility may be understood more clearly. Such efforts will result in the development of more
biocompatible materials for the benefit of patients and may also give fundamental information on the
living body itself.

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