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Biocompatibility

For the bead carbons to be used in biomedical filtration or adsorption applications it is essential that they show good bio-compatibility enabling them to be used without polymer coating, especially in direct contact with blood. An initial study [15] was carried out using plasma and a well plate produced from the phenolic resin carbon. Inflammatory blood cell and plasma protein mediation of the inflammatory response were evaluated on the novel carbon prototypes and compared with dialyzer membrane and tissue culture plate controls. Assays determining monocyte and granulocyte adhesion, platelet adhesion and activation, granulocyte activation and complement activation were performed. Preliminary analysis of the biocompatibility of the novel, polymer pyrolysed activated carbon prototype using static cell-material interactive conditions indicates an adsorptive but passivating carbon surface. Itis probable that the physicochemical properties of the carbon surface and carbon adsorption of plasma proteins influenced the moderate levels of monocyte and granulocyte adhesion. Granulocytes were not induced to activate, fully activated adherent platelets were not observed and the complement cascade was not activated by the carbons indicating a surface compatible with blood contact. These results supported the further development of the proposed carbon-based device for the treatment of sepsis.

Subsequent studies using the bead carbons [16] looked at cytotoxicity. Whilst there was some initial evidence for cell culture inhibition, this was traced to the removal of essential nutrients by the high-surface-area carbon and a revised test, using a lower level of the carbon showed no evidence for changes in colony formation.

Haemofiltration

This relates to any separation where the blood is taken out of the body, filtered and returned. This is the most difficult separation due to the risks of haemolysis, blood clotting and other issues with blood stability when in contact with the carbon adsorbent. Due to the problems associated with using blood most of these studies were carried out using plasma

The bead carbons have been evaluated for treatment of uraemia, which is a condition in which there are excessive nitrogenous and other waste materials present in a patient's blood. These metabolites would normally be excreted by the kidneys in urine. However, in renal failure these metabolites accumulate in the blood and will, if not treated, result in the death of the patient. The concept that the retention of uraemic toxins plays a role in these clinical problems is underscored by the success of dialysis type therapies in maintaining life quality in terminal renal failure patients and the symptomatic improvement following decreases in dietary protein intake. These uraemic toxins can be arbitrarily grouped by their molecular weight (MW): low (<300 Dalton, e.g., urea and creatinine); middle (300-15,000 Dalton, e.g., parathormone and 2-microglobulin); high (>15,000 Dalton, e.g., myoglobins). The uraemic toxins of the middle molecular weight range, are now known collectively as 'middle molecules' and have been hypothesised as playing a role in the development of uraemia. Whilst dialysis can adequately remove small toxins the removal of middle and higher molecular weight toxins is not possible. It is here that adsorption plays a role and where carbons with a wide range of pore sizes become necessary. The performance for a range of "small molecule” liver toxins is shown in Fig. 10.17 with the cytokine adsorption in Fig. 10.18 for a series of carbons with varying meso/macro pore structures at a single level of activation with the exception of AC1 and AC6, where AC6 was a more severely activated version of AC1. The pore sizes and surface areas can are summarised in Table 10.4. It can be seen that the smallest molecules (phenol and tryptophan) actually adsorb in the purely microporous beads as would be expected whilst the slightly larger molecule, cholic acid, is slightly better removed by the highly activated small mesopore carbon but shows reduced adsorption in the larger mesopore carbons.

"Small molecule" adsorption on bead carbons from plasma solutions

Figure 10.17 "Small molecule" adsorption on bead carbons from plasma solutions: (a) tryptophan, (b) cholic acid and (c) phenol (the testing was carried out at Brighton University).

Table 10.4 Materials used in the small-molecule studies

Sample

Pore size and surface area of the AC

^meso (nm)

Sbet (sq.m/g)

AC-1

Micropores

1204

AC-2

30

1559

AC-3

70

1493

AC-4

80

1548

AC-5

120

1235

AC-6

30

3101

Cytokine adsorption from plasma on bead carbons

Figure 10.18 Cytokine adsorption from plasma on bead carbons.

The beads have also been evaluated as a treatment for SIRS (systemic inflammatory response syndrome) which arises when the pro and anti-inflammatory balance is disrupted which can be triggered by bacterial, viral or fungal infection (sepsis) and blood exposure to external bypass circuits etc. It is a major cause of morbidity in intensive care units following open-heart surgery.

Table 10.5 Cytokine removal using commercial powder grade carbons, polymer coated carbon (ADSORBA) and a range of meso/ macro porous beads activated to between 29% and 60% burn-off

Carbon powder/resin

Activation

burn

■Sbet

(m2/g)

Уроге (cm3/g) at P/P0 = 0.98

Pore size (nm)

% Adsorption TnFa

% Adsorption 11-8

% adsorption IL-6

PICATIF EPII15-35 pm

647.9

0.35

0.82-2.0

42.69

82.17

43.67

PICATIF EPII 8-15

602.1

0.33

0.82-2.0

40.61

98.3

55.85

PICACATIF SC

2019

1.46

1.8, ~6-20

45,48

100

99.47

ADSORBA® 300 C

900

0.51

~1.0

25,42

40.41

22.26

PRB00C

0

454.4

0.52

~ 1.0, ~40

75,4

94.88

88.75

PRB 29 C02

29

847,6

0,76

~ 1.0, ~40

81.98

97.79

98.69

PRB 47C C02

47

1199.7

1.26

~ 1.0, ~40

91.11

99.56

98.55

PRB 47C AM*

47

1294.5

1.29

~ 1.0, ~40

93.65

97.71

98.01

PRB 59 C C02

59

1782.9

1.68

~ 1.0, ~40

97.72

100

99.94

PRB 60C AM*

60

1852.5

1.6

~ 1.0, ~40

99.1

100

99.89

It is estimated that there are 18 million cases of sepsis annually and 1500 deaths per day. The key mediators are TNFa, ILl-p,

IL-6 and IL-8. Laboratory studies using spiked human plasma confirmed the required removal of the of the cytokine mediators.

The data in Table 10.5 compares the mesoporous beads (PRB) activated to between 29 and 60% burn off, and in two cases air modified (AM) to make the surface acidic, with commercial chemical activated powdered carbons (PICACTIF series), CXV (commercial powdered carbons) and ASORBA, a polymer coated commercial granular carbon used in blood treatment. It can be seen that only the highly activated powdered carbon, CXV, approaches the performance of the much larger bead carbons (250-500 pm) but still has a lower performance for the largest of the cytokines, TNFa. It would not, however, be possible to use this material in the filters. It can also be seen that the air modification of the beads has had no discernible impact on the performance.

The beads were then fabricated into pleated 2D filter media housed in a specially designed enclosure (Fig. 10.19) which was then used successfully in pigs which were subjected to full open heart surgery using a the full filter assembly mounted in the arterial return line of a heart and lung machine.

Filter device design to use pleated bead media

Figure 10.19 Filter device design to use pleated bead media.

Oral Adsorption for the Treatment of Liver Disease

All the studies discussed so far have involved either the removal of toxins from circulating blood or plasma or the removal of poisons direct from the stomach contents. It has now been shown that the toxins responsible for chronic liver failure can be removed from the blood by the bead form carbons administered orally. Kureha have proposed the use of Kremezin, a microprous bead carbon for this application but clinical trials have proven negative. It has now been shown in both in-vitro and in vivo small animal studies that the meso/macro porous structure of the resin- derived beads [19] can remove the toxins resulting in reversal of liver failure in small animals.

 
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