Flow-Resistant Blood Microemboli - American Chemical Society

16 A Method to "Count" Flow-Resistant

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 28, 2018 | https://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch016

Blood Microemboli K. A. SOLEN and B. L. BETTERIDGE Brigham Young University, Department of Chemical Engineering, Provo, UT 84602

A constant-pressure filtration (CPF) test was developed to "count" those blood microemboli in a blood sample that are likely to occlude arterioles and capillaries. For preliminary testing, blood microemboli were generated by shearing fresh heparinized human blood between parallel discs of Plexiglass, polystyrene, or polycarbonate for 15, 30, or 90 min (shear range: 0-1200 s ). CPF measurements were then made on the blood using a 40-mm mercury driving pressure and 15-μm pore filters. Filtration flow rate curves conformed to mathe matical predictions from which "effective" microemboli con centrations were calculated. Microemboli production rates from the three materials were significantly different after 90 min of blood-material contact, with the order of increasing toxicity being polycarbonate < polystyrene < Plexiglass. -1

T

he contact o f b l o o d w i t h foreign materials o r interfaces results i n the formation o f b l o o d m i c r o e m b o l i . C l i n i c a l l y , m i c r o e m b o l i are generated

by pump-oxygenators (1-7), h e m o d i a l y z e r s (8), v e n t r i c u l a r assist devices (9),

prosthetic heart valves (10), b l o o d c o l l e c t i o n sets (11), a n d b l o o d storage (12-21). W h e n t h e m i c r o e m b o l i are sufficiently large a n d r i g i d , b l o o d flow t h r o u g h arterioles a n d capillaries is r e t a r d e d or p r e v e n t e d , a n d the c o n sequent blockage o f vascular beds results i n i m p a i r m e n t o f organ f u n c t i o n . F o r example, w i t h t h e use o f pump-oxygenators for c a r d i o p u l m o n a r y sup port, the p r e s e n c e o f m i c r o e m b o l i has b e e n related to post-operative

neu

rologic p r o b l e m s (22-25). To i m p r o v e biomaterials a n d b l o o d - h a n d l i n g devices f r o m the stand point o f b l o o d m i c r o e m b o l i p r o d u c t i o n , the f o l l o w i n g questions must b e ansv/ered: 1. W h a t are t h e m e c h a n i s m s of b l o o d m i c r o e m b o l i formation a n d the resultant m i c r o e m b o l i compositions? 0065-2393/82/0199-0221$06.00/0 ® 1982 American Chemical Society Cooper et al.; Biomaterials: Interfacial Phenomena and Applications Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

222

BIOMATERIALS: INTERFACIAL P H E N O M E N A A N D APPLICATIONS

2. W h a t are the flow p r o p e r t i e s of the various types of b l o o d m i c r o e m b o l i a n d t h e i r tendencies to retard or prevent m i c r o vascular flow?


3. W h a t flow parameters a n d b i o m a t e r i a l surface characteristics p r o m o t e the f o r m a t i o n of the various types of b l o o d m i c r o emboli? W h i l e studies of platelet a n d t h r o m b u s a c c u m u l a t i o n on surfaces have p r o v i d e d i m p o r t a n t i n f o r m a t i o n c o n c e r n i n g b l o o d - m a t e r i a l interactions, that a c c u m u l a t i o n is not a d i r e c t i n d e x of the rate of m i c r o e m b o l i generation [e.g., k i d n e y e m b o l i s m i n d u c e d b y i m p l a n t e d aortic rings often was most severe from rings that r e m a i n e d " c l e a n " (26, 27)]. T h u s , analytical tests that d i r e c t l y quantify m i c r o e m b o l i are n e e d e d . T h e p r o p e r t y of a b l o o d m i c r o p a r t i c l e that is c l i n i c a l l y important is the flow resistance of that p a r t i c l e , that is, w h e t h e r it w i l l lodge i n arterioles or capillaries a n d i m p e d e b l o o d flow or, instead, break u p or d e f o r m a n d therebypass t h r o u g h the microvasculature. U n f o r t u n a t e l y , present methods used to " c o u n t " m i c r o e m b o l i , such as u l t r a s o u n d (I, 4-6, 28), electronic counters ( 7 , 1 9 , 20, 29, 30), a n d f i l t e r c o l l e c t i o n at l o w , u n c o n t r o l l e d pressures (2, 31 ), do not d i s t i n g u i s h b e t w e e n " o c c l u d i n g " particles (those that w i l l i m p e d e flow) and " n o n o c c l u d i n g " particles (those that w i l l pass t h r o u g h capillaries). T h e K u s s e r o w k i d n e y e m b o l u s test (25) does make that d i s t i n c t i o n b y u s i n g the k i d n e y of a d o g to trap o c c l u d i n g m i c r o e m b o l i that are p r o d u c e d b y a r i n g of test material i m p l a n t e d i n the suprarenal aorta; however, the r e s u l t i n g renal infarction is difficult to quantify a n d is o b s c u r e d by biological variations and by compensatory a n d reparative processes of the k i d n e y . T h e one existing quantitative test of flow-resistant m i c r o e m b o l i is the screen filtration pres sure (SFP) test (32), w h i c h measures the filtration pressure after i m p o s e d constant flow of the b l o o d sample t h r o u g h a 20-μπι pore filter for 10 s. T h e S F P test has b e e n useful b o t h c l i n i c a l l y a n d i n research (8, 33-39), b u t the test suffers f r o m two significant drawbacks. F i r s t , the r e a d i n g of the pressure at o n l y one p o i n t a l o n g the pressure vs. t i m e curve, n a m e l y , after exactly 10 s, ignores the rest of that c u r v e ; thus, a variety of c o m p l e t e l y d i s s i m i l a r curves can p r o d u c e i d e n t i c a l final readings, a n d w i d e oscillations i n pressure i n that r e g i o n of the c u r v e can p r o d u c e significant variability i n the final reading. S e c o n d , the h i g h , n o n p h y s i o l o g i c a l pressures sometimes generated d u r i n g the S F P test (often as h i g h as 1500 m m m e r c u r y or higher) cause the particle selectivity to be q u i t e n o n p h y s i o l o g i c a l , that is, some microparticles that are forced t h r o u g h the filter at these h i g h pressures might not pass t h r o u g h the filter u n d e r p h y s i o l o g i c a l pressures. C o n s i d e r i n g this discussion, some features of an i m p r o v e d test to count flow-resistant m i c r o e m b o l i m i g h t be that the test: 1. counts o n l y those m i c r o e m b o l i satisfying some criteria.

flow-resistant

2. is based o n p h y s i o l o g i c a l models a n d calibration.

Cooper et al.; Biomaterials: Interfacial Phenomena and Applications Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

16.

SOLEN A N D BETTE RIDGE

Flow-Resistant Blood Microemboli

223

3. y i e l d s quantitative data based o n the entire sample. 4. is s i m p l e a n d r e p r o d u c i b l e (suggests an i n v i t r o test). 5. is sufficiently sensitive to d i s c r i m i n a t e b e t w e e n m i c r o e m b o l i generated b y different surfaces. This chapter describes the d e v e l o p m e n t a n d feasibility testing of a C P F


system that has the p o t e n t i a l to satisfy these r e q u i r e m e n t s .

Experimental The apparatus for the CPF test consisted of a vertical column [polyvinyl chloride (PVC) tubing] of saline solution with a Plexiglass filter assembly connected to the bottom of the column (Figure 1). The filter assembly supported a nickel-plated filter containing regularly spaced square pores of 15 ± 2 μηι on a side (Buckbee-Mears Co.) across theflowchannel, and the filter assembly and bottom 30 cm of the column were

Figure 1. The CPF apparatus.



224


maintained at 37°C in a circulating water bath. A constant pressure difference was maintained across the filter by the fixed height of the saline solution column. To determine the embolic content of a blood sample, the blood was inserted into the bottom of the column, displacing the saline solution. A stopcock was then opened to allow flow through the filter. A custom-made, low-flow venturi flow meter was mounted in the column, and a sensitive differential-pressure transducer (Validyne Engineering Corp., DP-103/CD15-1383) and recorder monitored and recorded the flow rate. For the tests described here, the pressure across the filter was set at 40 mm mercury. By comparison, pressure driving forces across microvascular beds range from approximately 20 mm mercury across capillaries to 80 mm mercury across arteriole-venule systems (40). Biomaterial-induced microemboli were obtained as follows: V^-in. sheets of Plexi glass G (Du Pont), polystyrene (Dow Resin F70502.00), or polycarbonate (Lexan, General Electric Co.) were cut, drilled, and mounted into the parallel-disc config uration shown in Figure 2. The surfaces were soaked in ethanol (95% for the poly carbonate and polystyrene and 50% for the Plexiglass) for at least 24 h, and then in saline solution for 12-18 h at 37°C just prior to exposure to the blood samples. On the day of the experiment, 20 mL of whole blood was drawn into heparin (6 units/mL; Riker Laboratories) by venipuncture from normal healthy volunteers. The saline solution was removed from the parallel-disc apparatus, and 10 mL of blood was inserted between the discs. The top disc was then rotated at 200 rpm (shear rate range 0-1200 s ) for 15, 30, or 90 min, while the entire assembly was maintained at 37°C in a free-convection incubator. The space between the top disc and the collar was less than 2 mm, to minimize blood-air contact, and a cover over the discs (not shown in Figure 2) contained a water reservoir to humidify the air over the discs and prevent drying of the blood. The remaining 10 mL of blood were filtered in the C P F apparatus to obtain a control curve, and after the prescribed period of disc rotation, the blood from the parallel-disc system was transferred to the C P F apparatus for the test run. Fresh, previously unused discs were used for each test, and each type of material -1

Mounting Flange

Discs of Γ" Biomaterial or of Support Material for Coating

-Gap = 1.0mm. Figure 2. Parallel-disc apparatus for exposing blood to biomaterials.


16.

SOLEN AND BETTERIDGE


225

(Plexiglass, polystyrene, and polycarbonate) was tested twice in 15-min tests, four times in 30-min tests, and four times in 90-min exposures. In addition, each donor was used twice on the same day for the testing of two different materials, so that all possible pairs of materials were tested with blood from a single donor.


Results and Discussion T h e anticipated filtration c u r v e for m i c r o e m b o l i - l a d e n b l o o d is d e scribed as follows: T h e rate o f o b s t r u c t i o n o f the filter pores b y r i g i d particles would be —dnldt — cqn

(1)

w h e r e η is the n u m b e r o f u n b l o c k e d pores at a given instant; c, the concen tration o f particles i n the b l o o d that can occlude one pore each; q, the v o l u m e t r i c flow rate of b l o o d t h r o u g h an u n b l o c k e d pore; and t, the t i m e . T h e solution to E q u a t i o n 1 is (2)

n=n e0

cqt

w h e r e n is the total n u m b e r o f filter pores. T h e total flow rate at any instant is 0

Q=nq=n qe-

cqt

0

Q=Qoe~

cqt

(3) (4)

w h e r e Q is the total v o l u m e t r i c flow rate of b l o o d t h r o u g h the filter at a given instant a n d Q , the v o l u m e t r i c flow rate w h e n a l l the pores are u n b l o c k e d . 0

C o n t r o l b l o o d (freshly d r a w n a n d not exposed to the biomaterial discs) should exhibit a constant f l o w rate, w h i l e b l o o d f r o m the parallel-disc ex posure s h o u l d p r o d u c e an e x p o n e n t i a l filtration curve ( E q u a t i o n 4) f r o m w h i c h the "effective" concentration o f m i c r o e m b o l i can be d e t e r m i n e d f r o m a s e m i l o g plot o f f l o w rate vs. t i m e . F r e s h h e p a r i n i z e d b l o o d f r o m the d o n o r typically r e q u i r e d 4 - 5 s to reach a steady filtration rate, a n d t h e n e x h i b i t e d a relatively constant flow rate t h r o u g h the m i c r o p o r e filter d u r i n g the 1 0 - 1 5 s r e q u i r e d to filter the entire sample ( F i g u r e 3a). I n contrast, b l o o d that h a d b e e n exposed to the P l e x i glass, p o l y s t y r e n e , o r polycarbonate discs progressively o c c l u d e d the filter w i t h as m u c h as 9 8 % r e d u c t i o n i n flow b y the e n d o f 30 s (Figure 3b). A s e m i l o g plot o f flow rate vs. t i m e for the latter sample was typically linear w i t h excellent c o r r e l a t i o n ( F i g u r e 3c; correlation coefficients ranged f r o m 0.994 to 1.000 for the 30 tests), i n d i c a t i n g an exponential decline i n flow rate, as p r e d i c t e d b y the m o d e l j u s t d e s c r i b e d .



Figure 3. Typical results of the CPF test using a 15-am pore size filter and fresh heparinized human blood. Key: a, control blood; b, blood exposed to Plexiglass discs (shear rates: 0-1200 s ~*) for 90 min; and c, semilog plot of the flowrate from Curve b.


C/5

ο ζ

§

α >

> >

Μ

Ο

r *o χ η

>

2

22 >

w Ο

[2

16.



227

C o n c e n t r a t i o n s o f m i c r o e m b o l i w e r e calculated f r o m the slopes o f the s e m i l o g plots o f flow rate a c c o r d i n g to E q u a t i o n 4. T h e concentrations p r o d u c e d b y the three biomaterials w e r e not significantly different after 15 or 30 m i n o f b l o o d - b i o m a t e r i a l contact (Table I). H o w e v e r , after 90 m i n o f contact, each o f the three materials p r o d u c e d significantly different m i c r o e m b o l i concentrations (as d e t e r m i n e d b y a paired-difference analysis), even w i t h the Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 28, 2018 | https://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch016

small n u m b e r o f m e a s u r e m e n t s made (see Table I). T h e o r d e r o f increasing toxicity was polycarbonate < p o l y s t y r e n e < Plexiglass.

Conclusions T h e C P F flow rate curves consistently c o n f o r m e d to E q u a t i o n 4, w i t h correlation coefficients f r o m the s e m i l o g plots (see F i g u r e 3c) r a n g i n g f r o m 0.994 to 1.000 for the 30 curves generated. T h e r e f o r e , nearly the entire curve (with the e x c e p t i o n o f an i n i t i a l 4^5-s unsteady-state period) c o u l d b e used to calculate an effective c o n c e n t r a t i o n o f m i c r o e m b o l i . T h e calculation itself is s i m p l e a n d r e l i a b l e . Because o f the p r e l i m i n a r y nature of this study, w e d i d not use the steps of b i o m a t e r i a l surface p r e p a r a t i o n a n d characterization suggested as " L e v e l O n e " ( m i n i m u m level) tests b y two recent study groups o f the N a t i o n a l H e a r t , L u n g , a n d B l o o d Institute (41, 42). N e i t h e r b u l k n o r surface p r o p e r ties w e r e a n a l y z e d , a n d the surfaces w e r e not c o n f i n e d to a dust-free e n v i r o n T a b l e I. C P F Test Results f o r T h r e e B i o m a t e r i a l s Exposure Time (min) 90 90 90 90 90 90

30 30 30 30 30 30

15 15 15

Significance of Material Polycarbonate Differences'"

Blood Emboli/Milliliter Plexiglass

Polystyrene

J.B. VJ. B.B. R.N. V.W. V.B.

1112 1928

296 770 824 957

Ave. sem

1238 241

712 144

D.D. B.K. B.R. D.S. J.L. T.P.

217 76

263 396 923 132

Ave. sem

346 182

429 173

D.C. EH. N.C.

407

367 263

Ave. sem

314 93

Donor

1105 806

883 209

221

"Based on a paired-difference analvsis.

315 52

156 292 658 212

}

94.5%

}

99.9%

}

95.5%

330 113

290 54 320 162

J

Not Sig.

J

Not Sig.

J

Not Sig.

207 61 360 155 258 103


228


ment. H o w e v e r , each t y p e o f m a t e r i a l was p u r c h a s e d as a single batch to insure u n i f o r m i t y . A l s o , care was taken i n h a n d l i n g o f the surfaces to avoid contact w i t h any t y p e o f o i l or grease, a n d the surfaces w e r e soaked i n ethanol and saline s o l u t i o n to extract leachable i m p u r i t i e s . W i t h these m i n i m a l p r e cautions a n d w i t h t h e s m a l l n u m b e r s o f tests c o n d u c t e d , the differences b e t w e e n m i c r o e m b o l i p r o d u c t i o n b y t h e three types o f materials w e r e d e Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 28, 2018 | https://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch016

tected b y t h e C P F test a n d w e r e statistically significant after 90 m i n o f b l o o d - b i o m a t e r i a l contact. U s i n g greater precautions against c h e m i c a l vari ation a n d surface c o n t a m i n a t i o n w o u l d l i k e l y p r o d u c e results of greater u n i f o r m i t y a n d m o r e significance b e t w e e n test groups. T h e s e considerations strongly suggest that t h e C P F test has potential as a standard test to screen b i o m e d i c a l materials a n d devices, a n d to evaluate surface treatments i n terms of m i c r o e m b o l i p o t e n t i a l . Tests are n e e d e d (and are planned) to evaluate the effect of any b l o o d filter i n t e r a c t i o n o n t h e test results. E v e n t h o u g h freshly d r a w n b l o o d ex hibits constant f l o w t h r o u g h t h e f i l t e r ( F i g u r e 3a), b l o o d that has b e e n exposed to biomaterials (particularly i n h i g h surface/volume configurations) may b e m o r e " r e a c t i v e " a n d capable o f reacting as i n d i v i d u a l cells to f o r m t h r o m b i o n t h e f i l t e r d u r i n g t h e 30 s o f the test. Possible methods o f exam i n i n g this q u e s t i o n i n c l u d e m i c r o s c o p i c examination o f the filter d u r i n g the test a n d c o m p a r i s o n o f the test results w i t h and w i t h o u t a n t i t h r o m b o g e n i c filter

coatings. A vital e l e m e n t i n t h e establishment o f a standard measure of " p h y s i o

logically significant" m i c r o e m b o l i is t h e calibration o f the test w i t h p h y s i o logical systems. Tests are u n d e r w a y i n o u r laboratory i n w h i c h m i c r o e m b o l i laden b l o o d is p e r f u s e d t h r o u g h cat h i n d l i m b s u n d e r c o n t r o l l e d pressure. T h e r e s u l t i n g f l o w curves w i l l b e m o d e l e d , and microvessel b l o c k i n g w i l l b e c o m p a r e d w i t h f i l t e r b l o c k i n g b y t h e same b l o o d samples. F i l t e r pore size and filtration pressure may t h e n b e v a r i e d to match the C P F test character istics to t h e i n v i v o system. T h e net result w i l l b e a r a p i d , sensitive, i n v i t r o test to detect p h y s i o l o g i c a l l y significant b l o o d m i c r o e m b o l i .

Literature Cited 1. Carlson, R. G.; Lande, A. J.; Landis, B.; Rogoz, B.; Baxter, J.; Patterson, R. H., Jr.; Stenzel, K.; Lillehei, C. W. J. Thorac. Cardiovasc. Surg. 1973, 66, 894-904. 2. Dutton, R. C.; Edmunds, L. H., Jr.; Hutchinson, J. C.; Roe, Β. B.J.Thorac. Cardiovasc. Surg. 1974, 67, 258-265. 3. Gervin, A. S.; McNeer, J. F.; Wolfe, W. G.; Puckett, C. L.; Silver, D. J. Thorac. Cardiovasc. Surg. 1974, 67, 237-242. 4. Lande, A. J.; Carlson, R. G.; Patterson, R. H., Jr.; Baxter, J.; Lillehei, C. W. Trans. Am. Soc. Artif. Intern. Organs 1972, 18, 532-537. 5. Patterson, R. H., Jr.; Kessler, J. Surg. Gynecol. Obstet. 1969, 129, 505-510. 6. Simmons, E.; MaGuire, C.; Lichti, E.; Helvey, W.; Almond, C.J.Thorac. Cardiovasc. Surg. 1972, 63, 613-621. 7. Solis, R. T.; Kennedy, P. S.; Beall, A. C., Jr.; Noon, G. P.; DeBakey, M. E. Circulation 1975, 52, 103-108. 8. Bischel, M. D.; Orrell, F. L.; Scoles, B. G.; Mohler, J. G.; Barbour, Β. H. Trans. Am. Soc. Artif. Intern. Organs 1973, 19, 492-497. Cooper et al.; Biomaterials: Interfacial Phenomena and Applications Advances in Chemistry; American Chemical Society: Washington, DC, 1982.


16.



229

9. Peters, J. L.; McRea, J. C.; Fukumasu, H.; Kolff, W. J. Trans. Am. Soc. Artif. Intern. Organs 1976, 22, 357-366. 10. Moggio, R. Α.; Hammond, G. L.; Stansel, H. C., Jr.; Glenn, W. W. L. J. Thorac. Cardiovasc. Surg. 1978, 75, 296-299. 11. Jaques, L. B. In "Blood Coagulation, Hemorrhage, & Thrombosis;" Tocantins, L. M.; Kazul, L. Α., Eds.; Grune and Stratton: New York, 1964. 12. Bennett, S. H.; Aaron, R. K.; Geelhoed, G. W.; Hoye, R.; Solis, R. T.J.Surg. Res. 1972, 13, 295-306. 13. Connell, R. S.; Swank, R. L. Ann. Surg. 1973, 177, 40-50. 14. Jenevein, E. P., Jr.; Weiss, D. L. Am. J. Pathol. 1964, 45, 313-325. 15. McNamara, J. J.; Boatright, D.; Burran, E. L.; Molot, M. D.; Summers, E.; Stremple, J. F. Ann. Surg. 1971, 174, 58-60. 16. McNamara, J. J.; Burran, E. L.; Larson, E.; Omiya, G.; Suehiro, G.; Yamase, H. Ann. Thorac. Surg. 1972, 14, 133-139. 17. Moseley, R. V.; Doty, D. B. Ann. Surg. 1970, 171, 329-335. 18. Solis, R. T.; Gibbs, M. B. Transfusion 1972, 12, 245-250. 19. Solis, R. T.; Goldfinger, D.; Gibbs, M. B.; Zeller, J. A. Transfusion (Philadel phia) 1974, 14, 538-550. 20. Solis, R. T.; Noon, G. P.; DeBakey, M. E. Trans. Am. Soc. Artif. Intern. Organs 1974, 20, 499-503. 21. Swank, R. L. N. Eng. J. Med. 1961, 265, 728-733. 22. Branthwaite, M. A. Thorax 1972, 27, 748-753. 23. Brennan, R. W.; Patterson, R. H., Jr.; Kessler, J. Neurology 1971, 21, 665-672. 24. Lee, W. H., Jr.; Brady, M. P.; Rowe, J. M.; Miller, W. C. Ann. Surg. 1971, 173, 1013-1023. 25. Witoszka, M. M.; Tamura, H. J.; Indeglia, R.; Hopkins, R. W.; Simeone, F. A. J. Thorac. Cardiovasc. Surg. 1973, 66, 855-864. 26. Kusserow, B.; Larrow, R.; Nichols, J. Trans. Am. Soc. Artif. Intern. Organs 1970, 16, 58-62. 27. Bruck, S. D. Ann. Ν.Y. Acad. Sci. 1977, 283, 332-355. 28. Kessler, J.; Patterson, R. H. Ann. Thorac. Surg. 1970, 9, 221-228. 29. Solis, R. T.; Wright, C. B.; Gibbs, M. B. J. Appl. Physiol. 1975, 38, 739-744. 30. Dewitz, T. S.; Martin, R. R.; Solis, R. T.; Hellums, J. D.; McIntyre, L. V. Microvasc. Res. 1978, 16, 263-271. 31. Dutton, R. C.; Edmunds, L. H., Jr., J. Thorac. Cardiovasc. Surg. 1973, 65, 523-530. 32. Swank, R. L.; Roth, J. G.; Jensen, J. J. Appl. Physiol. 1964, 19, 340-346. 33. Ashmore, P. G.; Svitek, V.; Ambrose, P. J. Thorac. Cardiovasc. Surg. 1968, 55, 691-697. 34. Ashmore, P. G.; Swank, R. L.; Gallery, R.; Ambrose, P.; Prichard, Κ. H. J. Thorac. Cardiovasc. Surg. 1972, 63, 240-248. 35. Rittenhouse, Ε. Α.; Hessel, Ε. Α.; Ito, C. S.; Merendino, K. A. Surg. Forum 1970, 21, 142-144. 36. Rittenhouse, Ε. Α.; Hessel, Ε. Α.; Ito, C. S.; Merendino, K. A. Ann. Surg. 1972, 175, 1-9. 37. Solen, Κ. Α.; Whiffen, J. D.; Lightfoot, Ε. N. J. Biomed. Mater. Res. 1978, 12, 381-399. 38. Solen, Κ. Α.; Whiffen, J. D.; Lightfoot, Ε. N. Biomat. Med. Dev. Artif. Org. 1980, 8, 35-48. 39. Solen, Κ. Α.; Whiffen, J. D.; Lightfoot, Ε. N. J. Lab. Clin. Med. 1981, 98, 206-216. 40. Burton, A. C. "Physiology and Biophysics of the Circulation"; Yearbook Med.: Chicago, 1965; p. 87. 41. Keller, Κ. H. "Final Report of the Working Group on Physiochemical Character ization of Biomaterials to the National Heart, Lung, and Blood Institute, National Institutes of Health," 1979. 42. Mason, R. G. "Final Report of the Working Group on Blood-Material Inter actions to the Devices and Technology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health," 1979. RECEIVED for review January 16, 1981. ACCEPTED October 6, 1981.


Flow-Resistant Blood Microemboli - American Chemical Society

Recommend Documents