Science - iacld.ir · PDF filehematology analyzer we tested met the basic requirements for use ... 3Wyle Science, Technology and Engineering, ... Most hematology analyzers

304 Lab Medicine Fall 2013 | Volume 44, Number 4 www.labmedicine.com

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Effects of Spaceflight on the Human BodyConditions during spaceflight cause many adverse health effects in humans, including loss of bone density and muscle strength due to hypokenesis and altered cardiac function due to significant fluid redistribution. The risk of cancer also increases with prolonged radiation expo-sure. Recent evidence1-3 indicates that immune function is altered during spaceflight; causal factors may include crewmember stress, isolation, altered nutrition, and/or disrupted circadian rhythms. Also, microgravity may have a direct effect on T-cell activation due to altered trans-duction of intracellular signals.4 Microgravity is defined

as the near zero-gravity environment of low-Earth orbital spaceflight. While orbiting the Earth, gravity still exerts most of its downward force (surface, 9.8 m/s2; Earth orbit, 9.0 m/s2). However, beyond the influence of atmospheric drag, orbital flight balances the force of gravity on the spacecraft by an outward force created by the tremen-dous speed of the craft as it circles the Earth (~27,359km/hr). This balance is defined as microgravity because it is not technically zero gravity (although objects still appear to float).

Crewmembers in spaceflight are also exposed to envi-ronmental dangers such as toxins that may accumulate in the closed environment and increased reactivation and shedding of latent herpes viruses.5,6 During Earth orbital flight, however, crews have remained in generally good health because countermeasures such as exercise, im-proved diet, and fluid intake offset bone and muscle loss to a certain extent. Immune system alterations during orbital flight do not usually result in clinical disease. How-ever, the health risks associated with spaceflight gener-ally increase as the mission length increases. One of the primary objectives of the International Space Station (ISS) is to investigate the medical consequences of prolonged spaceflight and develop and validate countermeasures necessary to enable deep-space missions beyond Earth orbit. A long-term goal of the United States space pro-gram is to develop heavy-lift rocket capabilities and crew vehicles that can enable exploration of near-Earth aster-oids, the moon, and Mars.

ABSTRACTSpaceflight has adverse effects on the human body that pose health risks to astronauts spending extended time in space missions. For clinical monitoring of astronauts and for in-flight biomedical research, laboratory instruments must be available in the spaceflight environment. Currently, no instrument has been shown to be capable of generating a white blood cell (WBC) count and differential during spaceflight to our knowledge, although this is a medical requirement of the National Aeronautics and Space Administration (NASA). We

evaluated a compact hematology analyzer for compatibility with a zero-gravity environment. We performed analyses in reduced-gravity during parabolic flight. Herein, we describe our engineering evaluation and report the reduced-gravity validation data we collected. The hematology analyzer we tested met the basic requirements for use in spaceflight and should be capable of accurately measuring WBC parameters aboard the International Space Station.

Keywords: spaceflight, hematology analyzer

DOI: 10.1309/LMD3THAYCHICF2XT

AbbreviationsISS, International Space Station; WBC, white blood cell; NASA, National Aeronautics and Space Administration; CCD, charge-coupled device; EDTA, ethylenediaminetetraacetic acid; CBC, complete blood cell; CLIA, Clinical Laboratory Improvement Amendments; IR&D, Internal Research and Development

1National Aeronautics and Space Administration (NASA)-Johnson Space Center, Houston, Texas, 2JES Tech, LLC, Houston, Texas3Wyle Science, Technology and Engineering, Houston, Texas4Universities Space Research Association, Houston, Texas

*To whom correspondence should be addressed. E-mail: [email protected]

A Miniaturized Analyzer Capable of White-Blood-Cell and Differential Analyses During SpaceflightBrian Crucian, PhD, MT(ASCP),1* Heather Quiriarte, BS,2 Terry Guess, BE,3 Robert Ploutz-Snyder, PhD,4 Kathleen McMonigal, MD,1 and Clarence Sams, PhD1

4-Science_Fall.indd 304 10/7/13 5:09 PM

www.labmedicine.com Fall 2013 | Volume 44, Number 4 Lab Medicine 305

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Laboratory Instruments and Spaceflight To enable medical monitoring of crewmembers and to perform basic clinical research, medical laboratory instru-ments are required aboard the ISS. However, very few laboratory instruments are currently deployed on the ISS because of technical constraints. The iSTAT Portable Clini-cal Analyzer (Abbott Laboratories, Abbott Park, IL) and a portable ultrasound imaging device have been flown successfully as scientific payloads. No other diagnos-tic medical instruments are currently available for use in spaceflight; most laboratory instruments are incompatible with spaceflight conditions. Most hematology analyzers and flow cytometers are large and heavy, have significant power requirements, use large amounts of reagents, and generate significant amounts of biohazardous waste. In-strument fluidics may be altered in microgravity; an exam-ple is the laminar flow/hydrodynamic focusing used in flow cytometers.7 These properties are potentially incompatible with spaceflight, although it should be possible to reengi-neer some laboratory instruments to achieve compatibility with spaceflight.8

Without clinical laboratory instruments, medical research onboard the ISS may be performed on specimens col-lected during flight but returned for terrestrial analysis. This pushes to capacity the storage space requirements aboard space vehicles returning to Earth, which have been extremely limited in the post-Shuttle era. Frozen samples can be collected at any time and stored on the space sta-tion before they return to earth for use. To return ambient, live blood samples, the samples can only be collected right before undock, and immediately returned. It is highly desir-able to have instruments for in-flight medical and research requirements. To our knowledge a suitable instrument for measuring white blood cell (WBC) count or differential dur-ing spaceflight has not been identified. The ability to obtain a WBC count is an unmet National Aeronautics and Space Administration (NASA) medical requirement during space-flight9 because no available analyzer has been validated for use in the unique environment of spaceflight.

To be adaptable to spaceflight conditions, a laboratory instrument must be small, use minimal power, require little or no maintenance, use minimal liquid reagent, generate minimal liquid biohazardous waste, and have a mechani-cal design that is robust and vibration tolerant. It is desir-able for reagents to be stable at room temperature for prolonged periods of time since refrigerated storage is

severely limited. The user interface should be simple and intuitive, and analysis time must be rapid. Crew time in orbit is very limited; crews routinely perform several pro-cedures at once. Most laboratory instruments do not meet these requirements.

Prototype In-Flight WBC AnalyzerRecently, a novel WBC/differential analyzer (WBC-DIFF) was developed by Hemocue, Inc. (Brea, CA, Image 1). This device is small (~6.0 × 6.0 ×7.5 inches), can operate on battery power, and does not use liquid reagents. Instead, a 10-μl blood sample is aspirated into a cuvette contain-ing a lysing reagent and a nuclear staining dye (Image 2). The cuvette is inserted into the instrument, and a charge-coupled device (CCD) camera captures an image of the specimen, producing a WBC and differential via nuclear morphology. The analysis takes approximately 3 minutes and 20 seconds. NASA occasionally uses commercially available equipment to support in-flight requirements, sometimes with no or minimal modifications. In most cases, commercially developed instruments have been extensively validated as a prerequisite for clinical use. Although de-signed for use in small laboratories and physicians’ offices, we identified the WBC-DIFF analyzer as being potentially compatible with spaceflight because it met most of the re-quirements previously described.

According to the technical specifications available from Hemocue, Inc, the instrument works within a range of 0.3 to 30.0 ×109 WBC/L; counts above or below this range generate an error message. The clinical validation of this instrument was described by Osei-Bimpong et al,10 who found that its results did not vary by greater than 5.0% ver-sus an automated hematology analyzer (Beckman Coulter Inc, LH-750, Brea, CA). Linearity within the detection range was verified. The accuracy of the WBC-DIFF was validated using 500 blood specimens spanning the detection range; less than 10% deviation from the reference method was observed and no bias was evident at the low or high ends of the line arrange. The authors noted that artificially ele-vated WBC counts were observed in certain clinical condi-tions (eg, sickle-cell disease and thalassaemia major); the WBC-DIFF did not alert the user to these results.10

In 2012, we obtained a NASA Human Health and Perfor-mance Directorate innovation grant to the Immunology Laboratory of the Johnson Space Center, Houston, TX, to



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A BImage 1

White blood cell and

differential blood cell ana-

lyzer by Hemocue, Inc.

(Brea, CA). A, Exterior

views. B, Interior views.

Image 2

Sampling cuvette for the Hemocue, Inc. (Brea, CA) white blood cell (WBC-DIFF) analyzer. A, The cuvette is designed to aspirate a

finger-stick sample. B, After collection, a lysing reagent lyses the red-blood-cell population within the optical scanning area. C, The

cuvette also contains a DNA dye that stains the WBC nuclei (original magnification, ×20). We used nuclear morphology to resolve the

various WBC subsets.

A B

C



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evaluate the WBC-DIFF for use in spaceflight. In this study, we purchased and evaluated a WBC-DIFF instrument, performed cursory validation to confirm the performance of the instrument, and undertook an engineering evaluation under spaceflight conditions, followed by a reduced-grav-ity evaluation aboard a NASA parabolic-flight aircraft.

Materials and Methods

Samples

Venous blood samples from healthy subjects were col-lected in ethylenediaminetetraacetic acid (EDTA) anticoag-ulant tubes and stored at room temperature until analysis. For the engineering evaluation, 8 test subjects participated in the confirmatory terrestrial comparative studies and 2 other subjects participated in the reduced-gravity evalua-tion. Parallel finger-stick blood samples were collected via lancet into WBC/differential microcuvettes (Hemocue, Inc.) according to the manufacturer’s instructions. Except where indicated (ie, in a sample-stability time-course study), all finger-stick samples were analyzed within 10 minutes of collection.

InstrumentsFor the reference method, we performed analysis of ve-nous blood samples in a College of American Pathologists (CAP)–certified clinical laboratory with a Coulter LH-750 hematology analyzer (Beckman Coulter Inc, Brea, CA). Test data were obtained by analyzing venous or finger-stick samples on the WBC-DIFF. The WBC-DIFF instrument generates an absolute WBC count and calculates percent-ages of neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

Comparison StudiesStatistical analyses were performed by Stata IC software (version 12.1, StataCorp LP, College Station, TX) using the 2-tailed alpha and a threshold of statistical significance of P <0.05. We used the concordance correlation coef-ficient (ρ) reported by Lin11,12 to evaluate agreement among measurements of WBC, granulocytes, lymphocytes, eosinophils, basophils, and monocytes by the reference hematology analyzer and the WBC-DIFF device. We also evaluated agreement between analyses of venous blood and finger-stick specimens. We calculated the mean dif-ferences between measures taken with the WBC-DIFF

device versus those taken using the reference analyzer, and between venous and finger-stick specimens; we report the 95% limits of agreement of these differences.13

Results

Laboratory Validation

Although extensive validation data for the WBC-DIFF is available from its manufacturer, we performed basic vali-dation studies in our laboratory on the delivered unit. In venous blood samples, we found the results generated by the WBC-DIFF to be reasonably comparable to the refer-ence hematology analyzer results for all measured parame-ters except monocytes (Figure 1). The statistical measures of concordance (SE) were as follows: WBC, .90(.07); granulocytes, .91(.07); lymphocytes, .87(.07); eosinophils, .94(.04); basophils, .60(.16); and monocytes, -.27(.18). Aver-age differences (SD) between the reference and WBC-DIFF measurements were WBC: .11(.38); granulocytes: .25(3.20); lymphocytes: -3.63(1.06); eosinophils: .21(.70); basophils: .11(.30); and monocytes: 2.66(2.97). Using only the WBC-DIFF analyzer, we evaluated the concordance between venous and finger-stick blood specimens. The results of these studies are summarized in Table 1. The findings agree with a published report14 that demonstrated finger-stick blood is an acceptable sample type for complete blood cell (CBC) measurements. We evaluated the stability of specimens in filled cuvettes over time; this may also be an indicator of intra-cuvette precision. Using a finger-stick sample, the filled cuvettes were stable for approximately 30 minutes. Errors due to evaporation of specimen from the filled cuvettes became significant after longer periods. Cuvette stability data are presented in Image 3.

Engineering EvaluationWe performed an engineering evaluation of the WBC-DIFF for compatibility with requirements for flight hardware and the possibility of engineering improvements to size or power consumption. The instrument has minimal unused internal space (Image 1). On loading a filled cuvette onto the plastic holder, the holder is manually moved along a guide into the view of the CCD camera. During movement, 2 magnets hold the sample in place and then immobilize the sample in the view of the camera; we found this to be an optimal sample-handling method for reduced-gravity



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Concordance correlation coefficient (ρ) evaluation of agreement of blood-outcome measures between the WBC-DIFF (x-axis) and stan-

dard methodology (y-axis). White blood cell levels are expressed as 103 cells/mL; relative percentage data are plotted for all other mea-

sures. The standard instrument for comparison was the Coulter LH-750 hematology analyzer (Beckman Coulter Inc, Brea, CA).



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operations. For zero-gravity evaluations, we determined that only minor modifications to affix the cuvette within the holder were required, which we accomplished by simply adding adhesive material to the cuvette-holding area. We determined that no other engineering changes were re-quired for our reduced-gravity evaluation.

Evaluation of hardware in reduced gravity is possible in a parabolic flight aircraft (Image 4). A NASA jet flies in a parabolic arc; a 30-second zero-gravity period is produced at the peak of the parabola, whereas a 2G force (twice the normal gravitational force) is generated at the bottom of the parabola. Many parabolic paths are flown in a repeated sequence to facilitate zero-gravity testing. In this evalu-ation, we successfully collected a series of finger-stick

blood specimens into reagent cuvettes during the zero-gravity phase of the flight (Image 5). To determine whether the analyzer was sensitive to gravitational effects, we per-formed analyses during parabolic flight. However, because the instrument requires more than 3 minutes to generate a result, it was not possible to restrict analysis to within the zero-gravity phase of flight. Therefore, we initiated the analytical cycle at the beginning of a parabolic path and allowed the analysis to continue to completion (Image 4). The analysis took place during a series of 3 consecutive zero-to-2G phases, with no intervening 1-fold (ie, normal) gravity-contamination condition. We conclude that a suc-cessful operation, spanning zero-gravity and 2G phases of flight, indicates that the instrument (which was continually analyzing images during the 3-minute analysis period) is

Table 1. Concordance Correlation Coefficient Evaluation (ρ) to Determine Agreement of Blood-Outcome Measures Between Venous and Fingerstick Measurements Using Only the WBC-DIFFa

Variable ρ SE Mean (SD) Difference 95% Limits of Agreement

WBC count .43 .32 .16 (1.09) –1.98 2.31Basophils .31 .26 –.43 (.45) –1.31 .45Eosinophils .80 .13 .63 (1.22) –1.76 3.01Granulocytes .78 .12 4.50 (3.51) –2.37 11.37Lymphocytes .87 .09 –2.63 (2.97) –8.45 3.20Monocytes .03 .17 –1.25 (1.19) –3.59 1.09 WBC, white blood cell. an=8; Hemocue, Inc (Brea, CA).

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Data indicating stained and lysed blood samples remain stable

within the WBC-DIFF reagent cuvette for approximately 30 min-

utes. Analysis was performed via the WBC-DIFF instrument.

A, Representative subject data from analysis immediately after

collection (0:00) to analysis at +45 minutes after collection. Note

that the instrument was able to generate a white blood cell (WBC)

count after the loss of differential resolution. Stability varies, and

it is suggested that analysis take place immediately following

sample collection. The primary reason for loss of sample integrity

is desiccation of the filled cuvettes (B).

WBC, white blood cell; neut, neutrophils; lymph, lymphocytes;

mono, monocytes; eos, eosiniphils; basos, basophils.



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Image 5

Finger-stick blood sample collection during zero-gravity

phase of parabolic flight.

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Image 4

Zero-gravity evaluation of the WBC-DIFF, which took place aboard

a National Aeronautics and Space Administration (NASA) parabolic

flight aircraft. A, Aircraft. B, Coauthor performing analysis. This air-

craft generates approximately 30 seconds of zero gravity by flying

in a parabolic arc. Because analysis takes longer than 30 seconds

to complete, analysis spanned repeated zero-gravity and 2-fold

gravity parabolas C, Graph showing the effects of hypogravity and

hypergravity, which were determined simultaneously.

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capable of functioning properly in either gravity condition. Data from 2 separate flights, with 1 test subject evaluated per flight, were collected. Control data at normal gravity was generated during level aircraft flight. Our data indi-cated that the WBC-DIFF functioned properly in normal, zero-, or 2-fold gravity conditions (Figure 2).

Study LimitationsThis study was the first evaluation of a hematology instru-ment for use aboard the ISS. The evaluation was necessar-ily limited because of the unique conditions under which the instrument would have to operate. Validation of a new instrument or method would be comprehensive, conform-ing to CAP or Clinical Laboratory Improvement Amend-ments (CLIA) standards. Typical validation studies involve hundreds of parallel measurements on both the candidate and the reference instrument, along with studies to estab-lish a normal range, confirm the sensitivity and linearity of measurements, and assess potential interferences. A ben-efit of using commercial technology (in this case, an FDA-approved method) is that extensive validation studies have already been performed by the manufacturer. However, these validation data do not entirely replace in-laboratory validation of a new instrument in the environment where the instrument will be operated. The WBC-DIFF instru-ment was assessed for use aboard the ISS. It would not be feasible to deploy the instrument to the ISS and perform the full spectrum of validation studies to comply with CAP/CLIA requirements. The primary goal for this study was to conduct engineering and microgravity evaluations of this instrument to determine its suitability for use in spaceflight. We considered the instrument size, power consumption, vibration tolerance, reagent stability, and reliable function in microgravity. In this report, we cited existing validation data

and performed a basic check of the analyzer. Limitations also exist regarding the availability and cost of the para-bolic-flight microgravity evaluation opportunities: only 1 aircraft exists in the United States that supports this flight profile. Each flight consists of 30 parabolas, each contain-ing approximately 25 seconds of microgravity time. Only 2 flights were available for this study, which was a severe limiting factor. Therefore, we developed an optimization strategy that allowed photographic and video recording of finger-stick sample collection during the microgravity phase for multiple operators. We collected microgravity and terrestrial hardware evaluation data for a single test subject on each flight. Although a normal terrestrial instru-ment evaluation would evaluate a significantly greater num-ber of test subjects, we were able to achieve a successful microgravity evaluation within these constraints.

DiscussionThe recently developed WBC-DIFF hematology analyzer is miniaturized, robust, and has an appropriate amount of reagent storage to satisfy the requirements of space-flight (eg, microgravity compatibility, size, minimal power consumption). This instrument is available for clinical use in Europe; however United States Food and Drug Admin-istration (FDA) approval is currently pending. In this study, a limited validation assessment versus a standard hema-tology instrument yielded mostly acceptable correlations; however, monocyte percentages measured by the evalu-ation unit were significantly different from measurements made on the reference analyzer (Figure 1). Studies are currently underway aboard the ISS to characterize space-flight-associated immune dysfunction. Currently it is not known whether specific cellular populations are altered in peripheral blood or have altered functional characteristics.

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Representative single-subject data from the WBC-DIFF. The

instrument yielded acceptable data when analysis spanned the

zero-gravity and 2-fold gravity conditions (in flight), compared

with the normal-gravity control data. Two separate analyses are

shown for flight conditions, 1 of which covered the normal-gravity

control condition.

WBCs, white blood cells; grans, granulocytes; lym, lymphocytes;

mono, monoctyles; eos, eosiniphils; basos, basophils.



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Although it may be important to monitor all WBC subpop-ulations, use of the WBC-DIFF for measuring the WBC and certain differential parameters has value. Given the current absence of in-flight hematology capabilities, the parameters validated in this instrument would augment current capabilities. Before selection of the WBC-DIFF for spaceflight, we anticipate that FDA approval and a full validation of the differential capabilities of the instrument would be required.

Using the WBC-DIFF analyzer only, finger-stick samples produced results generally similar to those from venous blood samples (Table 1), in agreement with literature previously published study.14 As validated in the current study, the WBC-DIFF instrument is able to perform anal-yses in a zero-gravity environment (Image 2). For all pa-rameters except monocyte percentages, we consider this instrument to be acceptable for use during spaceflight.

The primary goal of this study was to determine whether this WBC-DIFF instrument is capable of functioning in reduced gravity. NASA requires further engineering eval-uations before actual deployment to the space vehicles, possibly including tests of radiation tolerance, electro-magnetic emissions, release of any toxic compounds into the environment, and sensitivity to vibrations. Vibra-tion tolerance is a particular concern in the launch phase of deployment. Modifications to any candidate devices may be implemented to improve performance in any of these areas of concern. For example, vulnerable com-ponents such as lenses and mirrors may be additionally secured, circuit boards may be coated, and heat trans-fer may be improved by ventilation or fans. The results of our evaluation indicate that the WBC-DIFF instrument is suitable for performing WBC counts and certain dif-ferential components aboard the ISS. The instrument is small, uses minimal power, and delivers rapid results. Reagents (ie, very small cuvettes) are stored in desic-cated packaging and do not require refrigeration. There-fore, the reagents should be stable during the time frame required for space missions, and we would anticipate them to be relatively insensitive to increased radiation levels. Deployment of this analyzer would address a currently unmet need in orbit and enhance crew health and safety. It is appropriate to use the ISS as a test plat-form for development of this technology before its use on deep-space missions. Currently, the Human Health Countermeasures Element of NASA’s Human Research Program is investigating the requirements to flight certify the WBC-DIFF analyzer for a demonstration aboard the ISS. LM

AcknowledgmentsThe authors thank the NASA-Johnson Space Center (JSC) Internal Research and Development (IR&D) Program for funding this study, the JSC Clinical Laboratory for provid-ing control data, and the JSC Reduced Gravity Office for facilitating the parabolic-flight opportunity.

References 1. Williams D, Kuipers A, Mukai C, Thirsk R. Acclimation during

space flight: effects on human physiology. Can Med Assoc J. 2009;180(13):1317-1323.

2. Gueguinou N, Huin-Schohn C, Bascove M, et al. Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth’s orbit? J Leukoc Biol. 2009;86(5):1027-1038.

3. Crucian B, Sams C. Immune system dysregulation during spaceflight: clinical risk for exploration-class missions. J Leukoc Biol. 2009;86(5):1017-1018.

4. Boonyaratanakornkit JB, Cogoli A, Li CF, et al. Key gravity-sensitive signaling pathways drive T cell activation. FASEB J. 2005;19(14):2020-2022.

5. Wilson JW, Ott CM, Höner zu Bentrup K, et al. Space flight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq. Proc Natl Acad Sci U S A. 2007;104(41):16299-16304.

6. Cohrs RJ, Mehta SK, Schmid DS, Gilden DH, Pierson DL. Asymptomatic reactivation and shed of infectious varicella zoster virus in astronauts. J Med Virol. 2008;80(6):1116-1122.

7. Crucian B,Norman J, Brentz J, Pietrzyk R,Sams C. Laboratory outreach: student assessment of flow cytometer fluidics in zero-gravity. Lab Med. 2000:31(10):569-573.

8. Crucian B, Guess T, Quiriarte H, Sams C. Flow Cytometry in Space: To help mitigate risk to astronauts, spaceflight-compatible clinical laboratory instruments must be developed. ADVANCE Healthcare Network for Laboratory Web site. http://laboratory-manager.advanceweb.com/Features/Articles/Flow-Cytometry-in-Space-Part-1.aspx. Accessed September 3, 2013.

9. NASA Space Flight Human System Standard–Volume 1: Crew Health (NASA-STD-3000 and JSC 26882). Space Flight Health Requirements Document. 2009;Vol. 1, Chap. 7.

10. Osei-Bimpong A, Jury C, McLean R, Lewis SM. Point-of-care method for total white cell count: an evaluation of the HemoCue WBC device. Int J Lab Hematol. 2009;31(6):657-664.

11. Lin LI-K . A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989;45:255-268.

12. Lin L. A note on the concordance correlation coefficient. Biometrics.2000;56:324-325.

13. Bland, JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307-310.

14. Rao LV, Moiles D, Snyder M. Finger-stick complete blood counts: Comparison between venous and capillary blood. Point of Care. 2011;10:120-122.

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Science - iacld.ir · PDF filehematology analyzer we tested met the basic requirements for use ... 3Wyle Science, Technology and Engineering, ... Most hematology analyzers