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1 July 2008 In vivo detection of reduced scattering coefficient of C6 glioma in rat brain tissue by near-infrared spectroscopy
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Abstract
The purpose of this study is to investigate the reduced scattering coefficient of C6 glioma by the near-infrared (NIR) technique. Light scattering properties of C6 glioma in brain tissue is measured by NIR spectroscopy within the wavelength range from 700 to 850 nm. C6 gliomas were implanted in rats' right brains. The scattering properties of the left and right target corresponding to the position of normal and tumor tissue were measured by a bifurcated needle probe on postoperative days 3, 10, and 17. The results show that there was no significant difference in reduced scattering coefficient between left and right brain tissue at postoperative day 3, but significant decreases were found between left and right brains at postoperative days 10 and 17. This study proved our initial hypothesis that the NIR technique may have a potential for clinical application in brain µglioma diagnosis.

1.

Introduction

Gliomas are a group of multiform, accumulative tumors that appear in the neuroectoderm. They generally induce perifocal edema and a massive increase of intracranial pressure for their compression, infiltration, and destruction on brain tissues. The C6 rat intracerebral glioma model is prevalent in glioma research for its good growth yields and low mortality rate. Perifocal inflamed symptoms and neonatal blood vessels occur at postoperative day (POD) 5. On POD 10, tumors increase highly in size with cellular exponential growth. During days 15–20, tumors reveal malignant gliomas with intratumoral hemorrhage and necrosis.1, 2, 3, 4

Presently, near infrared spectroscopy is used widely in the differentiation tissue types.5, 6 It is known that near-infrared (NIR) light in the 700850nm wavelength range is special to tissues as light scattering is more prominent than light absorption. There is a significant difference in light-scattering properties between different tissue types and between healthy and diseased tissues due to their differences in anatomical substructure; cellular and intracellular organelles of diseased tissues undergo changes in their density, morphological size, and shape.6, 7, 8, 9 In this study, an effort was made to develop NIR technology as an alternate method for detection of certain characteristics of glioma.

The aim of this study is to determine the light-scattering patterns from rat cerebral glioma by using NIR reflectance spectroscopy. The C6 gliomas were induced in Sprague-Dawley rats (SD) by the stereotactic implantation technique.10 It has been reported that tumors generally have a lower scattering coefficient measured in vitro than normal tissue.7, 9 Therefore, for this study, our hypothesis is that gliomas will lead to a decrease in light scattering of the brain and can be differentiated by the in vivo NIR measurement.

2.

Materials and Methods

2.1.

Cell Cultivation

The C6 glioma cells were grown in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, 50μgmL streptomycin, and 50UmL penicillin. Cells were maintained in an incubator with 5%CO2 , 100% humidity at 37°C . Before implantation to the rat brain, cells growing in an exponential rate were harvested by Trypsin for 5min at 37°C . Trypsin was inactivated by medium with 10% FCS, and the cells centrifuged at 600g for 5min . The pellets were then resuspended in RPMI 1640 medium without any supplement, at a concentration of 106cellsμL . Gentle manual agitation was applied to keep the cells in suspension before implantation.

2.2.

Implantation Surgery

Thirty adult male Sprague-Dawley rats ( 230280g , Southeast University vivarium) were used in this study. The animals were kept in their habitual environment untill the day of the experiment. All animals were anesthetized with 4% Nembutal ( 40mgkg , i.p.) and mounted into a stereotactic frame (incisor bar 2.4mm below the interaural line) in a flat-skull position. After the periosteum was unmasked, two burr holes were performed with a 1mm dental drill in the calvaria, respectively, on the left and right sides, 3mm lateral from the midline, 1mm posterior to the bregma. Suspension (10μL) with 1×106 C6 glioma cells were stereotactically injected at a depth of 5mm , by a 25μL microamount syringe (the syringe was pricked 6mm depth, and then was drawn 1mm back) on the right side. The same volumes of sodium chloride were injected at the same depth on the left side. The holes were sealed with bone wax, and the operative field washed with saline solution and the skin sutured. The body temperature was maintained at 37±0.5°C using a homeothermic heating pad throughout the experiment. All the experimental procedures follow the institutional guidelines and were approved by the Southeast University, China.

2.3.

NIRs and Experiments

NIR spectroscopy (NIRS) experiments were performed on POD 3, 10, and 17 with 10 rats each time. The homebuilt NIRs experimental system11 includes a light source (HL-2000, Ocean Optics, Inc., Dunedin, FL), a bifurcated needle probe ( 600μm o.d. with two single mode fibers of 100μm ), a spectrometer (USB 2000, Ocean Optics, Inc.), step motor and its driver system, a laptop, as shown in Fig. 1 . The bifurcated needle probe is composed of two branches. One branch is connected to the light source and the other to the spectrometer. The backscattered intensity of light depends strongly on the absorption and scattering properties of the tissue. The optic fiber probe was held perpendicularly above the exposed calvaria surface and mounted on a step motor, which was attached to a stereotaxic frame. This step motor drives the fiber probe deep into the brain at an interval of 0.2mm .

Fig. 1

Diagram of the NIRS system for measurements on brain tissue. 15W halogen lamp as the light source. 2—Optic probe containing two silica fibers. 3—USB2000 spectrometer. 4—Computer and software. 5—MID-7604 driver. 6—PCI-7344 controller and step motor, a—the point of implant hole and the projection C6 glioma and b—symmetric point in the contralateral skull.

044003_1_032804jbo1.jpg

For data acquisition, LabView (National Instruments, Austin, TX) was used to program the interface between the spectrometer and the computer. The integration time, which was taken by the detector to read out the intensity of backscattered light, was kept constant at 100ms during the entire set of measurements. The measurements were taken on the left and right brain. On each side, 40 steps in each brain side were measured, starting from the cortex with a spatial interval of 0.2mm . The data were recorded for a period of 10s at 2Hz at each step.

2.4.

Calculating the Reduced Scattering Coefficient

The reduced scattering coefficient (μs) serves as an index for the light-scattering property of the tissue. In principle, the intensity of backscattered light highly depends on light-scattering features of the tissue. Johns 5 had found the slopes of reflectance spectra curves between 700 and 850nm could be used to differentiate cerebral gray matter and white matter. Qian 11 established a relationship among the reduced scattering coefficient, the profiles of the collected spectra from 700to850nm , and the wavelength. In this study, an empirical formula between the reduced scattering coefficient and the slope between 700 and 850nm was deduced by simulation experiment for the NIRs system before the rat experiments.

An intralipid solution of 8, 6, 4, 2, and 1% concentrations were chosen in the simulation experiment because these solutions yield light-scattering properties similar to those found in human tissues. The reduced scattering coefficients of these tissue simulation solutions (intralipid) were acquired by a standard Oximeter (model no. 96208, ISS, Inc., Illinois) working at 690 and 834nm . At the same time, the reflectance spectra of these solutions were collected by the fiber-optic spectrometer of the NIRs system. Figure 2 shows the slopes and the relative reduced scattering coefficients.

Fig. 2

The reduced scattering coefficients from tissue simulation solution (intralipid) at 690 and 834nm are shown with their slopes calculated from collected spectra of the same solutions. The coordinates of the y axis are μs , and the coordinates of the x axis are the slopes.

044003_1_032804jbo2.jpg

The relationship between the slopes and the reduced scattering coefficients is obtained by the data fitting. Thus, an empirical formula for calculating the reduced scattering coefficient is derived as

Eq. 1

μs690=4.5203exp(0.3241*slope)

Eq. 2

μs834=4.4645exp(0.3103*slope).
The reduced scattering coefficients of intralipid solution measured by the Oximeter and calculated by Eqs. 1, 2 and their differences are showed in Table 1 , where the difference is equal to values calculated by the equations minus values measured by the Oximeter.

Table 1

The reduced scattering coefficients of intralipid solution measured by Oximeter and calculated by Eqs. 1, 2 and their differences.

% IntralipidsolutionconcentrationSlope μs690′ (cm−1) μs834′ (cm−1)
Oxi-meterEq.1DifferenceOxi-meterEq.2Difference
8 8.54 73.272.0 1.2 63.263.20.0
6 7.63 54.653.6 1.0 49.447.6 1.8
4 6.6 35.338.43.132.134.62.5
2 3.68 16.514.9 1.6 15.314.0 1.3
1 2.08 8.48.90.58.18.50.4

The accuracy of Eqs. 1, 2 were further validated through the solid-tissue phantom experiment. Fifteen grams of Gelatin powder (Sigma, St Louis, MO, USA) made from porcine skin were added into 200mL of boiling water and was dissolved completely by stirring. After the solution was cooled down, the intralipid solution with a certain concentration was added to the prepared gelatin solution. After that, the solution was frozen for the formation of the gelatin phantom. The percentage concentration of the intralipid used was varied, depending on the required μs . Five solutions with intralipid concentrations of 1–4% were used to create different μs values for gelatin phantoms, whose μs690 and μs834 measured by the Oximeter and calculated by Eqs. 1, 2 and their differences are shown in Table 2 .

Table 2

The reduced scattering coefficients of gelatin phantoms measured by Oximeter and calculated by Eqs. 1, 2 and their differences.

% Intralipidconcentrationin phantomsSlope μs690′ (cm−1) μs834′ (cm−1)
Oxi-meterEq.1DifferenceOxi-meterEq.2Difference
4 6.39 37.935.9 2.0 30.732.41.7
3 5.38 28.325.8 2.5 22.423.71.3
2.5 4.85 23.521.8 1.7 19.620.10.5
1.5 3.34 14.113.3 0.8 11.912.60.7
1 2.08 98.9 0.1 8.58.50.0

It shows in Tables 1, 2 that the maximum difference is 3.1cm1 and mean difference at 690nm is bigger than at 834nm . The maximum difference at 834nm is 2.5cm1 . By combining the specific fiber-optic spectrometer with the empirical equations, an efficient method for real-time determination of the tissue reduced scattering coefficient is established.

2.5.

Magnetic Resonance Imaging (MRI) and Histology Studies

MRI exams were performed at POD 10 and 17 on a 1.5-T MRI scanner (Philips Eclipse) using a human wrist coil after NIRs measurement. Gd-DTPA was applied intravenously at concentrations of 0.2mmolkg , 5min before the scan. During the MRI scan, the rats were positioned in a plastic holder and anesthetized by 4% Nembutal ( 40mgkg , i.p.). Standard multislice sagittal and cross images were obtained by a TSE sequence with TR=4113ms , TE=96ms , NSA=2 , FOV=13cm , slice thickness=3.0mm , slice gap=0.5mm , resolution=256×384 , and seven slices.

After MRI, the rats were sacrificed with an anesthetic overdose and their brains were removed after the experiments. The brains were fixed in 10% formalin for more than 24h and embedded in paraffin; consecutive 5μm coronal sections were cut and stained with hematoxylin and eosin. A semiquantitative assessment of pathology was carried out by the neuropathologist for each individual specimen.

2.6.

Statistical Analysis

The data reported here consist of only the reduced scattering coefficient at 690 and 834nm . Spectral information between 700 and 850nm for each sampling at each location in the brain was acquired. Data were collected 20 times at each measured point in a 10-s acquisition period and then averaged. The μs data finally used in this study were the data at each point. For each side of a rat brain, there were 40 values because the probe went 8mm deep into the brain at an interval of 0.2mm . The μs values were also averaged on 10 rats at each point of each side for POD 3, 10, and 17. Furthermore, all the 30 C6 glioma models were confirmed by the MRI and histology.

3.

Results

3.1.

Spectra and Light Scattering

Representative traces for the right brain (glioma) measured by the NIRS are shown in Fig. 3 . They represent the different spectral value at different depths. The reduced scattering coefficients (μs) at 690 and 834nm were calculated by Eqs. (2.1) and (2.2) using these spectral slopes.

Fig. 3

Reflectance spectra in vivo obtained from right side on POD 10 during experiment from 1 to 8mm deep within the brain. Open square represents 1mm deep. Filled square represents 2mm deep. Open triangle represents 3mm deep. Filled triangle represents 4mm deep. Open diamond represents 5mm deep. Filled diamond represents 6mm deep. Open circle represents 7mm deep. Filled circle represents 8mm deep.

044003_1_032804jbo3.jpg

Analysis of μs showed that there were significant differences between left (control) and right (glioma) sides of the brain tissue (Fig. 4 ) on POD 10 and 17. Data in Fig. 4 are the average data at each point (n=20) . μs690 versus depth have the same trend as μs834 versus depth. It shows that μs of the right side within some range is lower than that of the left side at its corresponding position, and μs of POD 17 is lower than of POD 10 in the right side. On POD 10, there was significant difference between the left and right from a depth of 3.2to6.8mm . On POD 17, the difference between the left and right is from a depth 1.2to7.2mm . The μs values measured for the left (control) and right (glioma) brain side on POD 10 and 17 at depths of 18mm are listed in Table 3 as mean±SEM , respectively.

Fig. 4

μs values for the left (control) and right (glioma) side from 0.2to8mm deep within the brain. Open diamond represents 690nm of the left side. Filled diamond represents 834nm of the left side. Open square represents 690nm of the right side on POD 10. Filled square represents 834nm of the right side on POD 10. Open triangle represents 690nm of the right side on POD 17. Filled triangle represents 834nm of the right side on POD 17.

044003_1_032804jbo4.jpg

Table 3

The μs′ values for the left and right side on POD 10 and 17 at different deep within the brain (n=10) .

μs′ (cm−1) versus depth
1mm 2mm 3mm 4mm 5mm 6mm 7mm 8mm
Left (690nm) 12.1±2.9 14.6±3.3 19.9±4.8 25.5±5.2 25.2±5.7 23.8±5.4 19.9±5.2 16.5±4.6
Right (690nm) POD 10 12.0±2.0 14.7±3.8 17.4±2.5 16.5±3.9 19.4±5.5 21.9±7.0 18.3±4.7 16.5±2.4
POD 17 10.9±1.4 11.2±1.6 12.3±2.0 13.5±2.8 16.7±5.4 19.2±5.2 17.5±3.3 15.8±1.4
Left (834nm) 11.5±2.6 13.7±3.0 18.5±4.3 23.4±4.6 23.2±5.0 21.9±4.7 18.4±4.6 15.5±4.1
Right (834nm) POD 10 11.4±1.8 13.8±3.4 16.2±2.2 15.4±3.5 18.0±4.9 20.2±6.1 17.0±4.1 15.5±2.1
POD 17 10.4±1.3 10.6±1.4 11.6±1.8 12.7±2.5 15.6±4.8 17.8±4.6 16.3±2.9 14.8±1.2

3.2.

MRI Imaging

In images of T2-weighted spin-echo and gradient-echo with Gd-DTPA enhancement, there were ellipse high signals in the right hemisphere, and these high signals were inhomogeneous in some rats (Fig. 5 ).

Fig. 5

(a) Emerge low signals in the center of high signals, which represent necrosis or hemorrhage. (b) shows inhomogeneous high signal in the position where implant C6 glioma cells on POD 17.

044003_1_032804jbo5.jpg

3.3.

Histology

The histopathological alterations of C6 gliomas were shown in Fig. 5. On a semiquantitative grading scale, all specimens had been classed into II/III grade by a neuropathologist. Prominent mitotic activity was observed under microscope on POD 10 [Fig. 6a and 6b ], by which gliomas are classed into grade II. An amount of tumor cells necrosis and hemorrhage in the central region of tumors occurred on POD 17 [Fig. 6c and 6d], by which gliomas are classed into grade III.

Fig. 6

Microphotographs of C6 gliomas. A, C, D×200 E-H; B×400 E-H. (a) Shows grade I glioma (POD 10); (b) a mitotic phenomenon in the center of the photograph (arrows); (c) grade III, shows necrosis at low right; (d) grade III, hemorrhage in right side (POD 17).

044003_1_032804jbo6.jpg

4.

Discussion

The in vivo measurements yielded μs to be within the range 11–26 and 1024cm1 , respectively, for 690 and 834nm light in rat normal brain tissue, which is in good agreement with other in vivo measurements of μs in mammalian brains.12, 13 The upper and lower limits of the ranges can be taken as μs values of white matter and gray matter, respectively, at 690 and 834nm , according to their depth distributions in rat brain. For glioma on POD 10, the mean μs690 and μs834 are 19.3cm1 (standard error 1.8cm1 ) and 17.9cm1 (standard error 1.6cm1 ), respectively. For glioma on POD 17, the mean μs690 and μs834 are 16.0cm1 (standard error 2.6cm1 ) and 15.0cm1 (standard error 2.3cm1 ), respectively. To our knowledge, in vivo measurements of μs of glioma at these two wavelengths have not been reported.

Gliomas are neuroectodermal tumors. It induces perifocal edema and a massive increase of intracranial pressure for their compression, infiltration, and destruction of brain tissues. It was reported that glioma cells had abnormal chromosome and genetic expression, lower cytochrome-oxydase, creatine phosphate, adenosine triphosphate, and higher deoxyribonucleic acid than normal tissues.14, 15, 16 In the SD C6 glioma model, significant loss of both the mitochondrial enzyme activity and the mitochondrial protein concentration were reported.7

In principle, scattering properties of tissues vary with the light-scattering media in tissues such as the cell membrane and organelle membrane,8 the nuclei,17, 18 and other intracellular organelles, including the mitochondria.7, 19, 20, 21, 22, 23 Thus, light scattering can be a possible marker for tissue identification24, 25, 26 and cancer diagnosis.6 A lot of studies have documented that the scattering properties of gray and white matter in the brain differ significantly in the near-infrared range.5, 12, 27, 28, 29, 30 Recently, scattering properties are used to monitor and understand neuronal functions and physiological changes in vitro and in vivo.19, 20, 31, 32 It becomes a more recognized and frequently utilized research approach in the area of neuroscience.30, 31, 32, 33, 34

Because cellular and intracellular organelles of tumors undergo changes in their density, morphological size, and shape, it is expected that light-scattering properties of tumors will differ from that of normal tissues. According to the existing reports, 12, 13, 20, 35, 36, 37, 38, 39, 40 the reduced scattering coefficients of tumors were found to be greater or less than normal tissues, dependent on tissue type and detecting wavelength. In this study, we cultured C6 cells to induce cerebral glioma in SD rats. The NIR spectra reflected from glioma were measured by NIRS to determine the reduced scattering coefficient. The results show the reduced scattering coefficient of glioma decreased compared to normal tissues at the same position, which is in good agreement with the 632nm results reported by Angell-Petersen 13

The differences in reduced scattering coefficient observed in our in vivo data could be the mixed results of the following aspects:

  • 1. Mitochondrial protein concentration: μs is found proportional to the mitochondrial protein concentration and decreases as the concentration falls.19 Loss of mitochondrial protein concentration is found in glioma cells.7

  • 2. Cell nuclei size: Mie theory predicts a general decrease in scattering, increase in anisotropy, and a subsequently large decrease in reduced scattering as the radius of tissue scatterer (cell nuclei, etc.) increases. Tumor cell nuclei are often larger than normal,41 effectively decreasing the scattering from cell nuclei.

  • 3. Cell nuclei density: The increased numbers of mitoses and multiple nuclei in a cell in tumors41 act as additional scattering centers, which can partially offset the decrease in scattering.

  • 4. Absorption: The signal obtained by our NIRS is somewhat influenced by total hemoglobin concentration, which usually increases three to five times as a tumor develops.18 A simple experiment by adding two different concentrations of blood into 100mL 4% intralipid solution was conducted. μs690 and μs834 measured by our NIRS decreased 1.3 and 1.1cm1 , respectively, when total hemoglobin concentration increased from 13.4to59.7μmolL . In the rat experiments, μs690 and μs834 decreased 5.8–8.5 and 5.27.6cm1 in the center of the tumor (depth=5mm) , which shows absorption is not a main reason for μs changes observed in the rat experiments.

Although it is expected that the tissue undergoes disorganization within hours after C6 glioma implantation, we were unable to show such a change by the NIR technique on postoperative day 3. However, significant changes were found in our study on postoperative days 10 and 17, which correlate well with the expected pathological changes following glioma cells implantation. The following matters indicated the possibility by using in vivo NIR techniques to identify glioma. First, abnormal changes and their boundaries can be deduced by the μs curves. On the 10th day after C6 glioma cells were implanted at a depth of 5mm in rat brain, there is significant difference between the left and right sides from depth 3.2to6.8mm , which means the glioma enlarged, and depth 3.2mm is its upper boundary and depth 6.8mm is its lower boundary. On POD 17, the difference range between the left and right is from depth 1.2to7.2mm , which means the volume of glioma is bigger. The upper boundary read from the μs curve is approximately consistent with the data read from MRI images. Second, the μs curves show the potential for differentiating a grading scale of gliomas. The histopathological alterations of C6 gliomas classified gliomas on POD 10 into grade II and gliomas on POD 17 into grade III. On the other hand, the μs of glioma side on POD 17 is lower than that on POD 10; that is, μs of gliomas of grade III is lower than grade II. However, more studies are needed to work out the differentiating number.

We did not observe the significant differences on POD 3. One possible explanation for the failure to detect the differences is due to the small volume of the glioma in its early stage. In the Sprague-Dawley rat C6 gliomas models, gliomas just begin to form a tumorous entity 72h after the implantation.2 Qian 42 in previous research found that the probe used here has a look-ahead distance at 1mm , which means the reduced scattering coefficient measured by this system is depending on the contribution of tissues located 1mm under the probe. The percentage of intact versus diseased tissues in the 1mm range may affect the scattering readings. It would be beneficial to develop a more sensitive NIR probe with a better spatial resolution. A second possibility may be the positioning of the NIR probe. A slight change in positioning angle could affect the reading. This possibility seems unlikely to account for a lack of group differences because there was no systematic difference in probe positioning. However, increased accuracy in probe positioning could be obtained by developing an optic digital scanner that could provide a measurement for the distance around the center of the aiming surface. Such information could feed back to a microprocessor, which would adjust the angle of the micromanipulator.

In conclusion, this study reports μs of normal brain tissue and glioma at two wavelength obtained using an NIRS method and demonstrates that NIRS has the ability to detect cerebral gliomas microinvasively. The results have proven our initial hypothesis and may suggest that the NIR techniques have a potential for intraoperative application to identify gliomas within normal brain tissue. We believe that such a minimally invasive technique with simple, low-cost, and portable aspects could be utilized for multiple applications in the brain and inner body-studies, such as to measure dynamic light scattering changes during external stimulations. The possibility of characterizing light scattering under tumors in vivo may allow scientists to gain insight into tumor physiology from another angle besides tissue hemoglobin oxygenation, which has been done intensively in recent years.

Acknowledgments

This work was performed in Biophotonics Laboratory of Nanjing University of Aeronautics and Astronautics and supported by the National Nature Science Foundation of China (Grant No. 30671997).

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©(2008) Society of Photo-Optical Instrumentation Engineers (SPIE)
Lijuan Dai, Zhiyu Qian, Kuanzheng Li, Tianming Yang, and Huinan Wang "In vivo detection of reduced scattering coefficient of C6 glioma in rat brain tissue by near-infrared spectroscopy," Journal of Biomedical Optics 13(4), 044003 (1 July 2008). https://doi.org/10.1117/1.2957974
Published: 1 July 2008
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