JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 28, Number 0, 2015 ª Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/jamp.2014.1194
Effect of Oral Pathway on Charged Particles Deposition in Human Bronchial Airways Hussain Majid, PhD,1,2 Renate Winker-Heil, PhD,1 Pierre Madl, PhD,1 Werner Hofmann, PhD,1 and Khan Alam, PhD 3
Abstract
Background: In vitro studies to investigate the effect of charged particle deposition in the oral pathway of human adults have demonstrated substantial increases in deposition due to an induced charge effect. In the current study, charged particle deposition in the oral pathway was incorporated in the stochastic human airway generation model IDEAL (Inhalation, Deposition, and Exhalation of Aerosols in the Lung) to quantify their effect on bronchial airways deposition. Methods: Calculation of increased oral deposition due to charged particles was performed by a modified version of IDEAL for oral pathway, whereas deposition in the bronchial airways was carried out by the already employed efficiency equation. Deposition calculations were performed for 3, 4.5, and 6 lm particles at flow rates of 15 and 30 L/min. Results: The enhancement in deposition is found to be 40 times higher in oral pathway and 6 times higher in bronchial airways for 3 lm size particles carrying 2500 elementary charges. For particles larger than 3 lm, deposition by impaction dominates over deposition by particle charges, and hence higher deposition in oral pathway is observed primarily due to impaction. As a consequence of this increased oral deposition, bronchial airways deposition decreases. Conclusion: By controlling breathing, aerosol properties, and electrostatic charge, targeted deposition in the human airways can be improved. Hence, charged particles can therefore be utilized to give better control on regional drug delivery in the lungs or to filter out toxic constituents. Key words: bronchial airways, charged particles, deposition, oral pathway, stochastic lung model
since the freshly generated aerosols in workplace environments may contain highly charged particles.(2–4) Experimental studies based on human airways and in vivo experiments have shown the effect of electrostatic charge on particle deposition.(5–7) Experimental work carried out by Scheuch et al.(8) for human subjects showed more effective deposition of charged as compared to uncharged particles. Melandri et al.(5,9) found that unipolar charges on monodisperse aerosols result in increased deposition in the human lung that is proportional to the amount of charges carried per particle. Cohen et al.(10) found at least threefold enhanced deposition for mono-disperse nanoparticles carrying a single positive elementary charge. Similar
Introduction
O
ptimized aerosol inhalation and deposition for medical treatment of lung diseases [e.g., asthma and chronic obstructive pulmonary disease (COPD)] is important for reducing harmful side effects by reducing the administered dose. The knowledge of charged particle deposition in human respiratory tract can help to design high efficiency drug delivery systems. Aerosols produced by commercial metered dose inhalers can produce elementary charges per drug particle that range from zero to several ten thousands.(1) Similarly, in the industrial hygiene context, consideration of charged particles is important with respect to human health,
1 2 3
Division of Physics and Biophysics, Department of Materials Research and Physics University of Salzburg, Salzburg, Austria. Higher Education Commission of Pakistan, Islamabad, Pakistan. Department of Physics, University of Peshawar, Peshawar 25120, Pakistan.
1
2
MAJID ET AL.
effects of electrostatic forces on deposition were obtained by Bailey et al.(6) for 0.5 lm and 5.0 lm particles. The current study highlights the importance of charged particles deposition in the human lung. The extrathoracic (ET) region serves as a particle filter and affects the amount of aerosols inhaled and ultimately deposited in the lung airways.(11) Several models have been developed to predict the charged particles deposition in the human respiratory system.(9,12–14) But almost no data are available on charged particle deposition in the oral or nasal pathway to analyze its effect on bronchial airways deposition. Recently, Azhdarzadeh et al.(15–17) conducted in vitro studies to investigate the effect of charged particle deposition in the extrathoracic region. Substantial increases in oral deposition were shown due to induced electrostatics charges. The authors developed a dimensionless empirical correlation for predicting electrostatically charged particle deposition in the mouth–throat region of human adults.(15) The effect of charged particle deposition in the bronchial airways has already been implemented in the stochastic human lung model IDEAL (Inhalation, Deposition, and Exhalation of Aerosols in the Lung) to demonstrate enhanced deposition.(18) In the present study, the correlation for charged particles deposition in the oral pathway has been incorporated in the IDEAL to quantify its effect on bronchial deposition. The primary objectives of this study are (i) to incorporate charged particle deposition in the oral pathway into the stochastic human lung model (IDEAL), (ii) to predict enhanced deposition for various charged particles in the oral pathway and its effect on bronchial deposition, (iii) to quantify the effects of flow rate on charged particle deposition, and (iv) to calculate enhanced deposition and enhancement factors at flow rates of 15 and 30 L/min. Methods
Deposition of charged particles is caused either by space charge effects or by the image charge force. The space charge effect is noticeable for particle concentrations higher than 105 particles/cm3.(13) In the present study, the space charge effect was not taken into consideration because usually the particle concentrations are lower than the described number concentration. Therefore, the effect of charged particles deposition in airways was considered due to image force in which equal and opposite charges are induced by charged particles on the nearby airway surface called Coulomb force.(6,19) Deposition of uncharged particles in the oral pathway was calculated by employing the following efficiency equation derived by Grgic et al.(20) g ¼ 100
100 (11:5x þ 1)
[Eq: 1]
areffi Stokes andq Reynolds numbers where x = Stk1.912 Re0.0707 qffiffiffiffiffi ffiffiffiffiffi qd2 Q
2qQ p pL L defined as Stk ¼ 36l V 3 ; Re ¼ l pV respectively, which depend on the mouth–throat volume (V) and the center line path length (L). Here V = 76.8 cm3 for mouth– throat volume and L = 18.8 cm for center line path length are based on average values for seven realistic geometries Grgic et al.,(20) whereas q is density of inhaled air, l is the dy3
namitic viscosity of inhaled air, Q is the flow rate of inhaled air, and dp is the diameter of inhaled particles. To predict the combined effect of impaction and particle charge on oral deposition, the following modified form of Equation 1 was used: g ¼ 100
100 (11:5^ x þ 1)
[Eq: 2]
The value of x^ considered in Equation 2 was obtained by Azhdarzadeh et al.(15) and is derived as follows: x^ ¼ (0:3956Inc0:2680 þ Re0:37 Stk)(1 þ 2:4452Inc0:0045 ) [Eq: 3] where electrostatic induction ‘Inc’ is obtained by:
Inc ¼
qffiffiffiffiffiffiffiffiffiffiffiffi qp =q e2 n2 192pdp e0 Qx¢2
[Eq: 4]
Here qp, q*, e, n and e0 are the particle density, reference density (i.e. 1 g/cm3), elementary charge, number of elementary charges on each particle, and permittivity of free space, respectively. The variable x¢ = 0.025 is the nondimensional distance of the particle from the airway wall, as suggested by Finlay.(19) Equations 1 and 2 consider deposition of coarse particles due to impaction and electrostatic charges. The deposition mechanisms under diffusion and sedimentation were neglected in Equation 2 because diffusion is important for fine particles with diameter < 0.2 lm and sedimentation is important in peripheral airways. Bronchial deposition due to charged particles was calculated by the following efficiency equation:(13)
8B gq ¼ t0 pe0 dt3
1=2 (q q0 )
[Eq: 5]
where B is the mechanical mobility of the particle, q is the number of elementary charges, q0 is the threshold charge limit in bronchial airways (i.e., 50e), eo is the electric permittivity of air, t0 is the mean residence time of particles in an airway tube. and dt is the airway diameter. The enhanced deposition (ED) was calculated by applying the following formula: ED ¼
DFq DF0 · 100 DF0
[Eq: 6]
where DFq and DF0 are the deposition fractions with and without particle charges. The deposition fraction considered herein consists of number of particles depositing in a given airway generation with respect to the total number of particles entering the respiratory tract. Deposition fractions in oral and bronchial airways were calculated for unit density monodisperse particles with a diameter of 3, 4.5, or 6 lm. The assumed flow rates for deposition calculations were 15 and 30 L/min respectively. Furthermore, steady state breathing conditions with equal inspiration and expiration times were assumed. The particle
PARTICLE DEPOSITION IN BRONCHIAL AIRWAYS
3
FIG. 1. Deposition of charged particles in oral pathway of an human adult. The deposition fractions are calculated for different particle sizes at flow rates of 15 L/min (left) and 30 L/min (right).
diameter, particle charges, and breathing parameters assumed here are within the recommended validity range for efficiency Equations 1 and 2.(15) Deposition fractions of inhaled particles were computed by the stochastic lung model IDEAL, originally developed by Hofmann and Koblinger(21) and Koblinger and Hofmann.(22) In this model, individual paths of inhaled particles through the asymmetric airway system are randomly selected by Monte Carlo methods from the probability distributions of the airway parameters and their correlations. The stochastic particle deposition model simulates the random walk of inspired particles through the stochastic, asymmetric airway structure in which broncial airways may vary from generation 1 up to 16. Deposition of particles in bronchial airways is computed by analytical equations for the various deposition mechanisms (i.e., diffusion, sedimentation, and impaction) as described by Hussain et al.(23) Deposition probabilities of individual particles are given by their average probabilities. The probability that a particle is being deposited in a given airway or passes through it without deposition is randomly selected from these deposition efficiencies. This specific feature of the stochastic lung model leads to a significant variability of particle deposition. Calculated deposition fractions in bronchial and acinar airway generations are typically based on 10,000 to 100,000 simulations. Results and Discussion
mentary charges (Table 1). In a cadaver-based throat cast replica, Ali et al.(24) reported an increased deposition up to 244% for charged particles in the range of 0.5–4.5 lm at flow rate of 1 L/min. The deposition efficiencies increase almost linearly as a function of particle charges for all selected particle sizes. However with increasing particle size, the effect of particle charges on deposition decreases and for larger particles the deposition by impaction starts dominating over deposition by particles charges. The deposition increases with an increase of the flow rates from 15 to 30 L/min by 32, 73, and 77 % (average values) for 3, 4.5, and 6.0 lm size particles, respectively. For large particles, impaction is the dominant deposition mechanism; hence the oral deposition is highest for 6 lm
Table 1. Enhanced Deposition and Enhancement Factors in Oral Pathway Obtained Due to Charged Particle Deposition for Various Particle Sizes and Charge Loads Flow rate 15 L/min Flow rate 30 L/min Particle Particles Enhanced Size Charges deposition (lm) (e) (%) 3
Oral pathway
The deposition fractions were calculated for the whole breathing cycle of inhalation and exhalation, whereas in experimental studies by Azhdarzadeh et al.,(15) only one process (i.e., inhalation) could be performed to estimate deposition fractions. The deposition fractions for uncharged and charged particles in the oral pathway during inhalation and exhalation at flow rates of 15 and 30 L/min are shown in Figure 1. At a flow rate of 15 L/min, an enhanced oral deposition of about 3947%, 1633%, and 995% for 3, 4.5, and 6.0 lm particles carrying 2500 elementary charges could be observed compared to uncharged particles (Table 1). The corresponding deposition fractions at a flow rate of 30 L/min are about 1270% for 3 lm particles, 658% for 4.5 um particles, and 363% for 6.0 lm particles carrying 2500 ele-
4.5
6
2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000
3947 5807 8877 11342 13481 15342 1633 2060 2702 3205 3633 3996 995 1132 1322 1470 1592 1698
EF
Enhanced deposition (%)
EF
40 59 90 114 136 154 17 22 28 33 37 41 11 12 14 16 17 18
1270 1561 2002 2341 2624 2876 658 713 790 847 892 932 363 374 390 401 411 419
13.70 16.61 21.02 24.41 27.24 29.76 7.58 8.13 8.90 9.47 9.92 10.32 4.63 4.74 4.90 5.01 5.11 5.19
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MAJID ET AL.
FIG. 2. Bronchial airways deposition as a function of generation number for various particle charge loads. The deposition is calculated for two particle sizes (a = 3 lm, b = 6 lm) at a flow rate of 15 L/min. particles as compared to the smaller particles sizes of 3 and 4.5 lm. This suggests that enhanced deposition due to particle charges is less significant for large particles than that of smaller ones. An increase in the flow rate results in an increased deposition by impaction. The enhanced oral deposition predicted here are higher than the measured values by Azhdarzadeh et al.,(15) primarily due to the consideration of deposition during inhalation as well as exhalation. However, deposition efficiencies during inhalation are generally higher than during exhalation in the oral pathway. Only up to 4% deposition occurs during exhalation, depending upon the particle size and flow rate. Bronchial deposition
Computed bronchial deposition fractions for inhaled charged and uncharged particles at a flow rate of 15 L/min are plotted in Figure 2 as functions of the airway generation number. Deposition fractions exhibit significant peaks in central bronchial airway generations for uncharged particles. However, by introducing charged particles, the deposition peaks shift towards upper airway generations (Fig. 2). The higher the charge loads, the higher are the deposition fractions within upper airways (i.e., up to generation 6). Increased deposition in upper airway generation with introduction of charged aerosol has already been reported by Baily et al.(6) These shifts of maximum deposition with increasing particle charges reveals that controlled
drug delivery can be achieved by adjusting particle charges according to their size and flow rate. For a particular particle diameter, the average bronchial deposition fractions increase with increasing charge loads up to 5.0 · 103 particle charges, but with further increase in particle charges the bronchial deposition fractions decrease (Table 2). These decreasing mean deposition fractions in bronchial airways are a consequence of the enhanced oral deposition due to the particle charges. Similarly, at a particular charge load, the increase in particle diameter leads to decreasing deposition in bronchial airways, again a consequence of the more effective oral deposition with increasing particle size caused by inertial impaction (Table 2). Relative to central bronchial airways, deposition increase in upper
Table 3. Enhanced Deposition (ED) and Enhancement Factors (EFs) in Bronchial Airways Obtained with Charged Particles for Various Particle Sizes and Charge Loads Flow rate 15 L/min Flow rate 30 L/min Particle Particles Enhanced/ diameter Charges deposition (lm) (e) (%)
Enhanced/ decreased* EF deposition (%) EF
3
5.99 6.22 5.99 5.70 5.41 5.14 3.03 3.10 3.02 2.88 2.75 2.62 1.74 1.79 1.73 1.65 1.58 1.51
Table 2. Mean Bronchial Deposition Fractions at Flow Rates of 15 and 30 L/min at Various Charge Loads Mean bronchial deposition fraction flow rate 15 L/min
Mean bronchial deposition fraction flow rate 30 L/min
Particle Charges (e)
3 mm
4.5 mm
6 mm
3 mm
4.5 mm
6 mm
No charge 2500 5000 10000 15000 20000 25000
0.11 0.64 0.67 0.64 0.61 0.58 0.55
0.20 0.59 0.61 0.59 0.56 0.54 0.51
0.29 0.51 0.52 0.50 0.48 0.46 0.44
0.12 0.63 0.66 0.63 0.60 0.58 0.55
0.22 0.46 0.49 0.47 0.45 0.43 0.41
0.31 0.29 0.31 0.30 0.28 0.27 0.26
4.5
6
2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000
499 522 499 470 441 414 203 210 202 188 175 162 74 79 73 65 58 51
415 440 418 393 371 350 106 116 108 99 90 83 - 4.08 - 0.01 - 3.58 - 7.46 - 10.83 - 13.80
*Negative sign shows percentage decrease in deposition.
5.15 5.40 5.18 4.93 4.71 4.50 2.06 2.16 2.08 1.99 1.90 1.83 0.96 1.00 0.96 0.93 0.89 0.86
PARTICLE DEPOSITION IN BRONCHIAL AIRWAYS
5
FIG. 3. Bronchial airways deposition as a function of generation number at various particle charge loads. The deposition is calculated for two particle sizes (a = 3 lm, b = 6 lm) at a flow rate of 30 L/min. airway generations with increases in particle sizes with similar charge load due to impaction. At a flow rate of 15 L/min in the bronchial airways, the enhanced deposition fractions of the charged particles compared to uncharged particles are about 499, 203, and 74% for 3, 4.5, and 6.0 lm size particles, respectively, carrying 2500 elementary charges (Table 3). The corresponding deposition fractions at flow rate of 30 L/min are about 415, 106, and - 4.1% for 3, 4.5, and 6.0 lm diameter particles, respectively, carrying 2500 elementary charges (Table 3). Bronchial deposition fractions for inhaled charged and uncharged particles at flow rate of 30 L/min are shown in Figure 3. The increase of the flow rate from 15 to 30 L/min results in an enhanced oral deposition which, as a consequence, decreases the deposition within bronchial airways by up to 2, 19, and 37 % (average values) for 3, 4.5, and 6 lm size particles, respectively. Calculation of the enhancement factors (EFs)
Enhancement factors (EFs) for deposited charged particle at flow rates of 15 and 30 L/min are calculated and listed in Table 1 and 3. These EFs are calculated for oral pathway and in the bronchial airways by taking the ratio of the charged particle deposition fractions to that of uncharged particles
i:e:;
DFq DF0
.
The comparison of the various factors reveals that the enhanced deposition is lower at a flow rate of 30 L/min than that of 15 L/min. This decrease of the EFs with increasing flow rate is primarily caused by increased deposition in oral pathways due to impaction. This illustrates that, for larger particles, lower EFs are caused by the domination of deposition by impaction over particle charges. This phenomenon has been explained by Azhdarzadeh et al.(15) by the ratio of two dimensionless numbers: Inc/Stk, which illustrates the importance of the induced charge compared to the inertial impaction. If Inc=Stk[1, then the effect of charges on deposition of smaller particles will be larger. In summary, for the selected particle sizes and flow rates, up to 154 times higher oral deposition fractions and more than 6 times higher deposition fractions in bronchial airways can be achieved by inhaling charged particles. Conclusion
In this study, the effect of oral pathway on charged particles deposition in the human bronchial airways was investigated.
The study has been carried out by incorporating empirical relation for charged particles deposition in oral pathway in stochastic airway generation model IDEAL. The deposition fractions were calculated for 3, 4.5, and 6 lm diameter particles at various charge loadings at two different flow rates, 15 and 30 L/min. For particles larger than 3 lm, impaction is becoming more effective compared to the effects of particle charges. The deposition efficiencies in the oral pathway increase almost linearly for all selected particle sizes. At the flow rate of 15 L/min, the resulting enhanced oral deposition for charged particles compared to uncharged particles are about 3947%, 1633%, and 995% for 3, 4.5, and 6.0 lm particles, respectively, carrying 2500 elementary charges. In bronchial airways, the charged 3 and 4.5 lm diameter particles are more efficiently deposited as compared to the uncharged particles of the same diameter at flow rate of 15 L/min. In general, for larger particles the oral filtration efficiency increases and fewer particles can enter the bronchial airways, resulting in a decreased bronchial deposition. An increase of the flow rate from 15 to 30 L/min causes an increase of the oral deposition, which results in a decreased deposition in bronchial airways up to 32, 73, and 77% for 3, 4.5, and 6 lm diameter particles, respectively. The calculated enhancement factors (EFs) reveals that for the selected sizes and flow rates up to 154 times higher deposition in the oral pathway and more than 6 times in bronchial airways can be achieved by charged particles during inhalation. Hence, by introducing charged particles and by optimizing the flow rate and particle size, controlled drug delivery can be achieved in the lung. For example, if higher deposition is required in central or peripheral bronchial airways, use of a mouth piece is recommended to minimize deposition in mouth and upper bronchial airways. Charged particles can also be utilized to filter out toxic constituents that may approach sensitive lung regions. Acknowledgments
The authors wish to thank Dr. Mehdi Azhdarzadeh, University of Alberta Edmonton, Canada, for his support in reviewing and modifying the manuscript. Funding: This work was funded by the Higher Education Commission of Pakistan under the scholarship program (Overseas Scholarships for Pakistani Nationals).
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Author Disclosure Statement
The authors declare that there are no conflicting financial interests.
16.
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1. Kwok PCL, Glover W, and Chan HK: Electrostatic charge characteristics of aerosols produced from metered dose inhalers. J Pharm Sci. 2005;94:2789–2799. 2. Johnston AM, Vincent JH, and Jones AD: Measurements of electric charge for workplace aerosols. Ann Occup Hyg. 1985;29:271–284. 3. Vincent JH: On the practical significance of electrostatic lung deposition of isometric and fibrous aerosols. J Aerosol Sci. 1985;16:511–519. 4. Forsyth B, Liu BYH, and Romay FJ: Particle charge distribution measurement for commonly generated laboratory aerosols. Aerosol Sci Tech. 1998;28:489–501. 5. Melandri C, Tarroni G, Prodi V, De Zaiacomo T, Formignani M, and Lombardi CC: Deposition of charged particles in the human airways. J Aerosol Sci. 1983;14: 657–669. 6. Bailey AG, Hashish AH, and Williams T: Drug delivery by inhalation of charged particles. J Electrostatics. 1998;44: 3–10. 7. Balachandran W, Machowski W, Gaura E, and Hudson C: Control of drug aerosol in human airways using electrostatic forces. J Electrostat. 1997;40–41:579–584. 8. Scheuch G, Gebhart J, and Roth C: Uptake of electrical charges in the human respiratory tract during exposure to air loaded with negative ions. J Aerosol Sci. 1990;21:439–442. 9. Melandri C, Prodi V, Tarroni G, Formignani M, De Zaiacomo T, Bompane GF, and Maestri G: On the deposition of unipolar charged particles in the human respiratory tract. In: Walton WH (Ed). Inhaled Particles IV. Oxford: Pergamon Press; pp. 193–200, 1977. 10. Cohen BS, Xiong JQ, Fang C, and Li W: Deposition of charged particles in lung airways. Health Phys. 1998;74: 554–560. 11. Hussain M, Winker-Heil R, and Hofmann W: Effect of intersubject variability of extrathoracic morphometry, lung airways dimensions and respiratory parameters on particle deposition. J Thorac Dis. 2011;3:156–170. 12. Chan TL, and Yu CP: Charge effects on particle deposition in the human tracheobronchial tree. Ann Occup Hyg. 1982;26:65–75. 13. Yu CP: Theories of electrostatic lung deposition of inhaled aerosols. Ann Occup Hyg. 1985;29:219–227. 14. Hashish AH, Bailey AG, and Williams TJ: Modelling the effect of charge on selective deposition of particles in a diseased lung using aerosol boli. Phys Med Biol. 1994; 39:2247–2262. 15. Azhdarzadeh M, Olfert JS, Vehring R, and Finlay WH: Effect of electrostatic charge on oral-extrathoracic deposi-
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tion for uniformly charged monodisperse aerosols. J Aerosol Sci. 2014;68:38–45. Azhdarzadeh M, Olfert, JS, Vehring R, and Finlay WH: Effect of induced charge on deposition of uniformly charged particles in a pediatric oral-extrathoracic airway. Aerosols Sci Tech. 2014a;46:508–514. Azhdarzadeh M, Olfert, JS, Vehring R, and Finlay WH: Effect of electrostatic charge on deposition of uniformly charged monondisperse particles in the nasal extrathoracic airway of an infant. J Aerosols Med. 2015;28:30–34. Hussain M, Madl P, Hofmann W, and Alam K: Implementation of charged particle deposition in stochastic lung model and calculation of enhanced deposition. Aerosol Sci Tech. 2012;46:547–554. Finlay WH: The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press, London; 2001. Grgic B, Finlay WH, Burnell PKP, and Heenan AF: In vitro intersubject and intrasubject deposition measurements in realistic mouth–throat geometries. J Aerosol Sci. 2004; 35:102–1040. Hofmann W, and Koblinger L: Monte Carlo modeling of aerosol deposition in human lungs. Part II: Deposition fractions and their parameter variations. J Aerosol Sci. 1990;21:675–688. Koblinger L, and Hofmann W: Monte Carlo modeling of aerosol deposition in human lungs: Part I: Simulation of particle transport in a stochastic lung structure. J Aerosol Sci. 1990;21:661–674. Hussain M, Hofmann W, and Winker-Heil R: Comparison of stochastic lung deposition fractions with experimental data. Ann Occup Hyg. 2012a;56:278–291. Ali M, Reddy RN, and Mazumder MK: Electrostatic charge effect on respirable aerosol particle deposition in a cadaver based throat cast replica. J Electectrostat. 2008;66:401–406.
Received on November 3, 2014 in final form, February 8, 2015 Reviewed by: Philip Kwok Bahman Asgharian
Address correspondence to: Hussain Majid, PhD Division of Physics and Biophysics Department of Materials Research and Physics University of Salzburg Hellbrunnerstrasse 34 A-5020 Salzburg Austria E-mail: [email protected]
Effect of Oral Pathway on Charged Particles Deposition in Human Bronchial Airways Hussain Majid, PhD,1,2 Renate Winker-Heil, PhD,1 Pierre Madl, PhD,1 Werner Hofmann, PhD,1 and Khan Alam, PhD 3
Abstract
Background: In vitro studies to investigate the effect of charged particle deposition in the oral pathway of human adults have demonstrated substantial increases in deposition due to an induced charge effect. In the current study, charged particle deposition in the oral pathway was incorporated in the stochastic human airway generation model IDEAL (Inhalation, Deposition, and Exhalation of Aerosols in the Lung) to quantify their effect on bronchial airways deposition. Methods: Calculation of increased oral deposition due to charged particles was performed by a modified version of IDEAL for oral pathway, whereas deposition in the bronchial airways was carried out by the already employed efficiency equation. Deposition calculations were performed for 3, 4.5, and 6 lm particles at flow rates of 15 and 30 L/min. Results: The enhancement in deposition is found to be 40 times higher in oral pathway and 6 times higher in bronchial airways for 3 lm size particles carrying 2500 elementary charges. For particles larger than 3 lm, deposition by impaction dominates over deposition by particle charges, and hence higher deposition in oral pathway is observed primarily due to impaction. As a consequence of this increased oral deposition, bronchial airways deposition decreases. Conclusion: By controlling breathing, aerosol properties, and electrostatic charge, targeted deposition in the human airways can be improved. Hence, charged particles can therefore be utilized to give better control on regional drug delivery in the lungs or to filter out toxic constituents. Key words: bronchial airways, charged particles, deposition, oral pathway, stochastic lung model
since the freshly generated aerosols in workplace environments may contain highly charged particles.(2–4) Experimental studies based on human airways and in vivo experiments have shown the effect of electrostatic charge on particle deposition.(5–7) Experimental work carried out by Scheuch et al.(8) for human subjects showed more effective deposition of charged as compared to uncharged particles. Melandri et al.(5,9) found that unipolar charges on monodisperse aerosols result in increased deposition in the human lung that is proportional to the amount of charges carried per particle. Cohen et al.(10) found at least threefold enhanced deposition for mono-disperse nanoparticles carrying a single positive elementary charge. Similar
Introduction
O
ptimized aerosol inhalation and deposition for medical treatment of lung diseases [e.g., asthma and chronic obstructive pulmonary disease (COPD)] is important for reducing harmful side effects by reducing the administered dose. The knowledge of charged particle deposition in human respiratory tract can help to design high efficiency drug delivery systems. Aerosols produced by commercial metered dose inhalers can produce elementary charges per drug particle that range from zero to several ten thousands.(1) Similarly, in the industrial hygiene context, consideration of charged particles is important with respect to human health,
1 2 3
Division of Physics and Biophysics, Department of Materials Research and Physics University of Salzburg, Salzburg, Austria. Higher Education Commission of Pakistan, Islamabad, Pakistan. Department of Physics, University of Peshawar, Peshawar 25120, Pakistan.
1
2
MAJID ET AL.
effects of electrostatic forces on deposition were obtained by Bailey et al.(6) for 0.5 lm and 5.0 lm particles. The current study highlights the importance of charged particles deposition in the human lung. The extrathoracic (ET) region serves as a particle filter and affects the amount of aerosols inhaled and ultimately deposited in the lung airways.(11) Several models have been developed to predict the charged particles deposition in the human respiratory system.(9,12–14) But almost no data are available on charged particle deposition in the oral or nasal pathway to analyze its effect on bronchial airways deposition. Recently, Azhdarzadeh et al.(15–17) conducted in vitro studies to investigate the effect of charged particle deposition in the extrathoracic region. Substantial increases in oral deposition were shown due to induced electrostatics charges. The authors developed a dimensionless empirical correlation for predicting electrostatically charged particle deposition in the mouth–throat region of human adults.(15) The effect of charged particle deposition in the bronchial airways has already been implemented in the stochastic human lung model IDEAL (Inhalation, Deposition, and Exhalation of Aerosols in the Lung) to demonstrate enhanced deposition.(18) In the present study, the correlation for charged particles deposition in the oral pathway has been incorporated in the IDEAL to quantify its effect on bronchial deposition. The primary objectives of this study are (i) to incorporate charged particle deposition in the oral pathway into the stochastic human lung model (IDEAL), (ii) to predict enhanced deposition for various charged particles in the oral pathway and its effect on bronchial deposition, (iii) to quantify the effects of flow rate on charged particle deposition, and (iv) to calculate enhanced deposition and enhancement factors at flow rates of 15 and 30 L/min. Methods
Deposition of charged particles is caused either by space charge effects or by the image charge force. The space charge effect is noticeable for particle concentrations higher than 105 particles/cm3.(13) In the present study, the space charge effect was not taken into consideration because usually the particle concentrations are lower than the described number concentration. Therefore, the effect of charged particles deposition in airways was considered due to image force in which equal and opposite charges are induced by charged particles on the nearby airway surface called Coulomb force.(6,19) Deposition of uncharged particles in the oral pathway was calculated by employing the following efficiency equation derived by Grgic et al.(20) g ¼ 100
100 (11:5x þ 1)
[Eq: 1]
areffi Stokes andq Reynolds numbers where x = Stk1.912 Re0.0707 qffiffiffiffiffi ffiffiffiffiffi qd2 Q
2qQ p pL L defined as Stk ¼ 36l V 3 ; Re ¼ l pV respectively, which depend on the mouth–throat volume (V) and the center line path length (L). Here V = 76.8 cm3 for mouth– throat volume and L = 18.8 cm for center line path length are based on average values for seven realistic geometries Grgic et al.,(20) whereas q is density of inhaled air, l is the dy3
namitic viscosity of inhaled air, Q is the flow rate of inhaled air, and dp is the diameter of inhaled particles. To predict the combined effect of impaction and particle charge on oral deposition, the following modified form of Equation 1 was used: g ¼ 100
100 (11:5^ x þ 1)
[Eq: 2]
The value of x^ considered in Equation 2 was obtained by Azhdarzadeh et al.(15) and is derived as follows: x^ ¼ (0:3956Inc0:2680 þ Re0:37 Stk)(1 þ 2:4452Inc0:0045 ) [Eq: 3] where electrostatic induction ‘Inc’ is obtained by:
Inc ¼
qffiffiffiffiffiffiffiffiffiffiffiffi qp =q e2 n2 192pdp e0 Qx¢2
[Eq: 4]
Here qp, q*, e, n and e0 are the particle density, reference density (i.e. 1 g/cm3), elementary charge, number of elementary charges on each particle, and permittivity of free space, respectively. The variable x¢ = 0.025 is the nondimensional distance of the particle from the airway wall, as suggested by Finlay.(19) Equations 1 and 2 consider deposition of coarse particles due to impaction and electrostatic charges. The deposition mechanisms under diffusion and sedimentation were neglected in Equation 2 because diffusion is important for fine particles with diameter < 0.2 lm and sedimentation is important in peripheral airways. Bronchial deposition due to charged particles was calculated by the following efficiency equation:(13)
8B gq ¼ t0 pe0 dt3
1=2 (q q0 )
[Eq: 5]
where B is the mechanical mobility of the particle, q is the number of elementary charges, q0 is the threshold charge limit in bronchial airways (i.e., 50e), eo is the electric permittivity of air, t0 is the mean residence time of particles in an airway tube. and dt is the airway diameter. The enhanced deposition (ED) was calculated by applying the following formula: ED ¼
DFq DF0 · 100 DF0
[Eq: 6]
where DFq and DF0 are the deposition fractions with and without particle charges. The deposition fraction considered herein consists of number of particles depositing in a given airway generation with respect to the total number of particles entering the respiratory tract. Deposition fractions in oral and bronchial airways were calculated for unit density monodisperse particles with a diameter of 3, 4.5, or 6 lm. The assumed flow rates for deposition calculations were 15 and 30 L/min respectively. Furthermore, steady state breathing conditions with equal inspiration and expiration times were assumed. The particle
PARTICLE DEPOSITION IN BRONCHIAL AIRWAYS
3
FIG. 1. Deposition of charged particles in oral pathway of an human adult. The deposition fractions are calculated for different particle sizes at flow rates of 15 L/min (left) and 30 L/min (right).
diameter, particle charges, and breathing parameters assumed here are within the recommended validity range for efficiency Equations 1 and 2.(15) Deposition fractions of inhaled particles were computed by the stochastic lung model IDEAL, originally developed by Hofmann and Koblinger(21) and Koblinger and Hofmann.(22) In this model, individual paths of inhaled particles through the asymmetric airway system are randomly selected by Monte Carlo methods from the probability distributions of the airway parameters and their correlations. The stochastic particle deposition model simulates the random walk of inspired particles through the stochastic, asymmetric airway structure in which broncial airways may vary from generation 1 up to 16. Deposition of particles in bronchial airways is computed by analytical equations for the various deposition mechanisms (i.e., diffusion, sedimentation, and impaction) as described by Hussain et al.(23) Deposition probabilities of individual particles are given by their average probabilities. The probability that a particle is being deposited in a given airway or passes through it without deposition is randomly selected from these deposition efficiencies. This specific feature of the stochastic lung model leads to a significant variability of particle deposition. Calculated deposition fractions in bronchial and acinar airway generations are typically based on 10,000 to 100,000 simulations. Results and Discussion
mentary charges (Table 1). In a cadaver-based throat cast replica, Ali et al.(24) reported an increased deposition up to 244% for charged particles in the range of 0.5–4.5 lm at flow rate of 1 L/min. The deposition efficiencies increase almost linearly as a function of particle charges for all selected particle sizes. However with increasing particle size, the effect of particle charges on deposition decreases and for larger particles the deposition by impaction starts dominating over deposition by particles charges. The deposition increases with an increase of the flow rates from 15 to 30 L/min by 32, 73, and 77 % (average values) for 3, 4.5, and 6.0 lm size particles, respectively. For large particles, impaction is the dominant deposition mechanism; hence the oral deposition is highest for 6 lm
Table 1. Enhanced Deposition and Enhancement Factors in Oral Pathway Obtained Due to Charged Particle Deposition for Various Particle Sizes and Charge Loads Flow rate 15 L/min Flow rate 30 L/min Particle Particles Enhanced Size Charges deposition (lm) (e) (%) 3
Oral pathway
The deposition fractions were calculated for the whole breathing cycle of inhalation and exhalation, whereas in experimental studies by Azhdarzadeh et al.,(15) only one process (i.e., inhalation) could be performed to estimate deposition fractions. The deposition fractions for uncharged and charged particles in the oral pathway during inhalation and exhalation at flow rates of 15 and 30 L/min are shown in Figure 1. At a flow rate of 15 L/min, an enhanced oral deposition of about 3947%, 1633%, and 995% for 3, 4.5, and 6.0 lm particles carrying 2500 elementary charges could be observed compared to uncharged particles (Table 1). The corresponding deposition fractions at a flow rate of 30 L/min are about 1270% for 3 lm particles, 658% for 4.5 um particles, and 363% for 6.0 lm particles carrying 2500 ele-
4.5
6
2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000
3947 5807 8877 11342 13481 15342 1633 2060 2702 3205 3633 3996 995 1132 1322 1470 1592 1698
EF
Enhanced deposition (%)
EF
40 59 90 114 136 154 17 22 28 33 37 41 11 12 14 16 17 18
1270 1561 2002 2341 2624 2876 658 713 790 847 892 932 363 374 390 401 411 419
13.70 16.61 21.02 24.41 27.24 29.76 7.58 8.13 8.90 9.47 9.92 10.32 4.63 4.74 4.90 5.01 5.11 5.19
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FIG. 2. Bronchial airways deposition as a function of generation number for various particle charge loads. The deposition is calculated for two particle sizes (a = 3 lm, b = 6 lm) at a flow rate of 15 L/min. particles as compared to the smaller particles sizes of 3 and 4.5 lm. This suggests that enhanced deposition due to particle charges is less significant for large particles than that of smaller ones. An increase in the flow rate results in an increased deposition by impaction. The enhanced oral deposition predicted here are higher than the measured values by Azhdarzadeh et al.,(15) primarily due to the consideration of deposition during inhalation as well as exhalation. However, deposition efficiencies during inhalation are generally higher than during exhalation in the oral pathway. Only up to 4% deposition occurs during exhalation, depending upon the particle size and flow rate. Bronchial deposition
Computed bronchial deposition fractions for inhaled charged and uncharged particles at a flow rate of 15 L/min are plotted in Figure 2 as functions of the airway generation number. Deposition fractions exhibit significant peaks in central bronchial airway generations for uncharged particles. However, by introducing charged particles, the deposition peaks shift towards upper airway generations (Fig. 2). The higher the charge loads, the higher are the deposition fractions within upper airways (i.e., up to generation 6). Increased deposition in upper airway generation with introduction of charged aerosol has already been reported by Baily et al.(6) These shifts of maximum deposition with increasing particle charges reveals that controlled
drug delivery can be achieved by adjusting particle charges according to their size and flow rate. For a particular particle diameter, the average bronchial deposition fractions increase with increasing charge loads up to 5.0 · 103 particle charges, but with further increase in particle charges the bronchial deposition fractions decrease (Table 2). These decreasing mean deposition fractions in bronchial airways are a consequence of the enhanced oral deposition due to the particle charges. Similarly, at a particular charge load, the increase in particle diameter leads to decreasing deposition in bronchial airways, again a consequence of the more effective oral deposition with increasing particle size caused by inertial impaction (Table 2). Relative to central bronchial airways, deposition increase in upper
Table 3. Enhanced Deposition (ED) and Enhancement Factors (EFs) in Bronchial Airways Obtained with Charged Particles for Various Particle Sizes and Charge Loads Flow rate 15 L/min Flow rate 30 L/min Particle Particles Enhanced/ diameter Charges deposition (lm) (e) (%)
Enhanced/ decreased* EF deposition (%) EF
3
5.99 6.22 5.99 5.70 5.41 5.14 3.03 3.10 3.02 2.88 2.75 2.62 1.74 1.79 1.73 1.65 1.58 1.51
Table 2. Mean Bronchial Deposition Fractions at Flow Rates of 15 and 30 L/min at Various Charge Loads Mean bronchial deposition fraction flow rate 15 L/min
Mean bronchial deposition fraction flow rate 30 L/min
Particle Charges (e)
3 mm
4.5 mm
6 mm
3 mm
4.5 mm
6 mm
No charge 2500 5000 10000 15000 20000 25000
0.11 0.64 0.67 0.64 0.61 0.58 0.55
0.20 0.59 0.61 0.59 0.56 0.54 0.51
0.29 0.51 0.52 0.50 0.48 0.46 0.44
0.12 0.63 0.66 0.63 0.60 0.58 0.55
0.22 0.46 0.49 0.47 0.45 0.43 0.41
0.31 0.29 0.31 0.30 0.28 0.27 0.26
4.5
6
2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000 2500 5000 10000 15000 20000 25000
499 522 499 470 441 414 203 210 202 188 175 162 74 79 73 65 58 51
415 440 418 393 371 350 106 116 108 99 90 83 - 4.08 - 0.01 - 3.58 - 7.46 - 10.83 - 13.80
*Negative sign shows percentage decrease in deposition.
5.15 5.40 5.18 4.93 4.71 4.50 2.06 2.16 2.08 1.99 1.90 1.83 0.96 1.00 0.96 0.93 0.89 0.86
PARTICLE DEPOSITION IN BRONCHIAL AIRWAYS
5
FIG. 3. Bronchial airways deposition as a function of generation number at various particle charge loads. The deposition is calculated for two particle sizes (a = 3 lm, b = 6 lm) at a flow rate of 30 L/min. airway generations with increases in particle sizes with similar charge load due to impaction. At a flow rate of 15 L/min in the bronchial airways, the enhanced deposition fractions of the charged particles compared to uncharged particles are about 499, 203, and 74% for 3, 4.5, and 6.0 lm size particles, respectively, carrying 2500 elementary charges (Table 3). The corresponding deposition fractions at flow rate of 30 L/min are about 415, 106, and - 4.1% for 3, 4.5, and 6.0 lm diameter particles, respectively, carrying 2500 elementary charges (Table 3). Bronchial deposition fractions for inhaled charged and uncharged particles at flow rate of 30 L/min are shown in Figure 3. The increase of the flow rate from 15 to 30 L/min results in an enhanced oral deposition which, as a consequence, decreases the deposition within bronchial airways by up to 2, 19, and 37 % (average values) for 3, 4.5, and 6 lm size particles, respectively. Calculation of the enhancement factors (EFs)
Enhancement factors (EFs) for deposited charged particle at flow rates of 15 and 30 L/min are calculated and listed in Table 1 and 3. These EFs are calculated for oral pathway and in the bronchial airways by taking the ratio of the charged particle deposition fractions to that of uncharged particles
i:e:;
DFq DF0
.
The comparison of the various factors reveals that the enhanced deposition is lower at a flow rate of 30 L/min than that of 15 L/min. This decrease of the EFs with increasing flow rate is primarily caused by increased deposition in oral pathways due to impaction. This illustrates that, for larger particles, lower EFs are caused by the domination of deposition by impaction over particle charges. This phenomenon has been explained by Azhdarzadeh et al.(15) by the ratio of two dimensionless numbers: Inc/Stk, which illustrates the importance of the induced charge compared to the inertial impaction. If Inc=Stk[1, then the effect of charges on deposition of smaller particles will be larger. In summary, for the selected particle sizes and flow rates, up to 154 times higher oral deposition fractions and more than 6 times higher deposition fractions in bronchial airways can be achieved by inhaling charged particles. Conclusion
In this study, the effect of oral pathway on charged particles deposition in the human bronchial airways was investigated.
The study has been carried out by incorporating empirical relation for charged particles deposition in oral pathway in stochastic airway generation model IDEAL. The deposition fractions were calculated for 3, 4.5, and 6 lm diameter particles at various charge loadings at two different flow rates, 15 and 30 L/min. For particles larger than 3 lm, impaction is becoming more effective compared to the effects of particle charges. The deposition efficiencies in the oral pathway increase almost linearly for all selected particle sizes. At the flow rate of 15 L/min, the resulting enhanced oral deposition for charged particles compared to uncharged particles are about 3947%, 1633%, and 995% for 3, 4.5, and 6.0 lm particles, respectively, carrying 2500 elementary charges. In bronchial airways, the charged 3 and 4.5 lm diameter particles are more efficiently deposited as compared to the uncharged particles of the same diameter at flow rate of 15 L/min. In general, for larger particles the oral filtration efficiency increases and fewer particles can enter the bronchial airways, resulting in a decreased bronchial deposition. An increase of the flow rate from 15 to 30 L/min causes an increase of the oral deposition, which results in a decreased deposition in bronchial airways up to 32, 73, and 77% for 3, 4.5, and 6 lm diameter particles, respectively. The calculated enhancement factors (EFs) reveals that for the selected sizes and flow rates up to 154 times higher deposition in the oral pathway and more than 6 times in bronchial airways can be achieved by charged particles during inhalation. Hence, by introducing charged particles and by optimizing the flow rate and particle size, controlled drug delivery can be achieved in the lung. For example, if higher deposition is required in central or peripheral bronchial airways, use of a mouth piece is recommended to minimize deposition in mouth and upper bronchial airways. Charged particles can also be utilized to filter out toxic constituents that may approach sensitive lung regions. Acknowledgments
The authors wish to thank Dr. Mehdi Azhdarzadeh, University of Alberta Edmonton, Canada, for his support in reviewing and modifying the manuscript. Funding: This work was funded by the Higher Education Commission of Pakistan under the scholarship program (Overseas Scholarships for Pakistani Nationals).
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Author Disclosure Statement
The authors declare that there are no conflicting financial interests.
16.
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Received on November 3, 2014 in final form, February 8, 2015 Reviewed by: Philip Kwok Bahman Asgharian
Address correspondence to: Hussain Majid, PhD Division of Physics and Biophysics Department of Materials Research and Physics University of Salzburg Hellbrunnerstrasse 34 A-5020 Salzburg Austria E-mail: [email protected]
