Targeted delivery of liquid microvolumes into the lung

Abstract

The ability to deliver drugs to specific sites in the lung could radically improve therapeutic outcomes of a variety of lung diseases, including cystic fibrosis, severe bronchopneumonia, chronic obstructive pulmonary disease, and lung cancer. Using conventional methods for pulmonary drug administration, precise, localized delivery of exact doses of drugs to target regions remains challenging. Here we describe a more controlled delivery of soluble reagents (e.g., drugs, enzymes, and radionuclides) in microvolume liquid plugs to targeted branches of the pulmonary airway tree: upper airways, small airways (bronchioles), or the most distal alveoli. In this approach, a soluble liquid plug of very small volume (<1 mL) is instilled into the upper airways, and with programmed air ventilation of the lungs, the plug is pushed into a specific desired (more distal) airway to achieve deposition of liquid film onto the lung epithelium. The plug volume and ventilation conditions were determined by mathematical modeling of plug transport in a tubular geometry, and targeted liquid film deposition was demonstrated in rat lungs by three different in vivo imaging modalities. The experimental and modeling data suggest that instillation of microvolumes of liquid into a ventilated pulmonary airway could be an effective strategy to deliver exact doses of drugs to targeted pathologic regions of the lung, especially those inaccessible by bronchoscopy, to increase in situ efficacy of the drug and minimize systemic side effects.

Keywords: alveoli; liquid instillation; lung airway; lung disease; pulmonary drug delivery.

Fig. 1.

Liquid film deposition in targeted generations of the pulmonary airway. (A) Liquid film deposition in a targeted region of the lung can be achieved by varying the initial plug volume and ventilation parameters. Liquid film can be delivered to the proximal airways by instilling a small liquid plug and inspiring air or to the distal airways by repeated cycles of plug transport, rupture, and reformation during continued ventilation. (B) Steps of the process: (i) Instillation of a liquid plug into an airway by positive air pressure. (ii) Liquid film deposition on the airway surfaces by moving plugs. (iii) Plug rupture on the airway surface. (iv) Decrease in airway diameters during expiration. (v) Plug reformation due to sufficient reduction in airway diameter. (vi) Continued film deposition by transport of reformed plugs. (C) Liquid film movement by surface tension gradient or gravity. (D) The proximal and distal airways of human and rat lung airways.

Fig. 2.

Liquid plug transport and film generation in a tube. (A) A liquid plug traveling in a tube with inner radius r deposits a liquid film with dimensionless thickness b* = b/r ∼ Ca^2/3. (Inset) Microscopic image of a liquid plug of a length L in a glass capillary. Dotted lines outline menisci. (Scale bar: 500 μm.) (B) A plug of DI water produced b* = 1.65Ca^2/3 in a glass capillary. (C) A liquid plug ruptures and deposits a collar on the wall when its volume V reduces to the meniscus volume V_M = kr³. (D) V_M was obtained for various contact angles 20° < θ < 50° and tube radii 100 μm < r < 1,000 μm representing rat airway diameters. (E) When r decreases, a plug can be reformed and moved distally under pressure P₀ against the resisting viscous force F_Vis and surface tension force F_ST. (F) P₀ was determined for various surface tension of liquid plug σ_P. (G) The plug reformation volume V_R ∼ 5.6r³ was calculated for smaller airways. (H) Liquid film can move on the airway surfaces by gravity force F_G against resisting adhesion force F_Adh. (I) Liquid collar volume V_C required for the gravity-driven film flow was calculated. (J) Ratio of F_G to F_Adh was determined to estimate their relative contributions to film flow.

Fig. 3.

Analysis of liquid plug transport and film generation in rat lungs. (A) At total lung capacity (TLC ∼ 12 mL), airway diameters are a function of airway generation G_N as $d_N^{\mathrm{\ast }}=d_N/d_0=2^{-N/4.3}$. (B) Similarly, airway diameters at residual air volume (RV ∼ 2 mL) and functional residual capacity (FRC ∼ 6 mL) are $d_N^{\mathrm{\ast }}=2^{-N/3.3}$ and $d_N^{\mathrm{\ast }}=2^{-N/3.75}$, respectively. (C–E) In the proximal airways (G₀–G₁₅), the capillary number is Ca₀ = Ca₀(r₀/r_N)²/2^N (C); the dimensionless film thickness is $b_N^{\mathrm{\ast }}=kC{a}_N^{2/3}$, where k = 1.6 (D); and the dimensionless plug volume is $V_N^{\mathrm{\ast }}=\left(V_0^{\mathrm{\ast }}-{\displaystyle {\int }_0^{N-1}{V}_{ND}^{\mathrm{\ast }}dN}\right)/2^N$, as shown for $V_0^{\mathrm{\ast }}=0.15$, 0.4, and 1.2, and Ca₀ = 1.53 × 10⁻³ (E). (F) In the distal airways (G₁₆–G₂₃₊), the plug speed U_N depends on the plug viscosity μ_P and effective pressure P_E.

Fig. 4.

Liquid film deposition in targeted regions of the rat airway. (A) Near-infrared (NIR) imaging was used to visualize liquid film deposition on airway surfaces by instilling microliter-volume liquid plugs containing indocyanine green (ICG) dye. Confocal imaging was used to verify film deposition in alveoli by fluorescent microbeads. (B) Film deposition in G₀–G₅ (35-μL plug) and G₀–G₁₅ (110-μL plug) was verified by fluorescence imaging through the ventral aspect of the lung. (Scale bar: 1 cm.) (C) Film deposition into alveoli (i.e., G₀–G₂₃₊) was verified by fluorescent imaging following instillation of a 110-µL plug and continuous air ventilation for ∼10 min. Time constant τ of the fluorescence increase for plugs entering alveoli was determined to be ∼250 s. (Scale bar: 1 cm.) (D) Fluorescent images of lung cross-sections confirming CFSE film deposition in G₀–G₅, G₀–G₁₅, and G₀–G₂₃₊. (Scale bar: 200 µm.) (E) Liquid deposition into subpleural alveoli (i.e., G₀–G₂₃₊) was confirmed using fluorescent microbeads. (Scale bar: 50 μm.)