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Effect of air pockets in drug delivery in jet injections

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Needle-free jet injections are actuated by a pressure impulse that can be delivered by different mechanisms, and the resultant jets are O(10^2) m/s. Here, we report on the effect of entrapped air bubbles since filling procedures for pre-filled ampoules can induce bubbles, especially for viscous fluids. We use spring-piston devices as the principal actuation mechanism and vary both the location and size of the initial bubble. We find that the bubble location does have a statistically significant ( p <0.05) effect on the jet exit speed, based upon the volumetric flow rate. However, we reveal subtle features such as intermittent atomization when the gas pockets pass through the orifice and de-pressurize, which leads to spray formation and a temporary increase in jet dispersion, both of which can lead to product loss during an injection. These results have implications for the development of pre-filled ampoules for jet injection applications.
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Effect of air pockets in drug delivery in jet injections
Pankaj Rohilla, Emil Khusnatdinov, and Jeremy Marston
Department of Chemical Engineering, Texas Tech University, Lubbock, TX 79409
Needle-free jet injections are actuated by a pressure impulse that can be delivered
by different mechanisms, and the resultant jets are O(102) m/s. Here, we report
on the effect of entrapped air bubbles since filling procedures for pre-filled ampoules
can induce bubbles, especially for viscous fluids. We use spring-piston devices as
the principal actuation mechanism and vary both the location and size of the initial
bubble. We find that the bubble location does have a statistically significant (p <
0.05) effect on the jet exit speed, based upon the volumetric flow rate. However,
we reveal subtle features such as intermittent atomization when the gas pockets
pass through the orifice and de-pressurize, which leads to spray formation and a
temporary increase in jet dispersion, both of which can lead to product loss during an
injection. These results have implications for the development of prefilled ampoules
for jet injection applications.
INTRODUCTION
Conventional oral administration of drugs is
limited by low bioavailibility caused by the
acidic environment in the stomach and restric-
tive intestinal epithelium [1]. The most com-
mon alternative to oral drug delivery are hy-
podermic needle syringes, which have numer-
ous caveats including needle-stick injuries, cross-
contamination, and needle-phobia [2,3,4] and
potential limitation on injectability of viscous
drugs. Thus, evidently there is a need for an
effective needle-free technique for drug admin-
istration. Needle-free jet injections are one of
the alternative techniques where a high-speed
narrow jet (diameter, dj100-200 µm) punc-
tures the top layer of the skin (i.e. stratum
corneum) and deposits the drug into the intra-
dermal/subcutaneous/intramuscular tissue [5].
Hypodermic syringes and needle-free jet injec-
tors are medical devices which need an ampoule
or barrel to store medication or biological drugs
before injection. These ampoules are either sup-
plied prefilled or can be loaded manually. One of
the advantages of prefilled ampoules is the low
variability in the amount of drug without any air
pocket [6]. However, air pockets can form within
the liquid inside the ampoules during loading or
transportation, which can further be amplified
by the viscosity effects of the contained fluid.
Such air pockets can affect the volume and other
variables related to drug delivery. The effect of
air pockets on the efficacy of drug delivery is still
largely unknown. This demands a systematic
parametric study to further the current under-
standing.
In general, the presence of air pockets within a
drug is either undesirable or could be harnessed
in several medical applications[7,8,9,10,11].
Ultrasound imaging [12,13], lithotripsy [14],
controlled cavitation in gene delivery [13] and
laser-induced jet injection [15,16,17] are some
of the applications where energy generated due
to the formation and collapse of air pockets can
be utilized. On the other hand, the phenomenon
of collapsing air pocket also generates microjets
and shock waves, which can rupture red blood
cells in artificial heart valves and can be detri-
1
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mental to soft tissue [18,19,20].
Introducing air bubbles (0.1-0.2 ml) before
drawing medication into a syringe was common-
place practice among clinicians and nurses in
the United States before the widespread use of
disposable syringes in the 1960s [6,21]. These
air bubbles were used to correct the medica-
tion dosage to account for the dead volume in
the needle hub. Moreover, air pockets when in-
jected with the medication were thought to pre-
vent the seepage or backflow of the medication
into the subcutaneous layer through the needle
tracks [22]. Multiple studies showed contradic-
tory results to this hypothesis [23,24]. Moreover,
air bubbles occupy the available volume for the
medication which cause dosage inaccuracy [25].
Thus, it is recommended to avoid air bubbles in
syringe injections [6,21,25].
In jet injection, air bubbles can affect the co-
herency and continuity of the jet stream in addi-
tion to dosage errors. This phenomenon intensi-
fies with an increase in plunger speed. Thus, in
the context of jet injectors where the jet speeds
can be O(102) m/s, it is important to study
the effect of air pockets in the nozzle on drug
delivery via jet injection. Although researchers
have studied the effect of cavitation in the stor-
age and injection of therapeutics in the past
[7,8,26,27,28,29,30,31,32], there is a lack
of detailed study to understand the effect of air
pockets in intradermal injections via jet injec-
tors.
Here, we study the effect of air pockets present
at different locations within the nozzle cartridge
on the hydrodynamics and efficacy of drug deliv-
ery via jet injection. The physical properties of
the liquid and nozzle dimensions were kept con-
stant. We studied the atomization of the bubbles
within the liquid and the dispersion of the jet
when bubbles exit through the orifice. In addi-
tion, ex vivo studies were conducted on porcine
skin to understand the effect of air pockets on
the delivery efficiency.
MATERIAL AND METHODS
A spring-based jet injector (Bioject ID pen) was
used in the experiments, which is described in de-
tail in other works [33,34,35], but comprises a
stiff spring piston with a cartridge with an orifice
of diameter, do157 µm. DI water was filled in
a transparent nozzle cartridge with a volume ca-
pacity of 0.11 ml. Air pockets were introduced at
different locations inside the nozzle cartridge (as
shown in figure 1(a)) using 1 ml luer-lock syringe
with 24-gauge needle. Furthermore, the plunger
was carefully replaced to avoid the escape of air
pockets via the orifice exit. We have used five
different locations within the nozzle cartridge to
understand their effect on the bubble dynamics
with time. These locations were selected on the
basis of their probability of occurrence. For lo-
cation L1, an air pocket was introduced at or in
close proximity of the plunger tip. It should also
be noted that the bubble locations, L2and L3
are isotropic radially.
To capture the bubble and jet dynamics, a
high-speed video camera (Phantom V711, Vi-
sion Research Ltd.) was used at frame rates
in a range of 10,000-30,000 frames per second.
The tip of the plunger was tracked to get the
plunger displacement (figure 1(b)) with time
using Photron FASTCAM Analysis (PFA ver.
1.4.3.0 ) software. Plunger speed was then esti-
mated from the slope of the displacement-time
plot after the initial ringing phase, e.g. t > 5
ms (figure 1(c)). Furthermore, we estimated the
jet speed at the orifice exit, vj(figure 1(d)) from
plunger speed using mass conservation, assuming
the liquid to be incompressible at the experimen-
tal conditions.
A single side-view perspective was sufficient to
track the plunger tip. However, to understand
the bubble dynamics and for qualitative analysis
of bubbles within the nozzle during a jet injec-
tion, we employed two cameras (second camera:
Phantom Miro 311, Vision Research Ltd.) with
orthogonal views. In addition, using extension
tubes with Nikon micro-nikkor 60 mm lenses, we
achieved typical effective pixel sizes in a range of
10-30 µm/px.
Volume fraction was used to quantify the size
of the air pockets, which can be defined as a ratio
of the volume occupied by an air pocket (Vb) and
the total liquid volume inside a nozzle cartridge
without any air pocket (V). We measured the
2
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Figure 1: Air pockets in a nozzle cartridge. (a) Five different locations of air pockets inside a nozzle
cartridge, (b) trajectory (in red) of plunger motion inside the nozzle for different locations of air pockets,
(c) plunger-displacement with time for a jet injection with and without air pockets, and (d) volume fraction
(Vb/V ) and jet speed (vj) for different locations of air pockets. Scale bar represents 3 mm (a,b).
volume fraction occupied by air pockets at differ-
ent locations by weighing the liquid-filled nozzle
with and without air pockets. Figure 1(d) shows
the volume fraction of air pockets introduced at
different locations inside the nozzle.
To measure the force profile during the jet in-
jection, a miniature load button cell (Futek-LLB
130, 50 lb, FSH03380 ) was placed at a distance
of 2 mm away from the orifice exit of the nozzle
to avoid contact with the nozzle during jet injec-
tion. Force profiles of jet injection were recorded
at a sample rate of 4,800 Hz.
To conduct ex vivo studies, porcine skin was
used as a skin model for human skin. Porcine
skin patches (thickness 3-5 mm) were har-
vested from the side regions of Yorkshire-Cross
pigs (age: 13 weeks), euthanized in the depart-
ment of Animal Sciences (Texas Tech Univer-
sity). These skin patches were kept in a -80C
freezer, but thawed to room temperature before
jet injection. We cut skin across the center of the
injection site to visualize the dispersion of the
liquid after jet injection. Trypan Blue (Sigma
Aldrich) was used as a dye (1 mg/ml) in DI wa-
ter to aid in the visualization of skin blebs, and
a custom Matlab script was used to estimate the
dimensions of skin blebs. One must note that
although fresh porcine skin is a close model to
human skin at high humidity conditions [36], we
used skin after a single freeze-thaw cycle.
We performed one-way ANOVA tests to check
the statistical significance of various parameters
used in the study with a significance level of α
= 0.05.
RESULTS AND DISCUSSIONS
Bubble Dynamics
Air pocket collapses with the inertial impact of
the plunger, atomizing into multiple microbub-
3
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Figure 2: Snapshots of bubble dynamics for different locations of air pockets inside
the nozzle cartridge. Snapshots of bubble dynamics corresponding to different time
frames for location L1(ai)[0, 0.1, 0.2, 0.27, 0.37, 1.5, 2.27, 5.73, 61.07] ms; for location
L2(ai)[0, 0.2, 0.3, 0.5, 1.0, 2.9, 4.57, 6.23, 61.77 ms; for location L3(ai)v[0, 0.1, 0.2,
0.27, 0.37, 1.5, 2.27, 5.73, 61.07] ms; for location L4(ai)[0, 0.67, 0.167, 0.43, 0.67, 1.47, 2.23,
3.5, 64.67] ms; for location L5(ai)[0, 0.5, 0.6, 0.67, 0.73, 1.1, 1.83, 5.3, 30.33] ms.
bles. We captured the qualitative behavior of
these micro bubbles with time as the plunger
pushes the liquid out via a narrow orifice. As
shown in figure 1(c), plunger motion exhibits a
ringing phase caused by the sudden impact of
the spring piston on the plunger, followed by
a nearly linear and stable motion. Average jet
speeds were calculated from the slope of this lin-
4
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ear region of the plunger displacement-time plot.
Introduction of air pockets did not alter the jet
speed (vj) significantly which lied in a range of
142-146 m/s except for the case of air pocket
introduced at the center of the nozzle cartridge
(L5).
Among the different locations of air pockets,
L5showed a distinctive behavior. The plunger
moved 3.7 mm within a short period of 1.5
ms, thus resulting in a rapid collapse of the air
pocket. The collapsing air pocket generates a
pressure opposing the plunger motion, and the
interplay of forces during this period is mani-
fested by the recoiling trajectory of the plunger,
as shown in the last frame of figure 1(b). The
impulse is much stronger, and resistance in the
early stages is much weaker, leading to signif-
icant over-pressure (noted by a force increase
of 33%). This resulted in a prolonged re-
coil/ringing phase. Due to this extended ring-
ing phase, we calculated the average jet speed
by fitting a line after this phase to the plunger
displacement-time plot. For L5, average jet
speed was lower (128.5±3.8 m/s). Another im-
portant characteristic of air pockets introduced
at different locations inside the nozzle was the
volume fraction of the air pocket, which was
nearly half at location L5. In the case of other
locations, the air pockets occupied 20% of the
total available volume.
Figure 2shows a montage of frames summa-
rizing the bubble dynamics for air pockets placed
at different locations. When the plunger is trig-
gered, the fluid pressure in the cartridge in-
creases rapidly up to O(10 MPa), causing the
air pocket to collapse and disintegrate into mi-
crobubbles. The trajectory of such microbubbles
largely depends on the pressure gradient, which
further depends on the flow disturbance caused
by the bubbles collapsing under high pressure.
Although numerous studies have been conducted
to understand the behavior of bubbles with in-
ertial impact [29,30,37], the underlying physics
behind the bubble dynamics may vary on the
basis of applications.
The life cycle of microbubbles depends on the
location where the air pocket was introduced ini-
tially. For air pockets present near the outlet (L3
and L4), microbubbles exit the nozzle at an early
stage whereas for air pockets introduced farther
upstream, not all of these bubbles exit; it can
be noticed from ith frames in figure 2that mi-
crobubbles were present in the tapered section of
the nozzle at the end of injection for air pocket
introduced at locations L1,L2, and L5.
Figure 3: Orthogonal views of nozzle car-
tridge with microbubbles inside the liquid cor-
responding to time, t= 5.5 ms for air pocket
introduced at location L2.Scale bar represents 3
mm. Note: A vertical line on the left frame is an ar-
tifact of the nozzle and is not related to the contained
fluid or air pockets.
Figure 3shows orthogonal views of microbub-
bles inside the nozzle at same instant (t= 5.5
ms). Different views shown in figure 3yield dif-
ferent bubble size distributions at the same in-
stant of time due to the lensing effects of the
nozzle geometry. Thus, to avoid the erroneous
measurement, we did not quantify the bubble
size distribution with time.
Assuming the air bubble to be an ideal gas,
we can estimate the volume of the wedge-shaped
bubble cloud formed after the collapse of an air
pocket at location L5, using ideal gas law ( P V =
nRT =const.):
P1V1=P2V2(1)
Where P1and P2are atmospheric pres-
sure (105Pa) and pressure inside the bubble
(5×107Pa, using peak force of F1 N), re-
spectively. V1and V2are initial volume of air
pocket (55 µL) and the volume of the wedge-
shape bubble cloud after the collapse, respec-
tively. Minimum height of the bubble cloud
(hmin) was estimated using:
5
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Figure 4: Impact force profiles for jet injections for different locations of air pockets. L0
represents the jet injection without any air pocket inside the nozzle. Shaded region represents
ringing phase during jet injection. n=3.
hmin V2
(πDi
2
4)(2)
Where Diis the inner diameter of the nozzle
barrel.
A slight asymmetry in the plunger causes a
wedge-shaped air volume that disintegrates from
left to right in the image sequence L5(a-i), there-
fore, we can expect a size distribution with
rmin 10 µm and rmax 10 µm, evidenced
by zoomed images where bubbles with size of
O(100 µm) can be easily seen. Moreover, many
bubbles with a size of the order of 1 pixel or less
were also observed.
Force measurements
To measure the impact force, liquid jets were im-
pinged on a load cell placed at a distance of 2 mm
away from the orifice exit. Figure 4shows force
profiles of jets with air pockets present at differ-
ent locations. The time duration of the jets for
air pocket locations L1,L2,L3,L4and L5were
37.5 ms, 34.8 ms, 35.8 ms, 33.5 ms, and
16.9 ms, respectively. In the absence of an air
pocket, the time duration of a jet was 38 ms. It
is noteworthy that the time duration of injection
was lower in displacement-time plot (figure 1(c))
due to the difficulties associated with tracking
the plunger tip towards the end of injection.
As the spring piston strikes the plunger, a ring-
ing phase can be observed in force profiles in the
initial stage (10 ms) of liquid injection. In the
absence of any air pockets, the peak force was
0.63 N and a similar peak force was observed
for air pockets present at locations L1,L2,L3,
and L4with values of 0.62 N, 0.76 N, 0.67
N, and 0.78 N, respectively. However, L5ex-
hibited a higher force of 1.03 N, with an in-
crease of 63%. After the peak force, the magni-
tude of the force profile was nearly the same for
all cases with ¯
F'0.4 N ( ¯
F=ρvj2Ao, where Ao
is the cross-sectional area of orifice exit) except
the case of L5with lower magnitude of the mea-
sured force. Further implications of force pro-
file and injection duration will be discussed in ex
vivo studies.
6
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Figure 5: Effect of bubbles on the jet coherency with orthogonal views. (a) liquid jet without
any bubbles (t= 1.4 ms), (b) bubble cloud in tapered section before exit (t= 9.9 ms), (c) spray-like jet
formation as the bubbles exit with the jet (t= 10 ms), and (d) diminishing atomization of jet as bubble
clouds exits the tapered section (t= 10.1 ms). Scale bar: 2 mm
Effect of microbubbles on jet
As pressurized microbubbles exit the orifice, they
undergo a rapid depressurization and expand, re-
sulting in a spray-like jet (figure 5). The mag-
nitude of the effect of microbubbles on the jet
depends on the size and the number of bubbles
exiting the nozzle orifice along the liquid jet.
Figure 5shows the effect of a bubble cloud
exiting the nozzle on the liquid jet with orthog-
onal views captured using two high-speed cam-
eras at a frame rate of 10,000 fps. The liquid
jet free of any effect of bubbles is shown in fig-
ure 5(a), where orthogonal views show that the
jet looks coherent from one side and slightly dis-
persed from the other side. In the next frame
(figure 5(b)), a cloud of air pockets (highlighted
in dashed yellow outlines) appeared in the ta-
pered section of the nozzle with spray-like jets
as the bubbles exit with the jet. As more bubble
cloud exits the nozzle, the jet dispersion grows
as shown in figure 5(c). With the majority of air
pockets exiting the orifice exit, the remnant ef-
fects of the bubbles on the liquid jet can be seen
in figure 5(d), but the jet will resume the steady
stream upon clearance of air bubbles.
Ex vivo studies
Dyed water was injected into the porcine skin
to understand the effect of air pockets on the
percentage delivery. Porcine skins were thawed
to room temperature before administering in-
jections. The thickness of the dermis layer of
Figure 6: Cross section view of skin blebs for:
(a) no air pockets, (b) air pocket at location L1,(c)
air pocket at location L2,(d) air pocket at location
L3,(e) air pocket at location L4and (f ) air pocket
at location L5. Scale bar represents 5 mm.
porcine skin harvested from different pigs (hence,
different colors in figure 6) was within 3 mm.
The effect of force exerted by the jet injector
(loading) in the normal and axial direction dur-
ing injection has been reported in an earlier
study [35], and therefore we used a recommended
normal load of 1 kg for the maximum delivery ef-
ficiency at which the injection was actuated.
After impingement, the liquid jet creates a
hole in the skin through which liquid propagates
inside the skin. The stiff poro-elastic structure of
the dermal tissue resists the liquid inflow inside
the skin, thus, limits the amount of liquid that
can be delivered with a single injection. To visu-
alize the dispersion of liquid inside skin after jet
injection, the skins were cut across the point of
7
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injection. Figure 6shows cross-sections of skin
blebs corresponding to the different location of
air pockets.
Figure 7: Effect of air pockets on effective-
ness of drug delivery. (a) delivery efficiency and
projected area of bleb cross-sections for jet injections
with air pockets at different locations (n=5 ) and (b)
aspect ratio of the blebs (AR =d/w), where dand w
are depth and width of skin bleb respectively (n=10 ).
Figure 7shows the effect of the location of
the air pocket on the delivery efficiency and
the dimensions of the bleb formed inside the
skin after jet injection. Delivery efficiency (η=
(mmr)×100/m) was measured from the weight
of liquid rejected at the top of the skin after jet
injection (mr) and total available volume in noz-
zle cartridge (m). Whatman filter papers were
used to absorb the rejected liquid on the top of
skin.
Presence of air pockets at locations L1,L2,
and L5showed higher percentage delivery of liq-
uid inside the skin. Effect of varying the location
of air pockets on the delivery efficiency of dyed
water was significant (p < 0.05). It is notewor-
thy that the delivery efficiency was affected by
the confluence of changing location and available
liquid volume inside the nozzle. As discussed
earlier, the volume of liquid inside the nozzle
changes with introduction of air pockets inside
the nozzle. Introducing an air pocket at location
L1showed higher percentage delivery than the
case of no air pockets for nearly the same force
profile. This increase in the percentage delivery
could be done due to the reduced liquid volume
to be injected inside the skin.
As shown in earlier studies, higher percentage
delivery was obtained for jet injection of liquid
in lower volumes [35]. It was hypothesized that
there is a limit of liquid volume which can be
injected into the skin without significant rejec-
tion. Here, with the introduction of air pockets,
the available liquid volume to be injected was
lower for locations L1and L5, resulting in higher
efficiency.
In addition, the percentage delivery was nearly
the same for location L3and L4as compared to
control case of L0. Bubbles exit early with a jet
for air pockets present at locations L3and L4. As
the high-speed liquid jet penetrates skin, it cre-
ates a channel to facilitate the further delivery
of incoming liquid. Any disturbance in the jet
shape in the initial phase could have an adverse
effect on the channel formation for liquid propa-
gation, thus resulting in lower percentage deliv-
ery and narrow dispersion patterns, as observed
for L3and L4. Higher peak force also helps in
increasing percentage delivery. In the case of air
pocket introduced at location L5, higher percent-
age delivery was observed; partly due to high im-
pact force (1.03 N) and lower available volume
of liquid to be injected (0.044 ml).
The effect of location of air pockets was signif-
icant on the projected area (p < 0.05) and the
aspect ratio of skin blebs (p < 0.05). Projected
area showed nearly the same trend as of deliv-
ery efficiency. In case of injection with an air
pocket present near the exit (L3and L4), skin
blebs showed large intrasample variation in their
8
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shape and their dimensions.
CONCLUSIONS
We investigated the effect of introducing air
pockets at various locations within the liquid
contained in a nozzle cartridge for jet injec-
tors. Air pocket collapses and forms microbub-
bles which affects the shape of the liquid jet. Air
pockets at different locations affected the peak
force during the initial ringing phase. Further-
more, ex vivo studies conducted on porcine skin
showed nearly the same or higher percentage de-
livery of dyed water inside skin. We conclude
that the high percentage delivery obtained for
air pockets at different locations was due to lower
available volume to be injected and higher peak
force. Moreover, the projected area and aspect
ratio showed a significant effect of various loca-
tions of air pockets in addition to a significant
effect on percentage delivery. Although the in-
troduction of air pockets helped in enhancing the
delivery efficiency of the drug, air pockets should
be avoided in the nozzle as it causes dosage inac-
curacy which can alter the efficacy of the vaccine.
The measurement of the force profiles showed
higher peak forces in the initial ringing phase due
to hammer effect. Furthermore, ex vivo stud-
ies conducted on porcine skin showed similar or
higher percentage delivery of dyed water inside
the skin. We conclude that the high percent-
age delivery obtained for air pockets could be at-
tributed to the lower available volume and higher
peak force. In addition, the project area and
aspect ratio showed a significant effect for vari-
ous locations of air pockets in addition to a sig-
nificant effect on percentage delivery. Although
the introduction of air pockets helped in enhanc-
ing the delivery efficiency of the drug, air pock-
ets should be avoided in the nozzle as it causes
dosage inaccuracy which can alter the effect of
the vaccine.
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ACKNOWLEDGMENTS
This work was financially supported by The
National Science Foundation via award CBET-
1749382.
AUTHOR CONTRIBUTIONS
P.R. and J.M. designed the experiments. E.K.
and P.R. conducted the experiments. P. R. an-
alyzed the data and wrote the manuscript. J.M.
reviewed and edited the manuscript.
COMPETING INTERESTS
All the authors declare no competing interests.
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