Basic Principles And Mechanisms Of Liquid Jet Injectors Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

An earlier physical needle-free approach with an initial interest in the mid-twentieth century was the high-speed liquid jet injector which delivery drugs and vaccines employing high-speed jet to puncture the skin without the use of a needle (SCHRAMM-BAXTER & MITRAGOTRI, 2004 e 415).

Liquid jet injectors basically consist of a power source (compressed gas or spring responsible for generation of high-velocity jet), piston, drug-loaded compartment and a nozzle with orifice size in general ranging between 150 and 300 μM (ARORA et al., 2008). These devices are hand-held, thus the vaccinators hold the nozzle against the skin of a vaccinee and trigger the actuation mechanism, the power source pushes the piston which impacts the drug-loaded compartment and releases the drug solution through the nozzle orifice as a liquid jet (ARORA et al., 2008; GIUDICE & CAMPBELL, 2006). The high-speed jet (with velocity ranging from 100 and 200m/s) first form a hole in the skin followed by dispersion of the fluid through the hole into the porous skin structure (BAXTER & MITRAGOTRI, 2005). Then, the liquid jet penetrates the skin and delivers drugs subcutaneously, intradermally, or intramuscularly according to the mechanical properties of the fluid stream (GIUDICE & CAMPBELL, 2006; SCHRAMM & MITRAGOTRI, 2002).

The hole depth plays a key role to obtain a good injection once it influences the type of delivery (intradermal, subcutaneous or intramuscular) as well as the efficiency of delivery (SCHRAMM & MITRAGOTRI, 2002). Therefore, it is extremely important to study and understand the mechanism involved in the hole formation and liquid dispersion through the skin by the jet.

The penetration depth as well as the shape of liquid dispersion are governed by the orifice diameter and by jet exit speed so that different combinations of these parameters can yield the same jet dispersion pattern. Although neither jet velocity nor nozzle diameter are sufficient to completely characterize the outcome of a jet injection, the parameter exit jet power (P), demonstrated at equation 1, effectively describes the performance of jet injectors (ARORA et al., 2008; MITRAGOTRI, 2006).

P = 1/8 πρ D2U3 (1)

where, P is exit jet power, D is nozzle diameter, U is jet velocity and ρ is liquid density. This equation evidence that both nozzle diameter and jet velocity influence the characteristic of the jet injection (MITRAGOTRI, 2006).

After penetration into the skin, dispersion of the jet occurs by convective flow in porous media governed by Darcy's law described at Equation 2 (SCHRAMM & MITRAGOTRI, 2002):

Q = KD/μ x A x ∂P/∂r (2)

where Q is the volumetric flow rate, KD/μ is the hydraulic conductivity, A is the area available for fluid transport and ∂P/∂r is the pressure gradient.

Through the analyses of this law it can be noticed that various events in jet penetration are dependent on the jet parameters, diameter and velocity. The pressure gradient, which is created by the high impact pressure of the liquid jet on the skin, depends on the jet velocity and diameter. The A, which is the hole surface area created by jet, is also likely to depend on the diameter of the impacting jet (SCHRAMM & MITRAGOTRI, 2002).

Moreover, the mechanical properties of skin, mainly Young´s modulus, which is a measure of the skin elasticity, also have an important role to determine the jet penetration and dispersion within skin (BAXTER & MITRAGOTRI, 2005). The increase in Young´s modulus decreases the penetration depth and completeness of injection. For an example, an increase of threefold in skin´s Young´s modulus decreased the fullness of injection from near 100% to 10% (MITRAGOTRI, 2006).

The liquid jet injectors can be divided into two groups according to the number of injections executed with a single device (MITRAGOTRI, 2006):

a) Multi-use-nozzle Jet Injectors (MUNJIs):

MUNJIs that provide repeated injections from a single reservoir were the first kind of liquid jet injector used for immunization (MITRAGOTRI, 2006). The main advantage of such devices is the rapid immunization of a large number of people (allow up to 1000 subjects to be vaccinated per hour) and because of that they were widely used from the 1950s to the 1980s in mass vaccination against diseases such as smallpox, measles, yellow fever, cholera, hepatitis B, influenza and polio (MITRAGOTRI, 2005; GIUDICE & CAMPBELL, 2006; LEVINE, 2003).

However, the use of MUNJIs was discontinued by health authorities due to an outbreak of hepatitis B infection that occurred in 1985 and was related with the use of this device, presumably due to contamination of the jet injector by splash back of interstitial liquid or blood from the skin into the nozzle. MUNJIs did not have any disposable parts (ARORA et al., 2008; GIUDICE & CAMPBELL, 2006). Consequently, many efforts have been made to increase the safety of these devices (GIUDICE & CAMPBELL, 2006).

In this context, it was created a new generation MUNJI, one example is HIS-500ƒ’, with a disposable plastic cap to perform as a shield between the injector nozzle and the skin to reduce the risk of contamination between injections. Kelly, K., (2008) analyzed the safety of this device through determination of the presence of hepatitis B virus (HBV) contamination in post-injection samples immediately following injection in HBV-carrier adults, and found that of the 208 post-injection samples evaluated, 8,2% were positive for HBV, demonstrating a significantly higher contamination rate than the 0% threshold. Now, the company is working to discover the root cause of the HIS-500ƒ’ contamination identified in the safety study, this work will conduct to corrective actions and/or design modifications essential to eradicate the risk of contamination (KELLY et al., 2008).

b) Disposable Cartridge Jet Injectors (DCJIs):

DCJIs administrate a single injection from a reservoir and can be partly disposable (a disposable liquid reservoir in conjunction with a non-disposable actuation mechanism) or be fully disposable. These devices have the advantage of avoiding cross contamination, because the fluid stream is delivered within a disposable vaccine cartridge and nozzle, so it is used a new cartridge and nozzle for each patient .

The first DCJIs developed were used for lower workload situations, but nowadays some DCJIs can be used for mass immunization campaigns (GIUDICE & CAMPBELL, 2006). Currently there are several jet injectors that are FDA approved: Biojector® 2000, Medi-Jector Vision, Injexâ„¢ and LectraJet® (

An advantage of jet injectors is that they can operate with the same formulations designed for needle-based injections, reducing times of development and clinical trials. Although, many works in the literature suggest that drug stability is preserved after the exposure to high shear stresses during jet injection, it is necessary to check the stability of the vaccine administrated by this device (MITRAGOTRI, 2006). Furthermore, the jet injector enhance immune responses which might be due to a wide distribution of vaccine in the dermis, hypodermis and muscle promoted by these devices and also as a result of increased inflammation, leading to recruitment of more immune cells to the injection site. However, when comparing the tissue damage caused by the jet injector with the conventional needle injection, the results are controversy over the determination of which would cause more adverse events (LAMBERT & LAURENT, 2008).

Over the years many studies have been conducted in order to check the safety, tolerability and immunogenicity of needle-free liquid jet injection to delivery vaccines when compared with conventional syringe and needle-based immunizations, as demonstrated by Table X.


Therefore, although the needle-free liquid jet injection have been used for many years and have advantages such as improved safety for the vaccinator, vaccinee, and community; easier and speedier vaccine delivery; and reduced cost (GIUDICE & CAMPBELL, 2006), it has not yet attracted wide acceptance mainly due to cross-contamination, poor reliability, painful bruising and bleeding (MITRAGOTRI, 2006). It generally cause less or equal pain than a needle or syringe injections (KELLY et al., 2008).

New approaches have been developed and studied with the aimed to improve the needle-free liquid jet injection acceptance. As an alternative the use of devices with smaller nozzle diameter associated with reduction of injection volume could prove helpful once these changes may reduce the incidence of deep penetration, decreasing the pain and bleeding (MITRAGOTRI, 2006). By using this principle, it was developed a new strategy of jet injection, a pulsed microjet device, which operates with high-velocity but small jet diameters and extremely small volumes to allow shallow skin penetration, precise injections and potentially reduced pain and bleeding. This study was conducted using insulin as a model drug, but can be potentially used to delivery vaccines once the shallow penetration facilitates the contact of Langerhans cells with the antigen, being interesting for vaccination (ARORA et al., 2007).

More recently, it was hypothesized that the poor reliability as well as painful bruising and bleeding of the needle-free liquid jet injection was due in part to the high and constant jet velocity with which drugs are delivered, being important the employment of appropriate jet velocity. This one cannot be too low - to allow the jet to penetrate in the outermost layers of the skin, and cannot be too high - because in this case the skin is not able to absorb all the fluid entering it, resulting in significant splash-back and overflow of the drug fluid from the skin during the dispersion stage and also may be responsible for pain and bruising during the injections. Thus, a jet injector capable of dynamic control of the temporal jet velocity profile during a single injection pulse was developed and tested. The new liquid jet injector uses two jet velocities: At the beginning of the injection a higher jet velocity is employed to ensure tissue penetration and this one remains for a sufficient period to achieve the desired injection depth. The jet velocity then transitions to a lower velocity, which is not capable of causing skin penetration and which the liquid flow is adequate to the fluid absorption capacity of the tissues avoiding splash-back. This development has the prospective to improve the reliability of dosing in needle-free jet injections (STACHOWIAK et al., 2009).

4. Powder injectors- Basic principles/mechanism, currently available devices, safety

Device used to improve the permeation of drugs and vaccines, in solid form, through the skin. Also known as particle-mediated, ballistic or biobalistic and gene gun, with the latter term used exclusively for DNA delivery (PEACHMAN; RAO; ALVING, 2003).

The use of this method was first described in 1986 for the delivery of DNA-coated metal particles into plant cells to provide genetic modifications. By 1990, devices were developed for delivery of conventional and DNA vaccines to humans (MITRAGOTRI, 2005). It is considered the best established physical method of DNA vaccination (KENDALL, 2006).

In this needle-free technique, drugs or immunogenic, in dry powdered form, are accelerated in a high-speed gas jet forming a stream of particles capable to penetrate the skin (or mucosa) and provide a desirable pharmacological effect (KENDALL, 2006).

Powder injectors are composed of a chamber containing the compressed gas, which is the power source, one compartment with the particulate drug formulation, and a nozzle that directs the output flow of particles. The formulation compartment is isolated by two diaphragms of a few microns thick. Upon triggering the actuation mechanism, the compressed gas breaks the diaphragms forming a flow that carries the particles to the nozzle which directs the flow to skin. The jet impact on skin surface disrupts the stratum corneum barrier, leaving some particles trapped in this layer but the higher percentage reaches the viable epidermis for the desired therapeutic action (ARORA; PRAUSNITZ; MITRAGOTRI, 2008; LIU; COSTIGAN; BELLHOUSE, 2008).

The particle delivery across the stratum corneum is determined by the key parameters: the impact velocity of flow in the skin and particles size and density and in order to correlate the particles properties with their penetration into the skin, a combined parameter, namely particle impact parameter, which represents momentum per unit cross-sectional area of the particle, has been defined as ρνr, where ρ, ν and r are particle density, impact velocity and particle radius, respectively. This parameter is proportional to the depth of particles penetration into the skin (ARORA; PRAUSNITZ; MITRAGOTRI, 2008).

KENDALL et al., 2004 (VERIFICAR) noticed that for a given value of ρνr, an increase in particle size corresponds to a decrease in particle velocity at constant density which resulted in a decrease in penetration depths. Considering that it is important to maintain a uniform particle impact parameter for targeting specific skin layers, a way to control the velocity of the particles is varying gas pressure (ARORA; PRAUSNITZ; MITRAGOTRI, 2008). VER AS REFERÊNCIAS. - COLOCAR KENDALL ABAIXO…

The declining trend in the penetration depth due to increase in particle radius suggested above was confirmed by employing a theoretical penetration model, proposed by Dehn (1987), in which the force of deceleration acting on each particle is divided into a inertial force and a static force, required to accelerate the target material up to the speed of the particle and to yield the target material, respectively.

D = ½ ρtApν2 + 3Aσy (3)

D is the force acting on the particle, ν is the instantaneous particle velocity, A is the projected area of the particle, σy is the yield stress, ρ is the density and subscripts p and t apply to the particle and target, respectively. Integrating of expression (3) leads to the theoretical penetration depth relationship:

Where νi is the particle impact velocity (KENDALL; MITCHELL; WRIGHTON-SMITH, 2004; LIU; COSTIGAN; BELLHOUSE, 2008).

Therefore, parameters such as configuration of the delivery device, gas pressure and particle properties (size distribution, density and morphology) are key features for providing the delivery and distribution of an effective dose of vaccine powders into the skin and, thus, should be optimized (DEAN; CHEN, 2004; KENDALL; MITCHELL; WRIGHTON-SMITH, 2004).

Other parameters that influence the penetration depth of particles delivered ballistically to the skin are the operating conditions temperature and humidity and also the incomplete homogeneity of the skin target (variety of the skin). The mechanical properties of the stratum corneum are greatly influenced by its water content and temperature which, when increased, modify the fluidity of the stratum corneum favoring the particle penetration. Skin thickness also influences the final location of the particles that are found in deeper layers when the skin thickness is small. These parameters are strongly correlated with the region of skin application and by age (KENDALL; MITCHELL; WRIGHTON-SMITH, 2004; KENDALL et al., 2004; CEVC; VIERL, 2010; MITRAGOTRI, 2005).

These devices have the advantage of displaying a spatial distribution of particles in the skin which is preferential for DNA vaccine, for releasing the particles directly in its site of action as well as requiring small amounts of DNA (LIU, 2007; PEACHMAN; RAO; ALVING, 2003). Gene gun immunization has the advantage of targeting broader immunization areas than i.d. injection alone. The DNA gets into the cytoplasm of some cells, so it eliminates the problem of spreading DNAacross the plasma membrane.

Unlike liquid-jet injectors, which routinely deliver the vaccine to the subcutaneous or intramuscular space, ballistic methods mainly deliver the vaccine to the superficial layers of the skin and therefore naturally target Langerhans cells (413).

Langerhans cells have potent antigen-processing and -presentation ability and are important in the initiation and maintenance of immune responses. Delivering vaccines in close proximity to the Langerhans cells, sometimes directly to these cells by powder delivery, may facilitate the antigen-recognition and -uptake process. The relative lack of nerve endings in the epidermis will likely make the epidermal powder immunization safer than intradermal needle injection (424).

An additional and important advantage is the fact that vaccines in powder form are reasonably stable, which may eliminate the necessity of the "cold chain" in vaccine delivery, making transportation and storage simple and cost effectively. "Cold chain" refers to the materials, equipment and procedures required to maintain vaccines within a given temperature range from the time of their production until they are given to patients (LIU,2007; GIUDICE; CAMPBELL, 2006).

Clinical studies have shown that the use of these devices is safe and has been well tolerated in humans (FULLER; LOUDON; SCHMALJOHN, 2006). The symptoms that are frequently reported soon after the application include mild erythema, hyper-pigmentation, flaking and discoloration at the injection site and are due to antigen processing by antigen presenting cells (APC) and production of cytokines that recruit more cells to the application site. In some cases it has also been reported some transient sensations such as tingling, tightening or burning. Most symptoms disappeared within a month except the discoloration that persists for up to six months (ARORA; PRAUSNITZ; MITRAGOTRI, 2008; FULLER; LOUDON; SCHMALJOHN, 2006).

Table Y describes some of the various studies evaluating the aspects immunogenicity, safety, and tolerability of employing powder injection in humans.


Ler foneticamente


Dicionário - Ver dicionário detalhado







revelar um filme