Needle-Free Injection Assisted Drug Delivery-Histological Characterization of Cutaneous Deposition.

BACKGROUND AND OBJECTIVES: Many cutaneous drug-delivery techniques rely on passive diffusion to deliver topical compounds to the skin. When attempting to deliver drugs to thicker lesions, such as skin tumors, modalities that do not rely on diffusion may serve as a better drug-delivery method. In this histological study, we aim to investigate the cutaneous delivery patterns of an electronic pneumatic needle-free injection device. STUDY DESIGN/MATERIALS AND METHODS: Needle-free-injection was investigated in 24 ex vivo porcine skin samples and one basal cell carcinoma (BCC) tissue sample. A needle-free injection device with a nozzle size of 200 µm delivered 80 µl compound ink (0.1 cc black ink: 5.0 cc saline) at low (30%/3.1 bar; n = 6 porcine skin; n = 1 BCC tissue), medium (50%/3.9 bar; n = 6 porcine skin), high (65%/4.6 bar; n = 6 porcine skin), and stacked (30 + 50%/3.1 + 3.9 bar; n = 6 porcine skin) pressures. Depth, width, and depth of maximum width of ink deposition were evaluated on histological slides. RESULTS: Depositions with small ink-lined vacuoles were seen intra-dermally in all samples, including the BCC tissue. Deposition depth was similar at low and medium pressures (924 vs. 994 µm; P = 0.873) but increased significantly with high pressure (1,564 µm; P = 0.010). When injections were stacked (3.1 + 3.9 bar), the depth remained similar to that of a single injection (931 µm; P = 1.000). The width of the deposition stayed comparable for low, medium, and high pressures when a single needle-free injection was performed (30% = 2,394 µm; 50% = 2,226 µm; and 65% = 2,757 µm; P = 0.09), but increased significantly with stacking (2,979 µm; P = 0.037). The depth of maximal width was superficially located in the papillary dermis at low and medium pressures (321 and 305 µm; P = 0.748) but shifted to the deeper reticular dermis with high pressure (950 µm; P = 0.004) and with stacking (734 µm; P = 0.004). CONCLUSIONS: In conclusion, with an electronically controlled, pneumatic needle-free injector, depth and width of a cutaneous deposition can be influenced by pressure and stacking, respectively. The pneumatic needle-free injection can potentially serve as a viable drug-delivery technique for cutaneous pathologies where dermal deposition is essential. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Transcutaneous pneumatic injection of glucose solution: a morphometric evaluation of in vivo micropig skin and tissue-mimicking phantom.

BACKGROUND: Needle-free, transcutaneous pneumatic injection systems can be used to deliver therapeutic solutions to targeted layers of skin in a minimally invasive manner. METHODS: To evaluate jet infiltration patterns and tissue reactions, 5% isotonic and 20% hypertonic glucose solutions were pneumatically injected into in vivo micropig skin. Gelatin TM phantom was additionally prepared to analyze penetration and dispersion patterns for different experimental settings. RESULTS: As immediate tissue reactions in the in vivo micropig skin, distinct pneumatic injection injury zones (PIIZs) in the dermis, extending from the papillary dermis deep into the dermo-subcutaneous junction, were generated with the 5% and 20% glucose solutions and with pneumatic pressures of 4.64 and 5.7 bars, respectively. PIIZs markedly decreased in appearance at 1 day after treatment, accompanied by inflammatory cell infiltration, and disappeared at 7 days post-treatment with increased collagen and elastin production. In TM phantom study, the PIIZs created by 20% glucose mainly comprised a single, homogenous, round to oval zone, whereas those created by 5% glucose were irregular and multi-lobular. CONCLUSION: The present study suggests that transcutaneous pneumatic injection therapy may exert mechanical stimulatory effects, immediate tissue shrinkage via hypertonic solutions, and late tissue regeneration effects during wound healing.

A miniature shock wave driven micro-jet injector for needle-free vaccine/drug delivery.

This article presents a miniature shock wave driven micro-jet generator to deliver liquid drugs into human skin, to a controlled depth, with minimal invasion. The device can release the vaccine/drug to the depth of dermal blood vessels, without breaching much of the microcirculation system of dermis. The drug delivery technique is needle-free, which can reduce pain, trauma, and contamination besides minimal dosage and systemic exposure. The device can also be used to deliver liquid or colloidal drugs into soft tissues in human. The mechanical analyses of the device were carried out by analyzing the strength of the impulse of the shock wave, measuring the velocity of the generated jet and capturing the pressure exerted by the jet on the target. The penetrating ability of the jet was investigated by delivering it into sample of human skin and gelatin slabs. Theoretical analyses were carried out on the physics of the delivery and the predicted results had a close agreement with the experimental observations. The development can offer an important cost-effective solution to needle-free health care worldwide. Biotechnol. Bioeng. 2016;113: 2507-2512. © 2016 Wiley Periodicals, Inc.

Er:YAG laser pulse for small-dose splashback-free microjet transdermal drug delivery.

The microjet injector system accelerates drugs and delivers them without a needle, which is shown to overcome the weaknesses of existing jet injectors. A significant increase in the delivered dose of drugs is reported with multiple pulses of laser beam at lower laser energy than was previously used in a Nd:YAG system. The new injection scheme uses the beam wavelength best absorbable by water at a longer pulse mode for elongated microjet penetration into a skin target. A 2.9 µm Er:YAG laser at 250 µs pulse duration is used for fluorescent staining of guinea pig skin and for injection controllability study. Hydrodynamic theory confirms the nozzle exit jet velocity obtained by the present microjet system.

Jet injectors: Perspectives for small volume delivery with lasers.

Needle-free jet injectors have been proposed as an alternative to injections with hypodermic needles. Currently, a handful of commercial needle-free jet injectors already exist. However, these injectors are designed for specific injections, typically limited to large injection volumes into the deeper layers beneath the skin. There is growing evidence of advantages when delivering small volumes into the superficial skin layers, namely the epidermis and dermis. Injections such as vaccines and insulin would benefit from delivery into these superficial layers. Furthermore, the same technology for small volume needle-free injections can serve (medical) tattooing as well as other personalized medicine treatments. The research dedicated to needle-free jet injectors actuated by laser energy has increased in the last decade. In this case, the absorption of the optical energy by the liquid results in an explosively growing bubble. This bubble displaces the rest of the liquid, resulting in a fast microfluidic jet which can penetrate the skin. This technique allows for precise control over volumes (pL to µL) and penetration depths (µm to mm). Furthermore, these injections can be tuned without changing the device, by varying parameters such as laser power, beam diameter and filling level of the liquid container. Despite the published research on the working principles and capabilities of individual laser-actuated jet injectors, a thorough overview encompassing all of them is lacking. In this perspective, we will discuss the current status of laser-based jet injectors and contrast their advantages and limitations, as well as their potential and challenges.

Effect of X-ray free-electron laser-induced shockwaves on haemoglobin microcrystals delivered in a liquid jet.

X-ray free-electron lasers (XFELs) enable obtaining novel insights in structural biology. The recently available MHz repetition rate XFELs allow full data sets to be collected in shorter time and can also decrease sample consumption. However, the microsecond spacing of MHz XFEL pulses raises new challenges, including possible sample damage induced by shock waves that are launched by preceding pulses in the sample-carrying jet. We explored this matter with an X-ray-pump/X-ray-probe experiment employing haemoglobin microcrystals transported via a liquid jet into the XFEL beam. Diffraction data were collected using a shock-wave-free single-pulse scheme as well as the dual-pulse pump-probe scheme. The latter, relative to the former, reveals significant degradation of crystal hit rate, diffraction resolution and data quality. Crystal structures extracted from the two data sets also differ. Since our pump-probe attributes were chosen to emulate EuXFEL operation at its 4.5 MHz maximum pulse rate, this prompts concern about such data collection.

A novel device for endoscopic submucosal dissection that combines water-jet submucosal hydrodissection and elevation with electrocautery: initial experience in a porcine model.

BACKGROUND: Endoscopic submucosal dissection requires a high degree of endoscopic skill and specifically designed dissecting instruments. OBJECTIVE: To describe the technique for endoscopic submucosal dissection when using the ERBE Hybrid Knife, which combines an ultrafine high-pressure water jet with an electrocautery needle. DESIGN: Descriptive study (ex vivo and in vivo porcine esophagus, stomach, and colon). INTERVENTIONS: The only instrument used for the dissection was the ERBE Hybrid Knife. The high-pressure water jet was used at a pressure between 45 and 60 bar for creating submucosal fluid elevation. After this, circumferential mucosal incisions and submucosal dissection were performed with the FORCED COAG and ENDOCUT D modes of the same device. The water jet was used intermittently during the dissection process. MAIN OUTCOME MEASUREMENTS: At the end of the in vivo experiments, animals were killed and the organs removed for evaluation. RESULTS: Multiple endoscopic submucosal dissection procedures were successfully performed. It was possible to create submucosal fluid cushions rapidly. Repeated fluid injections during dissection were easily facilitated with the same device. All ex vivo gastric endoscopic submucosal dissections of 50 x 40-mm lesions were completed within 10 minutes. In the in vivo studies, the mean size of the gastric and colonic specimens was 3.7 +/- 2.1 x 2.3 +/- 1 cm, and the dissections were completed within 8 minutes. No thermal injury was observed on the serosa, and no perforations were detected. CONCLUSIONS: Endoscopic submucosal dissection can be safely and effectively achieved in a porcine model with the ERBE Hybrid Knife and should be considered a suitable device for this procedure in humans.

A model on liquid penetration into soft material with application to needle-free jet injection.

A mathematical model has been presented for a high speed liquid jet penetration into soft solid by a needle-free injection system. The model consists of a cylindrical column formed by the initial jet penetration and an expansion sphere due to continuous deposition of the liquid. By solving the equations of energy conservation and volume conservation, the penetration depth and the radius of the expansion sphere can be predicted. As an example, the calculation results were presented for a typical needle-free injection system into which a silicon rubber was injected into. The calculation results were compared with the experimental results.

Self-assembled hydro-jet system for submucosal elevation before endoscopic resection of nonpolypoid colorectal lesions (with video).

BACKGROUND: Endoscopic resection of colorectal nonpolypoid lesions requires adequate submucosal lifting of the lesion. OBJECTIVE: To evaluate a self-assembled hydro-jet system for tissue elevation to improve endoscopic resection of colorectal nonpolypoid lesions. DESIGN: Prospective study. SETTING: Single-center teaching hospital. MAIN OUTCOME MEASUREMENTS: Efficacy and safety of the hydro-jet system and rate of complete resection. RESULTS: The system was clinically applied in 31 patients to remove a total of 34 lesions throughout the colon. An adequate submucosal fluid cushion was achieved in all but 1 case without any lifting-associated complications. Complete endoscopic resection was possible in all 33 lifted lesions by using a snare. The size of the resected lesions ranged from 7 to 60 mm. Major intraprocedure bleeding occurred in only 1 case. No perforation or late bleeding was recorded. Histological examination showed a selective accumulation of fluid in the submucosa with edema and dissociation of submucosal structures, with no damage to the muscularis mucosa and very limited "burn effect" hampering assessment of radial margins. LIMITATIONS: Lack of controls. CONCLUSIONS: This inexpensive system allows safe and rapid submucosal lifting of colorectal nonpolypoid lesions to assist endoscopic resection.

What stands in the way of treating palmar hyperhidrosis as effectively as axillary hyperhidrosis with botulinum toxin type A.

Botulinum Toxin type A (BTX-A) has revolutionized the treatment of focal hyperhidrosis (HH) in recent years and has dramatically reduced the invasive surgical techniques that have been performed in the past to control severe focal HH unresponsive to topical therapies. Whereas BTX-A injections are easily performed to control axillary HH with little or no analgesia, pain management is a must during the injection of palmar and plantar HH with BTX-A because of the intense pain generated with the 30 to 40 needle punctures needed on each hand or foot through the densely innervated skin present in those areas. For that reason, many physicians who contentedly treat axillary HH with BTX-A injections, refuse to do so for palmar and plantar HH. Although pain is the major stumbling block deterring patients and physicians from choosing this treatment option, it is not the only one. Many other factors may play a role in deciding whether or not to treat palmar and plantar HH with BTX-A injections. This article reviews these factors and presents some personal data from patients who have already been treated with BTX-A injections on the palms and soles and who came back once or more for repeat treatments when the effect of BTX-A started to fade away. "Jet Anesthesia" was the pain management method used in this group.

[The evaluation of mechanical performance of a jet injection system].

In this study, the mechanical properties of a self-made jet injector and a foreign product are tested from three aspects: penetration ability, injection completeness and injection dispersion. Correspondingly, three different experiments are designed and performed: dynamic pressure measurement, injection into silicon rubbers with fixed hardness yet different thickness and injection into polyacrylamide gels with fixed hardness. The results show similar mechanical properties between self-made system and the foreign system. The evaluation of the mechanical performance of jet injectors that consists of penetration ability, injection completeness and injection dispersion can describe the jet injection process effectively.

[Development of a novel liquid injection system].

A liquid jet injector employs compressed gas or spring to produce a high-velocity stream to deliver liquid drug into human body through skin. There are many clinical jet injection products available, none of which is domestic. A new liquid jet injector is designed based on a comprehensive analysis of the current products. The injector consists of an ejector, trigger and a re-positioning mechanism. The jets characteristics of sample injector are tested, and the results show that the maximum exit pressure is above 15 MPa, a threshold value for penetrating into the skin.

Viscous Heating Assists Jet Formation During Needle-Free Jet Injection of Viscous Drugs.

OBJECTIVE: Jet injectors use a high-pressure liquid jet to pierce the skin and deliver drug into underlying tissues. This jet is formed through a short, narrow orifice; the geometry of the orifice and the properties of the fluid affect the nature of the flow. We aimed to discover information about the turbulent and viscous processes that contribute to pressure loss and flow patterns during jet injection. METHODS: We used computational fluid dynamics methods and experimental observation to investigate the effects of nozzle geometry, fluid viscosity, and viscous heating on jet production. We experimentally verified the temperature change of the jet during ejection, using an infrared camera. RESULTS: Our models accurately predict the average jet speed produced for two example nozzle geometries over two orders of magnitude of viscosity. The models reveal the previously unreported importance of viscous heating in the formation of the jet. Temperatures >65 °C were predicted at the edge of the flow as a result of viscous heating. These caused a significant local reduction in viscosity and effectively allowed the fluid to lubricate itself. Our experiments confirmed changes in mean jet temperature of up to 2.5 °C, which are similar to those predicted by our model (∼2.8 °C). CONCLUSION: These results reveal the importance of the viscous heating properties of a fluid in the formation of high-speed jets for drug delivery. SIGNIFICANCE: This property is crucial to consider when formulating new drugs for needle-free jet injection.

Characterization of jet injection efficiency with mouse cadavers.

Needle-free drug delivery is highly sought after for reduction in sharps waste, prevention of needle-stick injuries, and potential for improved drug dispersion and uptake. Whilst there is a wealth of literature on the array of different delivery methods, jet injection is proposed as the sole candidate for delivery of viscous fluids, which is especially relevant with the advent of DNA-based vaccines. The focus of this study was therefore to assess the role of viscosity and jet configuration (i.e. stand-off relative to the skin) upon injection efficiency for a fixed spring-loaded system (Bioject ID Pen). We performed this assessment in the context of mouse cadavers and found that the dominant factor in determining success rates was the time from euthanasia, which was taken as a proxy for the stiffness of the underlying tissue. For overall injection efficiency, ANOVA tests indicated that stiffness was highly significant (P <  < 0.001), stand-off was moderately significant (P < 0.1), and viscosity was insignificant. In contrast, both viscosity and standoff were found to be significant (P < 0.01) when evaluating the percentage delivered intradermally. Using high-resolution micro-computed tomography (µ-CT), we also determined the depth and overall dispersion pattern immediately after injection.

Development of Pyro-Drive Jet Injector With Controllable Jet Pressure.

Various jet injectors have been developed and used for the effective and efficient administration of drugs. Jet injections overcome the limitations of other drug delivery methods, such as ablation, iontophoresis, electroporation, sonophoresis, and microneedles, because jet injection is not limited by the diffusion rates of different drugs. However, controlling the jet pressure during drug delivery is difficult with most conventional jet injectors. Efficacy evaluation of such devices on laboratory animals is strongly required before initiating human clinical trials, but minimal research has been performed for the device developments. Therefore, we developed jet injector devices based on pyrotechnics using 2 types of explosives with different burning rates; we call these pyro-drive jet injectors. The liquid jet pressure profile suggests that the penetration depth and injection volume for soft materials and skin tissue are controllable. Here, we propose the pyro-drive jet injectors as another candidate well-controlled jet injector for laboratory animals in drug discovery testing as well as human clinical use.

Short communication safety, tolerability and pharmacokinetics of enfuvirtide administered by a needle-free injection system compared with subcutaneous injection.

BACKGROUND: Injection site reactions (ISRs) can present a challenge to patients when using enfuvirtide (ENF). This study compared ISRs associated with use of a needle-free injection device (NFID) with those associated with a standard 27-gauge half-inch needle/syringe (NS). METHODS: In this single-blind, crossover study, 58 ENF-naive participants were randomized to self-administer ENF with the NFID for 4 weeks (followed by 4 weeks using NS) or with the NS for 4 weeks (followed by 4 weeks using the NFID). A primary composite endpoint of painful ISR was defined as the combination of grade 1-3 ongoing pain plus either associated grade 3-4 (> or =25 mm) induration or grade 2-4 nodules/cysts (>20 mm). An ISR summary score described ISR frequency/severity. Self-reported device preference was also evaluated at baseline and at study completion. RESULTS: Fewer participants using NFID experienced the primary composite endpoint of painful ISRs (10/28; 35.7%) compared with NS (20/28; 71.4%) (P=0.004). There was a trend towards a reduced incidence/severity of ISR signs and symptoms with NFID, with significant reductions seen in pain/discomfort and pruritus (P<0.05 and P<0.01, respectively). At the end of the study, most participants (22/25; 88%) expressed a preference for NFID. Haematoma was the sole NFID-related serious adverse event, but this did not lead to discontinuation. CONCLUSIONS: Compared with a standard NS, use of an NFID to administer ENF was associated with a substantially lower incidence of painful ISRs, was generally safe and well-tolerated, and was preferred by most participants in the study.

Power-efficient controlled jet injection using a compound ampoule.

We present a new mechanism for achieving needle free jet injection that significantly reduces the power required to perform a given injection. Our 'compound ampoule' produces two phases of jet speed under a constant force input by changing the effective piston area part-way through the injection. In this paper we define the benefits associated with a compound ampoule, relative to those of the conventional single piston design, by developing expressions for the power and energy required to perform an injection. We demonstrate that a compound ampoule can reduce the maximum input power required to perform a jet injection to less than one fifth of that previously required, enabling motors of less than half the mass to perform the same injection. We then detail the development of a prototype compound ampoule injector. Results from testing of this prototype demonstrate the function of a compound ampoule and verify the expected reduction in the required power and energy. Injections into post mortem porcine tissue confirm that our compound ampoule prototype can achieve the delivery of 1 mL of liquid into post-mortem tissue at least as effectively as a conventional ampoule. This approach will advance progress toward light-weight and power-efficient needle-free jet injectors for transdermal drug delivery.

Immunogenicity and safety of measles-mumps-rubella vaccine delivered by disposable-syringe jet injector in India: A randomized, parallel group, non-inferiority trial.

BACKGROUND: We conducted a randomized, non-inferiority, clinical study of MMR vaccine by a disposable-syringe jet injector (DSJI) in toddlers in India in comparison with the conventional administration. METHODS: MMR vaccine was administered subcutaneously by DSJI or needle-syringe (N-S) to toddlers (15-18 months) who had received a measles vaccine at 9 months. Seropositivity to measles, mumps, and rubella serum IgG antibodies was assessed 35 days after vaccination. Non-inferiority was concluded if the upper limit of the 95% CI for the difference in the percent of seropositive between groups was less than 10%. Solicited reactions were collected for 14 days after vaccination by using structured diaries. RESULTS: In each study group, 170 subjects received MMR vaccine. On day 35, seropositivity for measles was 97.5% [95% CI (93.8%, 99.3%)] in the DSJI group and 98.7% [95% CI (95.5%, 99.8%)] in the N-S group; for mumps, 98.8% [95% CI (95.6%, 99.8%)] and 98.7% [95% CI (95.5%, 99.8%)]; and for rubella, 98.8% [95% CI (95.6%, 99.8%)] and 100% [95% CI (97.7%, 100.0%)]; none of the differences were significant. The day 35 post-vaccination GMTs in DSJI and N-S groups were measles: 5.48 IU/ml [95% CI (3.71, 8.11)] and 5.94 IU/ml [95% CI (3.92, 9.01)], mumps: 3.83 ISR [95% CI (3.53, 4.14)] and 3.66 ISR [95% CI (3.39, 3.95)] and rubella: 95.27 IU/ml [95% CI (70.39, 128.95)] and 107.06 IU/ml [95% CI (79.02, 145.06)]; none of the differences were significant. The DSJI group reported 173 solicited local reactions and the N-S group reported 112; most were mild grade. Of the total of 156 solicited systemic adverse events, most were mild, and incidence between the two groups was similar. CONCLUSIONS: MMR vaccination via DSJI is as immunogenic as vaccination by N-S. Safety profile of DSJI method is similar to N-S except for injection site reactions which are more with DSJI and are well-tolerated. Registration US National Institutes of Health clinical trials identifier - NCT02253407. Clinical trial registry of India identifier - CTRI/2013/05/003702.