Large volume subcutaneous delivery using multi-orifice jet injection.

Needle-free jet injection is an alternative drug delivery technique that uses the liquid drug itself to penetrate through the skin. This technology is not only a promising alternative to hypodermic needles but also has the potential to replace intravenous delivery with rapid, needle-free subcutaneous delivery for large-volume treatments. In this work we propose a parallelised, 'multi-orifice' approach to overcome the volume constraints of subcutaneous tissue. We present a prototype multi-orifice nozzle with up to seven orifices and use this nozzle to perform injections into samples of ex vivo porcine tissue. These injections demonstrated the rapid (<0.15 s) delivery of up to 2 mL into the tissue using both three and seven orifices. Delivery success (measured as the percentage of fluid deposited in the tissue relative to the total volume that left the device) was very similar when using three versus seven injection orifices. A computational fluid dynamic model of multi-orifice jet injection is also presented. This model predicts that jet production is largely unaffected as the spacing between orifices is changed from 3 mm to 48 mm. This finding is supported by measurements of the speed, volume, and shape of the jets produced by the prototype nozzle that showed very similar jets were produced through all seven orifices. These findings demonstrate the feasibility of multi-orifice jet injection for needle-free delivery of large volumes. This promising technique has the potential to improve patient experience and reduce healthcare costs in large volume parenteral delivery applications.

Preliminary pharmacokinetics and patient experience of jet-injected dexmedetomidine in healthy adults.

Jet injection is a drug delivery system without a needle. A compressed liquid drug formulation pierces the skin, depositing the drug into the subcutaneous or intramuscular tissues. We investigated the pharmacokinetics and patient experience of dexmedetomidine administered using jet injection in six healthy adult study participants. This needleless jet injection device was used to administer dexmedetomidine 0.5 µg/kg to the subcutaneous tissues overlying the deltoid muscle. Serum concentrations of dexmedetomidine were assayed at approximately 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours after administration. Pharmacokinetic interrogation of concentration time profiles estimated an absorption half time for jet-injected dexmedetomidine of 21 minutes (coefficient of variation 69.4%) with a relative bioavailability assumed unity. In our samples the measured median peak (range) concentration was 0.164 µg/l (0.011-0.325 µg/l), observed in the sample taken at a median (range) of 13.5 minutes (11-30 minutes). The Richmond agitation sedation scale was used to assess the sedative effect, and scored 0 (alert and calm) or -1 (drowsy) in all participants. Five of the six participants stated they would prefer jet injection to needle injection in the future and one had no preference. The findings suggest that the use of a larger dose (>2 µg/kg) would be required to achieve the clinically relevant target concentration of 1 µg/l necessary to achieve deeper sedation (Richmond agitation sedation scale ≤3).

Home-Use Hyaluronic Acid Jet Injectors: Unreliable and Unsafe.

BACKGROUND: Needle-free hyaluronic acid (HA) jet injectors are gaining popularity for rejuvenation treatment. The devices are widely available online and are used for self-injection or in beauty salons by nonphysicians. However, little is known about their performance and safety. OBJECTIVE: To explore the injection efficiency and cutaneous biodistribution patterns administered with home-use compared with medical jet injectors and to assess safety aspects. MATERIALS AND METHODS: The authors injected HA into ex vivo human skin with 4 home-use and 2 medical injectors. The intracutaneous dose of HA was calculated, and the cutaneous biodistribution of HA was assessed using a 3-dimensional Fluorescent Imaging Cryomicrotome System (3D-FICS). Safety aspects were evaluated based on the presence of a manual, CE (conformité européenne) mark, and sterility. RESULTS: The intracutaneous dose delivered by the home-use injectors was markedly lower compared with the medical injectors. 3D imaging for home-use injectors showed superficial epidermal distribution with low distribution volumes. For medical injectors, volumes were substantially larger and mainly middermal. All evaluated safety aspects were lacking. CONCLUSION: Results of this study suggest that the specific combinations of home-use injectors and HA used in this study are unreliable and unsafe, which casts doubts on the performance of these treatments in general.

Rotatable Orifice for Needle-Free Jet Injection.

This research explores a new development in orifice technology for needle-free jet injection. The premise lies in the ability to control the angle at which the drug is delivered into the tissue to increase the lateral dispersion of the drug. Towards this aim, a spherical orifice that can rotate to adjust the injection angle is explored. This work tests the design and feasibility of the spherical orifice, its housing, and the orifice seats. The results show that the most successful way to create a fluid seal within the housing was to use an o-ring to create a fluid seal at the inlet side of the sphere and an extended brass seat on the outlet side of the sphere. This allowed jet speeds up to approximately 123 m/s through a 0.2 mm orifice machined into 9.5 mm diameter brass sphere. Jet speeds large enough to penetrate porcine tissue were reached at jet angles of 0° to 50° relative to the base of the injector. Although the jets successfully penetrated the tissue, the amount of fluid delivered varied depending on the injection angle. With a shallow angle injection, the fluid retention rate (the percentage of the ejected fluid from the injector which the tissue sample retained) was on average 44%. When the spherical orifice was at its maximum angle, the injection achieved an average fluid retention rate of 22%. At its widest angle, lateral dispersion of the drug also increased by approximately 40%, in comparison to conventional needles and traditional perpendicular jet injection. In summary, a spherical orifice needle-free injection system successfully produced high-speed jets and delivered liquid into porcine tissue at injection angles from 0° to 50°, demonstrating the feasibility of this technique that offers unique advantages over typical orifice plates and conventional needles.Clinical Relevance-A rotatable nozzle can be used to control the angle of needle-free drug delivery.

Measurement of Blood Dilution during Lancet-Free Blood Sampling.

In this paper, we report on a fluorescent and colorimetric system for measuring the dilution of capillary blood released by a needle-free jet injector. Jet injection uses a high-speed liquid jet to penetrate tissue, and in the process can release capillary blood that can be collected for performing blood tests. In this way, blood sampling can be performed without the use of a lancet. However, any injectate that mixes with the collected blood dilutes the sample and may significantly impact subsequent analyses. By adding the fluorescent marker indocyanine green to the injected liquid, the fraction of injectate mixed into the collected blood can be measured. The incorporation of colorimetry allows our system to also correct for the impact of hematocrit on fluorescence. The results from this system show that it can determine the dilution of blood that has been diluted by up to 10 %, the upper limit of dilution typically observed in lancet-free blood sampling via jet injection.Clinical Relevance- Blood samples can be collected by jet injection without significant dilution, avoiding the need for lancing.

Needle-free electronically controlled jet injection with corticosteroids in recalcitrant keloid scars: a retrospective study and patient survey.

First-line treatment of keloids consists of intralesional needle injections with corticosteroids, but generally entails multiple painful sessions, resulting in variable clinical outcomes. Novel needle-free jet injectors may facilitate more effective and patient-friendly dermal drug delivery. Here, we evaluated the effectiveness, tolerability and patient satisfaction of intralesional triamcinolone-acetonide (TCA) treatment in recalcitrant keloids using an electronically controlled pneumatic injector (EPI). A retrospective study was conducted in recalcitrant keloid patients with a history of severe pain during needle injections who received three sessions of EPI + TCA. Outcome measures included Patient and Observer Scar Assessment Scale (POSAS), Global Aesthetic Improvement Scale (GAIS), treatment-related pain (NRS), adverse effects, and patient satisfaction (survey). Ten patients with in total 283 keloids were included. The POSAS score significantly improved at follow-up and GAIS was reported as '(very) improved' for all patients. EPI + TCA was well-tolerated with a significantly lower NRS pain score compared to needle + TCA (pilot treatment). Only minor adverse effects occurred, and 90% of patients preferred EPI over needle treatment. EPI + TCA is an effective and tolerable treatment for patients with recalcitrant keloids. The minimal treatment-related pain and high patient satisfaction makes it a promising treatment for patients with needle-phobia and/or severe pain during needle injections.

Experimental investigation of the optimal driving pressure for a larger-volume controllable jet injection system.

Jet injection technology has become the alternative drug delivery method of conventional needle-based injection due to its obvious advantages. In order to meet the demand for larger volume injection, the pneumatic jet injection systems have efficiently administrated vaccine up to 1 mL in human. Our recent study has also demonstrated that controlling the driving pressure enabled the pneumatic jet injection system to deliver larger volumes of drugs to target sites at desired rates and times. This work continues to explore the optimal two-phase driving pressure combination with better injection efficiency for typical larger-volume (1.0 mL) jet injection with controllable pneumatic jet injection system. Under the combination of a first phase driving pressure of 1.00 MPa and a second phase driving pressure ranging from 0.25 to 0.90 MPa, dynamic characteristics, dispersion characteristics and pharmacokinetic characteristics of this controllable jet injection system were quantitatively analyzed. In all experiments, it was confirmed that the optimal driving pressure combination of 1.0 mL ejection volume was close to (1.00-0.50) MPa. That is, the injection velocities of 151.85 m/s and 102.01 m/s for the first and second phase respectively facilitated better injection performance with a controlled release of 1.0 mL ejection volume. This strategy is practical for facilitating the clinical application of large-volume controllable jet injection systems.

Bubble dynamics and speed of jets for needle-free injections produced by thermocavitation.

Significance: The number of injections administered has increased dramatically worldwide due to vaccination campaigns following the COVID-19 pandemic, creating a problem of disposing of syringes and needles. Accidental needle sticks occur among medical and cleaning staff, exposing them to highly contagious diseases, such as hepatitis and human immunodeficiency virus. In addition, needle phobia may prevent adequate treatment. To overcome these problems, we propose a needle-free injector based on thermocavitation. Aim: Experimentally study the dynamics of vapor bubbles produced by thermocavitation inside a fully buried 3D fused silica chamber and the resulting high-speed jets emerging through a small nozzle made at the top of it. The injected volume can range from ∼0.1 to 2 µL per shot. We also demonstrate that these jets have the ability to penetrate agar skin phantoms and ex-vivo porcine skin. Approach: Through the use of a high-speed camera, the dynamics of liquid jets ejected from a microfluidic device were studied. Thermocavitation bubbles are generated by a continuous wave laser (1064 nm). The 3D chamber was fabricated by ultra-short pulse laser-assisted chemical etching. Penetration tests are conducted using agar gels (1%, 1.25%, 1.5%, 1.75%, and 2% concentrations) and porcine tissue as a model for human skin. Result: High-speed camera video analysis showed that the average maximum bubble wall speed is about 10 to 25 m/s for almost any combination of pump laser parameters; however, a clever design of the chamber and nozzle enables one to obtain jets with an average speed of ∼70 m/s. The expelled volume per shot (0.1 to 2 µl) can be controlled by the pump laser intensity. Our injector can deliver up to 20 shots before chamber refill. Penetration of jets into agar of different concentrations and ex-vivo porcine skin is demonstrated. Conclusions: The needle-free injectors based on thermocavitation may hold promise for commercial development, due to their cost and compactness.

Humoral immunogenicity of a Coronavirus Disease 2019 (COVID-19) DNA vaccine in rhesus macaques (Macaca mulatta) delivered using needle-free jet injection.

A SARS-CoV-2 DNA vaccine targeting the spike protein and delivered by jet injection, nCOV-S(JET), previously shown to protect wild-type and immunosuppressed Syrian hamsters (Mesocricetus auratus), was evaluated via two needle-free delivery methods in rhesus macaques (Macaca mulatta). The methods included intramuscular delivery of 2 mg per vaccination with the PharmaJet Stratis device and intradermal delivery of 0.4 mg per vaccination with the PharmaJet Tropis device. We hypothesized that the nCOV-S(JET) vaccine would mount detectable neutralizing antibody responses when delivered by needle-free jet injection by either the intradermal or intramuscular route. When delivered intramuscularly, the vaccines elicited neutralizing and variant (Beta, Gamma, and Delta) cross-neutralizing antibodies against SARS-CoV-2 in all six animals after three vaccinations. The neutralizing response to Omicron was lower with only 4 of 6 animals responding. When delivered at a lower dose by the intradermal route, strong neutralizing antibody responses were only detected in two of six animals. This study confirms that a vaccine previously shown to protect in a hamster model can elicit neutralizing and cross-neutralizing antibodies against SARS-CoV-2 in nonhuman primates. We posit that nCOV-S(JET) has the potential for use as booster vaccine in heterologous vaccination strategies against COVID-19.

A Promising Needle-Free Pyro-Drive Jet Injector for Augmentation of Immunity by Intradermal Injection as a Physical Adjuvant.

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of the presence of numerous immune cells, such as professional antigen-presenting dendritic cells. Therefore, intradermal injection is considered superior to intramuscular injection for the induction of protective immunity, but more proficiency is required for the injection. To improve these issues, several different types of more versatile jet injectors have been developed to deliver DNAs, proteins or drugs by high jet velocity through the skin without a needle. Among them, a new needle-free pyro-drive jet injector has a unique characteristic that utilizes gunpower as a mechanical driving force, in particular, bi-phasic pyrotechnics to provoke high jet velocity and consequently the wide dispersion of the injected DNA solution in the skin. A significant amount of evidence has revealed that it is highly effective as a vaccinating tool to induce potent protective cellular and humoral immunity against cancers and infectious diseases. This is presumably explained by the fact that shear stress generated by the high jet velocity facilitates the uptake of DNA in the cells and, consequently, its protein expression. The shear stress also possibly elicits danger signals which, together with the plasmid DNA, subsequently induces the activation of innate immunity including dendritic cell maturation, leading to the establishment of adaptive immunity. This review summarizes the recent advances in needle-free jet injectors to augment the cellular and humoral immunity by intradermal injection and the possible mechanism of action.

DNA Aß42 immunization via needle-less Jet injection in mice and rabbits as potential immunotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1-42 (Aß42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aß42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aß peptides in brains of the DNA Aß42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aß42 vaccine for AD prevention in a clinical trial.

Determining Losses in Jet Injection Subcutaneous Insulin Delivery: A Model-Based Approach.

OBJECTIVE: Accurate, safe glycemic management requires reliable delivery of insulin doses. Insulin can be delivered subcutaneously for action over a longer period of time. Needle-free jet injectors provide subcutaneous (SC) delivery without requiring needle use, but the volume of insulin absorbed varies due to losses associated with the delivery method. This study employs model-based methods to determine the expected proportion of active insulin present from a needle-free SC dose. METHODS: Insulin, C-peptide, and glucose assay data from a frequently sampled insulin-modified oral glucose tolerance test trial with 2U SC insulin delivery, paired with a well-validated metabolic model, predict metabolic outcomes for N = 7 healthy adults. Subject-specific nonlinear hepatic clearance profiles are modeled over time using third-order basis splines with knots located at assay times. Hepatic clearance profiles are constrained within a physiological rate of change, and relative to plasma glucose profiles. Insulin loss proportions yielding optimal insulin predictions are then identified, quantifying delivery losses. RESULTS: Optimal parameter identification suggests losses of up to 22% of the nominal 2U SC dose. The degree of loss varies between subjects and between trials on the same subject. Insulin fit accuracy improves where loss greater than 5% is identified, relative to where delivery loss is not modeled. CONCLUSIONS: Modeling shows needle-free SC jet injection of a nominal dose of insulin does not necessarily provide metabolic action equivalent to total dose, and this availability significantly varies between trials. By quantifying and accounting for variability of jet injection insulin doses, better glycemic management outcomes using SC jet injection may be achieved.

Therapeutic efficacy of metronidazole by needle-free jet injection combined with blue light therapy in Moderate-to-Severe facial acne vulgaris.

BACKGROUND: Acne vulgaris is one of the most common dermatological diseases. Some topical treatments for acne used in combination, such as blue light and topical antibiotics (such as metronidazole) by needle-free jet injection (NFJI), are becoming prevalent in clinical practice, but the efficacy remains uncertain. METHODS: In order to investigate the effect of blue light combined with metronidazole by NFJI in the treatment of acne, the 251 enrolled patients were randomly assigned into the blue light group, metronidazole (MNZ) group, and MNZ + blue light group, and then received 6-weeks' treatment. A variety of objective and subjective methods such as clinical pictures, skin barrier physiological parameters (including trans-epidermal water loss (TEWL), stratum corneum hydration, facail surface sebum, erythema and pigmentation), the Investigator Global Assessment score, acne lesion count assessment, Patients' Self-Assessment, and VAS score were used to evaluate the efficacy and side effects of the treatments. RESULTS: Compared to the baseline, the MNZ + blue light group showed significant improvement in acne lesion count reduction, TEWL, straum corneum hydration, facial surface sebum and erythema (p < 0.05). The MNZ + blue light group showed significant differences compared with the MNZ group and blue light group in terms of acne lesion count reduction and erythema (p < 0.05) Compared to the MNZ group, the MNZ + blue light group demonstrated significant improvement in TEWL and sebum (p < 0.05). While compared to the blue light group, the MNZ + blue light group showed significant improvement in hydration (p < 0.05). There was no statistically significant difference among the three groups in pigmentation (p > 0.05). CONCLUSION: The combination of MNZ by NFJI and blue light has a synergistic effect and can relieve acne skin lesion within 6 weeks in the treatment of moderate and moderate-to-severe facial acne vulgaris, meanwhile, this method has a good safety.

Drug injection and dispersion characteristics of an air-powered needle-free injector.

The present study aims to reveal the operational characteristics of the needle-free injector. Effects of operating parameters on the injection performance were experimentally investigated. A visualization experiment was performed to describe the dispersion pattern of water in gel. The results show that the peak stagnation pressure increases continuously with the driving pressure. The injection process comprises two distinct stages, which are characterized by the penetration and the dispersion of the drug, respectively. The nozzle diameter imposes a significant effect on the penetration ability of the needle-free injector. As the nozzle diameter increases, the stagnation pressure decreases nearly linearly and the injection duration is considerably shortened, but the jet power is increased. Among the three nozzle diameters investigated, the nozzle diameter of 0.25 mm satisfies the proposed criterion of the injection power. It is evidenced through the visualization experiment that the maximum penetration depth increases with the nozzle diameter. The width of the projection area of the water bulk is insensitive to the nozzle diameter. For a certain nozzle diameter, the projection area of the diffused water bulk increases linearly with increasing liquid volume.

Jet injection needle-free dental anaesthesia: Initial findings.

OBJECTIVES: We evaluated patient preference and reported levels of anxiety and discomfort of participants treated with a new needle-free electric motor-driven device vs. conventional local anaesthetic for dental extractions in a proof-of-principle study. Healing and response of gingival tissues to injection were also evaluated at 1, 3- and 7-days post-procedure. METHODS: After informed consent, eight participants who required bilateral maxillary extractions were included in the trial. The side and order of placement for the needle-free and conventional anaesthetic were randomized. The same operator delivered anaesthesia and ensured teeth were anaesthetized on both sides. Another operator, unaware of order and type of anaesthesia placed, performed the extractions. RESULTS: Participant's average discomfort scores were low for both techniques, and lower for the needle-free injection at all timepoints. Needle-free local anaesthesia was the preferred technique by most participants at most timepoints. The average volume of anaesthetic dispensed was similar between techniques. Successful anaesthesia with the needle-free device was achieved in 6 out of 8 participants. Healing of the extraction sockets and adjacent oral mucosa progressed normally for all participants, with no evidence of infection, trauma or hematoma in the injection sites of the test and conventional sides. CONCLUSIONS: The needle-free local anaesthetic technique investigated achieved sufficient anaesthesia for tooth extractions in the maxilla in 75% of the subjects. A larger clinical trial is needed to further validate the technique tested and to investigate whether needle-free local anaesthesia can be successfully applied to the provision of restorative therapy. CLINICAL SIGNIFICANCE: The results of this study can be used by clinicians treating patients who suffer from dental anxiety and needle-phobia.

A one-time pneumatic jet-injection of 5-fluorouracil and triamcinolone acetonide for treatment of hypertrophic scars-A blinded randomized controlled trial.

BACKGROUND: Patients with hypertrophic scars (HTS) risk reduced quality of life due to itching, pain, poor cosmesis, and restriction of movement. Despite good clinical efficacy, patients are often reluctant to undergo repeated needle injections due to pain or needle phobia. OBJECTIVES: To evaluate the applicability of needle-free pneumatic jet injection (PJI) and assess changes in hypertrophic scars following a single PJI treatment with 5-fluorouracil (5-FU) and triamcinolone acetonide (TAC). METHODS: Twenty patients completed this blinded, randomized, controlled, split-scar trial. The intervention side of the HTS received a one-time treatment with PJIs containing a mixture of TAC + 5-FU injected at 5 mm intervals (mean 7 PJI per HTS); the control side received no treatment. Assessments were made at baseline and 4 weeks posttreatment. Outcome measures included change in (1) Vancouver Scar Scale (VSS) total score and subscores, (2) scar volume and surface area assessed by three-dimensional imaging, (3) skin microarchitecture measured by optical-coherence tomography (OCT), (4) photo-assessed scar cosmesis (0-100), (5) patient-reported pain and satisfaction (0-10), and (6) depiction of drug biodistribution after PJI. RESULTS: PJI with TAC + 5-FU significantly decreased both HTS height (-1 VSS; p = 0.01) and pliability (-1 VSS; p < 0.01) with a nonstatistically significant reduction of -1 in total VSS score (0 in control; p = 0.09). On 3D imaging, a 33% decrease in scar volume (p = 0.016) and a 37% decrease in surface area (p = 0.008) was observed. OCT indicated trends towards smoother scar surface (Ra 11.1-10.3; p = 0.61), normalized dermal microarchitecture (attenuation coefficient: 1.52-1.68; p = 0.44), and a reduction in blood flow between 9% and 17% (p = 0.50-0.79). Despite advances in VSS subscores and OCT, no improved photo-assessed cosmesis was found (-3.2 treatment vs. -1.4 control; p = 0.265). Patient-reported pain was low (2/10) and 90% of the patients that had previously received needle injections preferred PJI to needle injection. Depositions of TAC + FU were imaged reaching deep into the scar at levels corresponding to the reticular dermis. CONCLUSION: A single PJI injection containing 5-FU and TAC can significantly improve the height and pliability of HTS. PJI is favored by the patients and may serve as a complement to conventional needle injections, especially for patients with needle phobia.

A Comparison in Patient Comfort Using Conventional Syringe and Needleless Jet Anesthesia Technique in Periodontal Surgery-A Split-Mouth Randomized Clinical Trial.

Background and Objectives: Periodontal surgery requires local anesthetic coverage to alleviate patient discomfort. Needles and injections can engender feelings of fear and anxiety in individuals. This study aimed to assess the level of comfort and anxiety in patients during the administration of local anesthesia using needleless jet anesthesia (JA) when compared to a conventional syringe (CS) in periodontal surgery. Method and Materials: 60 sites were designated for injection in a split-mouth design in 30 subjects who required periodontal surgery. Local anesthesia was administered in two appointments scheduled one week apart using either a JA system or a CS. The Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Beck's anxiety inventory were used to report the pain and anxiety levels while injecting local anesthesia. Statistical analysis of the results was performed using the Shapiro-Wilks test and Paired t-test. Results: Patients reported greater comfort with JA. The VAS and VRS values were statistically significant-(p = 0.003) and (p = 0.001), respectively. Patients showed fear and were nervous about receiving a local anesthetic using a CS. A few subjects experienced lingering pain with the CS, whereas greater comfort and no lingering soreness were reported post-operatively at the site of JA administration. Conclusions: This study provides the first comprehensive assessment of using JA for periodontal surgical procedures. Lower pain scores were consistently observed with the use of jet injectors. Patients were at ease and reported lesser anxiety and greater comfort with jet injectors, making it ideally suited for providing local anesthesia in periodontal surgery.

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.

Clinical endpoints of needle-free jet injector treatment: An in depth understanding of immediate skin responses.

OBJECTIVES: Needle-free jet injectors have been used in dermatological practice for many years. However, predefined clinical endpoints that guide physicians to choose optimal device settings have not been clearly defined. Here, we evaluate immediate skin responses as clinical endpoints for needle-free jet injector treatments. METHODS: We injected methylene blue in ex vivo human skin using an electronically-controllable pneumatic injector (EPI; 3-6 bar, 50-130 µl; n = 63), and a spring-loaded jet injector (SLI) with fixed settings (100 µl; n = 9). We measured the immediate skin papule (3D-camera), residual surface fluid (pipette), dermal dye distribution by estimating depth and width, and subcutaneous dye deposition. RESULTS: EPI with 4 bar and 100 µl resulted in the largest skin papule of 48.7 mm3 (35.4-62.6 mm3 ) and widest dermal distribution of 8.0 mm (5.5-9.0 mm) compared to EPI with 6 bar and 100 µl (p < 0.001, p = 0.018, respectively). The skin papule volume showed a significant moderate to high positive correlation with the width and depth of dye distribution in the dermis (rs = 0.63, rs = 0.58, respectively; p < 0.001 for both correlations). SLI showed high variability for all outcome measures. Finally, a trend was observed that a small skin papule (≤7 mm) and little residual surface fluid (≤10% of injection volume) were warning signs for subcutaneous deposition. CONCLUSIONS: The immediate skin papule and residual surface fluid correspond with dermal drug deposition and are relevant clinical endpoints for needle-free jet injector treatments in dermatological practice.