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.

Delivery of immunoreactive antigen using a controllable needle-free jet injector.

Intradermal immunization of mice against hepatitis B surface antigen (HBsAg) using a novel real-time controlled jet injector was assessed by comparison with intradermal and subcutaneous injection of antigen using a 27G needle and syringe. Three doses of aluminium-absorbed HBsAg were delivered at 0, 14, and 28days. Antibodies to HBsAg were detected only in mice injected with antigen with antibody levels increasing with secondary injections. Mice vaccinated by intradermal injection using the jet injector or subcutaneous needle injection exhibited comparable immune responses at day 47. Differences in titer observed between intradermal jet injected and needle injected animals reflect differences in the volume of antigen delivered. With the exception of minor bleeding at the injection site in a few animals injected either by jet injection or needle, no adverse events were observed in any of the mice used in the study.

Penetration and delivery characteristics of repetitive microjet injection into the skin.

Drugs can be delivered transdermally using jet injectors, which can be an advantageous route compared to oral administration. However, these devices inject large volumes deep into the skin or tissues underneath the skin often causing bruising and pain. This may be prevented by injecting smaller volumes at lower depth in a repetitive way using a microjet injection device. Such a device could be used to apply drugs in a controllable and sustainable manner. However, the efficacy of microjet injection has been rarely examined. In this study, the penetration and delivery capacity was examined of a repetitive microjet injection device. Various experiments were performed on epidermal and full-thickness ex vivo human as well as ex vivo porcine skin samples. Results revealed that microjets with a velocity exceeding 90m/s penetrated an epidermal skin sample with a delivery efficiency of approximately 96%. In full-thickness human skin, the delivery efficiency drastically decreased to a value of approximately 12%. Experiments on full-thickness skin revealed that the microjets penetrated to a depth corresponding to the transition between the papillary and reticular dermis. This depth did not further increase with increasing number of microjets. In vivo studies on rats indicated that intact insulin was absorbed into the systemic circulation. Hence, the microjet injection device was able to deliver medication into the skin, although the drug delivery efficiency should be increased.

A randomized clinical trial in adults and newborns in South Africa to compare the safety and immunogenicity of bacille Calmette-Guérin (BCG) vaccine administration via a disposable-syringe jet injector to conventional technique with needle and syringe.

INTRODUCTION: Intradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa. METHOD: Thirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1 mL in adults; 0.05 mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30 min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30 min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses. RESULTS: More infant BCG vaccinations by DSJI deposited >5 µL fluid on the skin surface, compared to NS (49% versus 9%, p=0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p<0.001). Median wheal diameter, in participants for which an SOI wheal formed, did not differ significantly between groups in infants (combined 3.0mm IQR 2.0 to 4.0, p=0.59) or in adults (combined 9.0mm IQR 7.0 to 10.0, p=0.13). Adverse events were similar between study arms. Proportion of participants with BCG scars after three months did not differ in adults (combined 97%, p=0.67) or infants (combined 62%, p=0.13). Frequencies of BCG-specific clusters of differentiation 4 (CD4) and clusters of differentiation 8 (CD8) T-cells co-expressing IFN-γ, TNF-α, IL-2, and/or IL-17 were not different in the DSJI and NS groups. CONCLUSION: BCG vaccination of newborn infants via DSJI was more likely to deliver an appropriate intradermal wheal at the SOI as compared to NS, despite leaving more fluid on the surface of the skin. Safety, reactogenicity, and antigen-specific T-cell immune responses did not differ between DSJI and NS techniques.

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment.

Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection (PNI) device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors (gas pressure, cylinder volume, and nozzle distance) were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs.

Positive lidocaine toxicology screen after J-Tip for venipuncture.

Venipuncture is common in children, and topical anesthetics are often used to alleviate the pain of the procedure. The J-Tip (National Medical Products, Inc, Irvine, Calif) device has become popular as a rapid and effective means of delivering lidocaine noninvasively. We report a case of a positive lidocaine blood toxicology screen after the use of the J-Tip device in a child pre-venipuncture. A repeat toxicology screen obtained 1 hour later by venipuncture without J-Tip use was negative. This report serves to remind clinicians that topical anesthetics may interfere with toxicology assays, leading to unreliable toxicology results.

Effectiveness of the new injection program 'saline test injection mode' for use power injector in pediatric contrast CT.

To improve the safety of the use of a power injector for pediatric contrast CT, we newly developed a saline test injection mode for a power injector and investigated its usefulness. We used an injection route and investigated the relationship of the injection pressure to the injection rate of saline and the contrast medium. From this relationship, we investigated it was possible to estimate the change of pressure injection of contrast medium from the pressure change of saline injection. The correlation between the saline test injection pressure and the contrast medium injection pressure was investigated in 64 clinical cases. The detection rate of side effects from the saline test injection was investigated in 473 patients. Regarding the correlation between the injection rate and pressure for both saline and contrast, the pressure rose as the rate increased. The contrast medium injection pressure could be estimated from the correlation observed with saline. The clinical data were obtained had a relationship similar to that with phantom data. The detection rate of side effects from the saline test injection was 4.4% in the clinical cases. In these cases, examinations were completed by re-establishing an injection route or administering hypnotics. Our results suggest that contrast medium pressure can be estimated from a saline test injection, thus aiding in prediction of the risk of injection abnormality. Reactions to injections could be observed in the present study, facilitating the prevention of examination failure. Countermeasures can be taken against the cause of the reaction, and the examination can be performed after confirming the absence of a reaction to injection. Therefore, a saline test injection may be useful in pediatric contrast CT.

Patient device assessment evaluation of two insulin injection devices in a mixed cohort of insulin-treated patients with type 1 or type 2 diabetes mellitus.

OBJECTIVE: FT (FlexTouch*) is a new disposable insulin injection pen device for use in insulin-treated patients with diabetes mellitus. The aim of this study was to evaluate patient perception of FT versus IL (InnoLet†) with respect to the ease of use and patient preference in a mixed patient cohort with different kinds and degrees of visual or dexterity impairments. METHODS: Ninety patients were included into this investigation (54 male/36 female, age [mean ± SD]: 62 ± 8 yrs, disease duration: 18 ± 11 yrs, HbA1c: 7.2 ± 1.0%). After assessment of visual acuity and dexterity skills (by Jebsen-Taylor Hand Function Test), the patients were introduced to the two pen devices in random order, and were asked to perform mock injections with 10 IU, 30 IU and 50 IU doses before completing a 41 item standardized device assessment questionnaire. The questions asked were covering five topics of pen use (confidence in delivering a correct dose, dose setting, performance of the injection, general handling, and others) and could be answered with a rank scale from '1 = very easy' to '5 = very difficult'. RESULTS: FT was ranked superior to IL with respect to the injection procedure (FT: 1.2 ± 0.1 vs. IL: 2.1 ± 0.4, p < 0.001) and general handling (1.3 ± 0.2 vs. 2.3 ± 0.7, p < 0.001), and numerically better with respect to confidence in correct dosing (1.4 ± 0.2 vs. 2.1 ± 0.9, n.s.). The two devices were ranked equally for ease of dose setting (1.6 ± 0.3 vs. 1.7 ± 0.4, n.s.). When ranked individually, FT use was recommended by 92.2% of the patients (IL: 30.0%). KEY LIMITATIONS: Patients of this investigation were from one local area (San Jose, CA, USA) only. The subgroups may be considered small for the performed analysis. CONCLUSIONS: In summary, FT was perceived to be easier to use than IL in this investigation.

Glycemic control, reported pain and leakage with a 4 mm × 32 G pen needle in obese and non-obese adults with diabetes: a post hoc analysis.

OBJECTIVE: The shortest pen needle (PN) for subcutaneous insulin therapy is 4 mm. Clinicians may hesitate to use it in obese patients. We report a post hoc analysis of a previously published study of the 4 mm × 32 G PN, evaluating responses in obese (≥30 kg/m(2)) and non-obese (<30 kg/m(2)). METHODS: Subjects (BMI 20 to 49 kg/m(2), 52% obese) with diabetes used 4 mm × 32 G PNs and either 5 mm or 8 mm PNs (both 31 G) in two, 3-week treatment periods in a randomized noninferiority cross-over trial. Percentage absolute change in fructosamine (%â”‚Δ Fru│) was the primary endpoint. Equivalent glycemic control was defined as %â”‚Δ Fru│ within 20% (including 95% CI). The impact of obesity on change in fructosamine, pain and reported insulin leakage from the skin is described. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov - identifier: NCT00928057. LIMITATIONS: This report is a post hoc analysis of two BMI subgroups resulting in smaller sample sizes. RESULTS: Of 168 who completed the study, 163 were included in the fructosamine analyses - 83 and 80 in the 4/5 mm and 4/8 mm groups, respectively. For the 4/5 mm group, mean BMI ± SD in non-obese and obese groups were 25.9 ± 2.3 and 35.0 ± 4.9 kg/m(2), respectively; 4/8 mm group 25.2 ± 2.6 and 35.6 ± 4.2 kg/m(2). BMI group was not significant for %â”‚Δ Fru│ for either 4/5 mm or 4/8 mm. Between BMI groups, the difference of the means in %â”‚Δ Fru│ was 0.4% (4/5 mm) and 0.3% (4/8 mm). The 4 mm PN was significantly less painful in all subject groups, except non-obese in 4/5 mm. Regardless of needle size, obese subjects reported more leakage events. For both BMI groups, there were fewer total reported leakage events when using the 4 mm vs 5 mm and 8 mm needles. CONCLUSIONS: The 4 mm pen needle provided equivalent glycemic control in both obese and non-obese patients compared to 5 mm and 8 mm needles with no increase in reports of skin leakage, in this post-hoc analysis. These findings should be confirmed in a prospective randomized controlled trial.

Safety, tolerability, and immunogenicity of inactivated trivalent seasonal influenza vaccine administered with a needle-free disposable-syringe jet injector.

BACKGROUND: Jet injectors (JIs) avoid safety drawbacks of needle-syringe (N-S) while generating similar immune responses. A new generation of disposable-syringe jet injectors (DSJIs) overcomes the cross-contamination risk of multi-use-nozzle devices used in 20th-century campaigns. In the first study in humans, the newly-US-licensed LectraJet(®) model M3 RA DSJI was compared to N-S. METHODS: Sixty healthy adults received one 0.5 mL intramuscular dose of the 2009-2010 seasonal, trivalent, inactivated influenza vaccine (TIV) in randomized, double-masked fashion by either DSJI (n=30) or N-S (n=30). Adverse reactions were monitored for 90 days after injection, and serologic responses assayed by hemagglutination inhibition (HI) at days 28 and 90. RESULTS: There were no related serious adverse events (SAEs), nor differing rates of unsolicited AEs between DSJI and N-S. Solicited erythema and induration occurred more often after DSJI, but were transient and well-tolerated; a trend was noted for fewer systemic reactions by DSJI. Pre-vaccination HI geometric mean titers (GMT) increased by 28 days for H1N1, H3N2, and B antigens by 13-, 14-, and 8-fold via DSJI, and by 7-, 10-, and 7-fold for N-S, respectively. No trending differences in GMT, seroconversion, or seroprotection were noted; sample sizes precluded non-inferiority assessment. CONCLUSIONS: DSJI delivery of TIV is well-tolerated and immunogenic.

[High pressure injection injuries of the hand. Rare but often underestimated]. / Hochdruckinjektionsverletzungen an der Hand. Selten, aber oft unterschätzt.

INTRODUCTION: Injection injuries of the hand are often underestimated because the full extent of the injury often only emerges after a delay. Flap coverage is often needed to avoid amputation. CASE REPORT: In the case presented an epoxy resin injection trauma to the left index finger occurred. A critical blood circulation resulted and after demarcation of the injury a radical débridement was carried out. A heterodigital island flap was used to reconstruct the dorsum of the finger and 3 years after the trauma the patient has no impairments in daily activities. DISCUSSION: The extent of the injury and the carcinogenic properties of the injected material are crucial for adequate treatment of injection injuries. Patients should be referred to specialized hand centers at an early stage.

Clinical results of skin remodeling using a novel pneumatic technology.

BACKGROUND: A myriad of technologies are available for the treatment of aging skin. These, however, still lack the ability to combine immediate, short-term and long-term aesthetic results with no downtime. Furthermore, the treatment of fine wrinkles on large surfaces remains challenging, as does the treatment of delicate regions, such as the dorsal hand, neck, and chest. OBJECTIVES: The aims of this study were to evaluate the short-term as well as the long-term efficacy and safety of a new skin remodeling device that pneumatically accelerates a jet of hyaluronic acid (HA) solution under high pressure into the dermis. METHODS: Thirty-four participants at three clinical sites underwent treatments with the Airgent device on the face, neck, chest, and dorsal hands for a total of 69 sites. Safety and efficacy were evaluated in short-term (1-3 months) and long-term follow-up (up to 18 months) by photography, by an independent reviewer and by participant self-evaluation. Histology was assessed before and 4 months after the third treatment. RESULTS: A total of 69 treatment areas were evaluable at 1-3 months follow-up. Photographic analysis demonstrated improvement in skin variables at all body sites treated. Treatment of the face and neck reduced the mean Fitzpatrick-Goldman Wrinkle Classification score by 39.4 and 30.4%, respectively, representing a full wrinkle class improvement. Treatments of the chest demonstrated significant visual improvement. Treatment of the dorsal hands produced good overall improvement (OI), with good improvement of protruding veins. Overall improvement increased with increasing number of treatments. A total of 56 treatment areas were evaluable for long-term follow-up. Treatment of the face and neck reduced the mean Fitzpatrick-Goldman Wrinkle Classification score by 27.6 and 21.2%, respectively. Improvement after treatment of the face represented a full wrinkle class reduction. Treatment of the chest and dorsal hands yielded significant visual improvement. Overall, 80% of subjects were satisfied with the treatment outcome and would recommend the treatment to friends and family. Histological analysis demonstrated increased dermal collagen ΙΙΙ. CONCLUSIONS: Pneumatic injection of HA under high pressure provides a safe, well-tolerated and effective method for improving the appearance of wrinkles on the face, neck, chest, and dorsal hands. Improvement can be seen as early as 1 month and as long as 18 months after treatment.

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.

A randomized study to evaluate injection site reactions using three different enfuvirtide delivery mechanisms (the OPTIONS study).

BACKGROUND: The antiretroviral enfuvirtide (ENF) is injected subcutaneously using a 27-gauge needle. Injection site reactions (ISRs) can affect long-term ENF tolerability. Alternative ENF delivery methods may ameliorate ISRs. METHODS: We conducted a multicentre, open-label, randomized controlled trial in which patients receiving ENF were randomized to continue receiving ENF by a 27-gauge needle, a shorter 31-gauge needle or a gas-powered, needle-free injection device (NFID). The primary study endpoint was the proportion of participants with < grade 2 ISR induration at week 12. RESULTS: Sixty patients received treatment and were included in the intention-to-treat population. The cohort was predominantly male (95%) with a mean age of 49.1 (SD +/- 7.7) years who had injected ENF for a mean of 821 (SD +/- 561) days. Response rates for ISR induration at week 12 were 38%, 25% and 42% for the 27-gauge, 31-gauge and NFID groups, respectively (all pairwise treatment comparison P-values > 0.2). There was no significant between-group difference for any ISR endpoint, except for changes in the composite ISR score (that is, no ongoing pain of > grade 1 or ISR for ongoing pain > or = grade 1 with induration ISR < grade 3 and for nodules < grade 2), which favoured the 27-gauge needle and NFID groups over the 31-gauge group (P = 0.012 and 0.047, respectively). Plasma HIV RNA load was unaffected. There were seven adverse events related to the delivery system: five attributed to the NFID. At week 12, 85% of participants elected to use the NFID. CONCLUSION: Needle-free ENF injection offers a reasonable, reliable alternative to needle-based injecting in this population, at least in the short term.

An open-label safety study of enfuvirtide injection with a needle-free injection device or needle/syringe: the Biojector 2000 Open-label Safety Study (BOSS).

Enfuvirtide (ENF) administration by needle/syringe is commonly associated with injection site reactions (ISRs). This study assessed ISRs and participant preference between a needle-free injection device (NFID) and a 27-gauge 1/2-inch needle/syringe (NS). A total of 349 participants with human immunodeficiency virus infection, who had difficulty tolerating long-term administration of ENF by NS, underwent randomization (2:1) to ENF administered twice daily by NFID for 8 weeks, or by NS for 4 weeks followed by NFID for 4 weeks. The objectives of the study were to compare ISRs associated with ENF injection using NFID or NS based on a composite endpoint, ISR incidence/severity, overall ISR scores, and discontinuations. In the NFID group, ISRs improved as the percentage of participants meeting the composite endpoint decreased from baseline (40.1%) to week 4 (25.4%) and remained stable at week 8 (21.2%). In the NS --> NFID group, the percentage meeting the composite endpoint worsened from baseline (36.5%) to week 4 (45.1%), but improved at week 8 (26.1%) after switching. Between-participant comparison showed a statistically significant greater improvement from baseline to week 4 in overall ISR score in the NFID group compared to the NS group. Within-participant comparison of the NS --> NFID group showed a significantly greater decrease in overall ISR score from baseline to week 8. In responses to a questionnaire, 87.2% of the participants surveyed preferred the NFID delivery system over NS. NFID is an alternative injection method that may reduce the incidence and severity of treatment-limiting ISRs associated with ENF administration.

Preventing contamination between injections with multiple-use nozzle needle-free injectors: a safety trial.

Multiple-use nozzle jet injectors (MUNJIs), a type of needle-free injector, use a high-pressure stream to penetrate skin and deliver medicament. Concerns for their potential to transmit blood borne pathogens led to development of a hybrid MUNJI for use in mass immunizations. The HSI-500, referred to here as a protector cap needle-free injector (PCNFI), utilizes a disposable cap as a shield between the reusable injector nozzle and the skin to reduce the risk of contamination. This study aimed to determine the presence of hepatitis B virus (HBV) contamination in post-injection ("next person") samples immediately following injection in HBV-carrier adults. Tolerability and pain were also assessed. The study ended early because the PCNFI failed to prevent contamination in the first batch tested (8.2% failure rate). The injections were very well tolerated, with most followed by no bleeding (81.2%) or mild bleeding (7.8%). 55.2% of participants experienced no pain while 42.3% experienced mild pain following injection.