Efficacy and safety of needle-free jet injector-assisted intralesional treatments in dermatology—a systematic review

Needle-free jet injectors are used for the intralesional treatment of various dermatological indications. However, a systematic review that evaluates the efficacy and safety of these treatments has not been published. The objectives of this study are to evaluate the efficacy and safety of needle-free jet injections for dermatological indications and to provide evidence-based treatment recommendations. An electronic literature search was conducted in April 2022. Two reviewers independently selected studies based on predefined criteria and performed a methodological quality assessment using the Cochrane Collaborations risk-of-bias 2.0 assessment tool and Newcastle–Ottawa Scale. Thirty-seven articles were included, involving 1911 participants. Dermatological indications included scars, alopecia areata, hyperhidrosis, nail diseases, non-melanoma skin cancer, common warts, local anesthesia, and aesthetic indications. Keloids and other types of scars (hypertrophic, atrophic, and burn scars) were investigated most frequently (n = 7). The included studies reported favorable efficacy and safety outcomes for intralesional jet injector-assisted treatment with triamcinolone acetonide/hexacetonide, 5-fluorouracil, bleomycin, or hyaluronic acid. Two high-quality studies showed good efficacy and tolerability of intralesional jet injections with a combination of 5-fluorouracil and triamcinolone acetonide in hypertrophic scars and with saline in boxcar and rolling acne scars. No serious adverse reactions and good tolerability were reported in the included studies. Overall, the methodological quality of the included studies was low. Limited evidence suggests that needle-free jet injector-assisted intralesional treatment is efficacious and safe for hypertrophic and atrophic acne scars. More well-powered RCTs investigating the efficacy and safety of jet injector treatment in dermatology are warranted to make further evidence-based recommendations. Graphical Abstract


Introduction
Intradermal drug delivery has many advantages over other routes of administration, especially high bioavailability in the skin [1,2]. Over the past decades, a variety of needle-free devices that enable intradermal drug delivery has been developed, including fractional ablative lasers, iontophoresis, sonophoresis, and various types of mechanical and energy-based jet injectors [3][4][5].
Jet injectors are commonly used for the intralesional treatment of several dermatological conditions such as keloids, hypertrophic scars, and recalcitrant viral warts [6,7]. Traditional mechanical jet injectors act with a fixed pressure predetermined by spring size [8]. Innovative electronically controlled pneumatic jet injectors are devices in which volume and pressure can be controlled by accelerated and compressed gas as pressure source, which dispense fluids into the skin [7,9]. Other types of jet injectors are controlled by Lorentz or piezoelectric actuators, lasers, and shockwaves to pressurize the injected drug [10].
In contemporary healthcare, we are moving towards more patient-centered care. It is important to improve patient comfort and avoid physical or psychological harm as much as possible. According to a previous study, 63% of children and 24% of the adult population in the USA fear needles [11]. This is one of the reasons why jet injectors can be a viable alternative for conventional needles.
Needle-free jet injectors can be an attractive alternative for hypodermic needles for patients experiencing needle phobia, minimize treatment-related pain, and are free of risk for needlestick injuries and cross-contamination. Additionally, jet injectors enable accurate and reproducible dermal delivery of liquid drugs and disperse the drug more evenly in the skin than conventional needle injections [7,9,12,13].
At present, there are a few overviews and narrative reviews describing the use of jet injector-assisted intralesional treatment for different dermatological indications [7,10,12,14]. However, a systematic and critical review that evaluates the efficacy and safety of jet injector-assisted intralesional treatment in dermatology is lacking. In this review, we aimed to systematically review and evaluate the quality of clinical evidence for intralesional treatment of dermatological indications using needle-free jet injector systems and provide evidence-based recommendations for clinical practice.

Materials and methods
A literature search was conducted in April 2022 using Embase, MEDLINE ALL Ovid, Web of Science, and Cochrane Central Register of Controlled Trials databases, to identify relevant publications. This systematic review was registered in the PROSPERO (CRD42021258278) and followed the Preferred Reporting Items for the PRISMA 2020 checklist [15].
Studies were included if they were human studies, written in English, published from inception to April 2022, randomized controlled trials (RCTs), controlled clinical trials (CCTs), prospective or retrospective cohort studies, and case series and included patients of all ages with dermatological indications eligible for intralesional treatment using needlefree jet injectors. Exclusion criteria included studies with fewer than 10 patients and intramuscular or subcutaneous drug delivery.
Selection of the articles, standardized data extraction, and methodological quality assessment of the included studies were performed independently by two authors (V.B. and J.V.H.). Articles were screened based on title and abstract. The primary outcome measure was efficacy, and the secondary outcome measure was safety. For data extraction, we converted pressure settings, total injection volume, and drug concentration to psi, ml, and mg/ml, respectively. If possible, efficacy measures were simplified to percentages in terms of clinical response compared to baseline. Methodological quality was assessed using the Cochrane Collaborations risk-of-bias 2.0 tool (ROB 2.0) for RCTs and CCTs, and the Newcastle-Ottawa Scale (NOS) for cohort studies and case series [16][17][18][19]. Final selection of the articles was based on screening of full texts. Discrepancies between reviewers were discussed and resolved by consensus and involved a third author (L.B.) if necessary. Illustrations of the methodological quality assessments were created using Robvis [17].

Alopecia areata
Four studies investigated jet injections to treat alopecia areata (Table 1) [29][30][31][32]. Jet injections with betamethasone dipropionate sodium phosphate vs. saline in group A and cyclosporine A vs. saline in group B resulted in hair regrowth in respectively 88.2%, 11.7%, 66.6%, and 16.6% of the patients (4 treatments; no statistical analyses) [29]. Spring-loaded jet injections with TCA resulted in hair regrowth in 62% of the patients (3 treatments; no comparative intervention; no statistical analyses) [30]. TCA with spring-loaded jet injections resulted in hair regrowth in 75% of the patients (3-4 treatments; no comparative intervention; no statistical analyses) [31]. Spring-loaded jet injections with TCA resulted in hair regrowth in 43-49% (≤ 3 treatments; no comparative intervention; no statistical analyses) [32].  Minor: pain, hematoma [42] Hyperhidrosis Four studies investigated a single jet injector treatment for hyperhidrosis (Table 1) [33][34][35][36]. Pneumatic powered jet injections compared to needle injections with onabotuli-numtoxinA were administered to treat palmar hyperhidrosis and reduced hyperhidrosis disease severity (HDSS) compared to baseline with respectively 1.6 (p = 0.031) and 1.25 (p = 0.1925) and no significant difference in pain between treatments [33]. Botulinum neurotoxin-A administered with spring-loaded jet injections and needle injections significantly reduced sweat production with respectively 24.7 mg/ ml vs. 54.1 mg/ml in palmar and axillar hyperhidrosis compared to baseline (p < 0.05; p < 0.0001). However, pain was "unacceptable" in half of the patients treated with needle injections and in none of the patients treated with jet injections [34]. Pneumatic jet injections with botulinum neurotoxin-A, resulted in HDSS reduction of 2 and 3 compared to baseline, respectively in patients with axillar and palmoplantar hyperhidrosis (no comparative intervention; p < 0.001 in both groups) [35]. Spring-loaded jet injections with botulinum toxin type A resulted in a complete relief of symptoms in 70% of the patients with plantar hyperhidrosis (no comparative intervention; no statistical analyses) [36].

Nail diseases
Three studies investigated jet injections to treat nail diseases (Table 1) [37][38][39]. Pneumatic jet injections with TCA were administered periungual to treat nail psoriasis, showing a Nail Psoriasis Severity Index (NAPSI) reduction of 3.7 compared to baseline (4 treatments; no comparative intervention; p = 0.0007) [37]. Spring-loaded jet injections with TCA in the posterior nail fold improved nail matrix psoriasis and hyponychial varying from "slight or marked improvement" to "normal nail" in 26% and 90% of the patients respectively (3 treatments; no statistical analyses) [38]. In comparison, the same device with TCA injections in the posterior nail fold showed "matrix improvement" in 73-95%, in psoriasis or lichen planus nails, and "onycholysis improvement" in 47-70% in psoriasis or idiopathic onycholysis nails (≥ 3 treatments, no comparative intervention; no statistical analyses) [39].

Common warts
Two studies investigated spring-loaded jet injectors to treat palmar and plantar warts (Table 1) [42,43]. Jet injections with bleomycin resulted in a complete response in 77.5% of the patients (5 treatments; no comparative intervention; no statistical analyses) [42]. Jet injections composed of interferon alfa-n3 resulted in a complete response in 73% of the patients (mean 15 treatments; no comparative intervention; no statistical analyses) [43].

Local anesthesia
Three studies investigated local anesthesia administered by a spring-loaded jet injector before suturing or performing dermatological surgery (Table 2) [48][49][50]. Jet injections with mepivacaine chloride resulted in "no pain" in 79.6% of the lesions during surgery (no comparative intervention; no statistical analyses) [50]. Lidocaine administered with a jet injector compared to injections with a hypodermic needle resulted in a mean anesthesia-related Visual Analogue Scale (VAS) score of 1.1 vs. 4.4 respectively (p < 0.0001), while suturing-related pain was not significantly different (p > 0.05) [48]. Lidocaine administered with a jet injector vs. needle injections resulted in "no pain" during suturing in respectively 94% vs. 83% of the children [49].

Aesthetics
Six studies investigated intralesional pneumatic jet injections in the face or neck for aesthetic purposes (Table 2) [51 -56]. Jet injections with hypertonic glucose compared to isotonic glucose improved GAIS with a mean score of respectively 2.5 ± 0.7 vs. 3.1 ± 0.9 (3 treatments; p = 0.005) [51]. To compare, jet injections with non-crosslinked hyaluronic acid resulted in "improved" and "much improved" GAIS in 42.9% and 57.1% of the patients respectively (5 treatments; no comparative intervention; no statistical analyses) [54]. Crosslinked hyaluronic acid using jet injections reduced mean Fitzpatrick-Goldman Wrinkle Classification with 21.2% and 27.6%, respectively in the neck and face (1-4 treatments; no comparative intervention; p < 0.05; p < 0.05) [56]. Hyaluronic acid with jet injections or multi-needle injections and placebo with jet injections or multi-needle injections reduced Wrinkle Severity Rating Scale compared to baseline with 1.0 ± 0.6 vs.

Adverse reactions
The majority of the adverse reactions were mild and the most common were local erythema, pain, hypo-and hyperpigmentation, bruising, hematoma, atrophy, swelling, and itching (Tables 1 and 2). No serious adverse events were reported. However, two studies that investigated bleomycin or interferon alfa-n2 delivered with a spring-loaded jet injector for palmar and plantar warts reported severe events including cellulitis, lymphangitis, and large hematomas, which needed surgical drainage and debridement [42,43]. Also, TCA administered by a spring-loaded jet injector for the treatment of alopecia areata resulted in bleeding from the arteria temporalis in one patient, which was controlled by firm pressure [32].

Methodological quality assessment
Overall risk of bias assessed with Cochrane's ROB 2.0 tool was "high" in six RCTs and CCTs, "some concerns" in four studies, and "low" in two studies (Fig. 2a). Methodological quality was particularly poor due to deviations from the intended intervention and selection bias (Fig. 2b). According to the Newcastle-Ottawa Scale, overall risk of bias in the included cohorts and case series was "high" in eleven, "some concerns" in another eleven, and "low" in three studies (Fig. 3a) [16]. Methodological quality was particularly poor due to lack of comparative cohorts, lack of blinding, and short follow-up time (Fig. 3b).

Discussion
In this systematic review, we summarized and critically appraised the current evidence on the efficacy and safety of jet injector-assisted intralesional treatments for dermatological indications. We selected 37 studies including 12 (randomized) controlled trials. The majority of studies had a "high risk of bias" or "some concerns" and only five studies (investigating acne scars, hypertrophic scars, keloids, and non-melanoma skin cancer) had "low risk of bias". Furthermore, 19 of 37 studies lacked statistical analysis for the reported outcomes. Due to large heterogeneity among studies with respect to a.o. study design, indication, type of jet injector, therapeutics, and outcome measures, a meta-analysis could not be performed.
Significant favorable effectiveness was reported in 13 of 15 studies, in which statistical analyses were reported. These studies investigated intralesional jet injections in scars, hyperhidrosis, nail psoriasis, non-melanoma skin cancer, seborrheic dermatitis, local anesthesia, and aesthetic indications. Most studies investigated keloids and other types of scars (hypertrophic, atrophic, and burn scars) and showed good efficacy and high tolerability [21][22][23][24][25][26]. Additionally, our review shows that despite differences in viscosity, several fluids have been successfully administered with jet injectors.
None of the included studies compared the use of springloaded vs. pneumatic jet injectors. In studies published before 2000, only spring-loaded jet injectors were used because pneumatic jet injectors were not yet introduced. Importantly, spring-loaded jet injectors were associated with a number of severe adverse reactions, including fluctuating cortisol levels and arteria temporalis damage in alopecia areata treated with TCA. Cellulitis, large hematomas, and lymphangitis occurred in patients with warts treated with spring-loaded devices and bleomycin or interferon alfa-n3 [30,32,42,43]. In contrast, no severe adverse reactions were reported in studies that investigated pneumatic Fig. 2 a Risk of bias in the included (non) randomized controlled trials was categorized as high, low or some concerns according to the Cochrane risk-of-bias 2.0 assessment tool. Overall, risk of bias was high because of poor methodological quality, particularly in domain 2 and 5. b Methodological quality of the (non) randomized controlled trials according to the Cochrane Collaborations risk-of-bias 2.0 tool assessment Fig. 2 (continued) jet injectors. Possibly, this could be related to the tunable settings for pneumatic jet injectors enabling safer and more effective treatment settings based on clinical endpoints, which are not available for spring-loaded injectors [57].
Only five of the included studies compared patientreported pain between needle-free jet injectors and conventional needle injections [33,34,41,48,49]. Jet injections with lidocaine caused significantly less injection-related pain, and less procedure-related pain with 5-ALA and PDT treatment in non-melanoma skin cancer compared to needle injections with 5-ALA and PDT [34,41,48]. Jet injections with botulinum toxin for palmar and axillar hyperhidrosis and with xylocaine for local anesthesia in children were better tolerated than conventional needle injections; however, no statistical analyses were performed [34,49]. On the other hand, two studies investigating local anesthesia with lidocaine and palmar hyperhidrosis with onabotulinumtoxinA reported no significant difference in procedure-related pain between jet injections and conventional needle injections [33,48].
Risk of bias assessment resulted in two high-quality RCTs. The results of these studies suggest that jet injections with 5-FU and TCA and jet injections with saline in atrophic acne scars (boxcar and rolling) are efficacious, safe, and well-tolerated [20,22]. Also, favorable efficacy and safety were found in cohort studies with low risk of bias for intralesional jet injections with 5-FU combined with corticosteroids in keloids and with hyaluronic acid in atrophic acne scars.
To our knowledge, this is the first systematic review that evaluated the efficacy and safety of intralesional treatment with jet injectors for dermatological indications. The strengths of this study include the use of a comprehensive database search, reporting of outcome measures as efficacy and adverse reactions, addressing jet injector settings, critical methodological quality assessment, and inclusion of all study designs with no limitation to publication date. Limitations of this systematic review include a majority of studies in cohorts or case series, noncomparative studies, poor methodological quality of the included studies, and missing of important clinical data such as skin type.
At our tertiary outpatient clinic, patients with keloids, hypertrophic scars, and recalcitrant warts are commonly treated with spring-loaded or pneumatic injectors to administer TCA, bleomycin or a mixture of both.
Moreover, we believe there is a significant clinical benefit of jet injector treatment in children (e.g., for keloids and hypertrophic scars), because in our experience they tolerate the jet injections much better and cause less anxiety than conventional hypodermic needle injections.
Importantly, we strongly recommend the use of protective safety measures such as smoke evacuators and face masks due to the potential formation of harmful aerosols, especially Fig. 3 a Risk of bias in the included cohort studies and case series was categorized as high, low, some concerns or not applicable according to the Newcastle-Ottawa Scale. Overall, risk of bias was high because of poor methodological quality, particularly in domains 2, 6, and 7. b Methodological quality of the included cohort studies and case series according to the Newcastle-Ottawa Scale when antineoplastic drugs such as bleomycin or 5-FU are administered [9]. Moreover, caution should be taken when using spring-loaded jet injectors in anatomical areas around large vessels, nerves, and bone, because potential damage can be inflicted with this type of fixed-setting jet injectors [32].
Contemporary deficiencies of modern jet injectors include drug spill (residual fluid on the skin surface and formation of potentially harmful airborne small-droplet aerosols). Also, gas-compressed energy-based jet injectors create a relatively loud noise during the injection phase which may lead to anxiety in some patients [6,12,58,59]. Therefore, opportunities for improvement of the needle-free injection technology in the future will lie in optimizing the injection efficiency, creating less noisy (smaller) devices, and the development of new technology to reduce the production or capture potentially harmful aerosols. Moreover, with respect to future research, good quality RCTs investigating the efficacy and safety of jet injectors in dermatology are highly needed to conduct a meta-analysis and produce stronger evidence that can be used to provide solid evidence-based recommendations for the use of jet injectors in clinical practice.
In conclusion, this systematic review presents an overview and methodological quality assessment of clinical data on the efficacy and safety of intralesional jet injection treatments for dermatological indications. Limited good quality data suggest that intralesional jet injection treatments with 5-FU and TCA in hypertrophic scars and with saline in atrophic acne scars are efficacious and well-tolerated [20,22]. In addition, some evidence suggests that jet injector treatment might be less painful for patients than conventional needle injections for certain indications. More highquality randomized controlled trials are needed to provide future evidence-based recommendations for clinical practice.