Clinical Effectiveness and Safety of Laser Lancing for Heel Puncture in Preterm Infants: A Randomized Crossover Non-Inferiority Trial

Clinical Effectiveness and Safety of Laser Lancing for Heel Puncture in Preterm Infants: A Randomized Crossover Non-Inferiority Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical Effectiveness and Safety of Laser Lancing for Heel Puncture in Preterm Infants: A Randomized Crossover Non-Inferiority Trial Byung Min Choi, Chul Kyu Yun, Hye Won Cho, Eui Kyung Choi, Kim Jaeyoung, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8611028/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract OBJECTIVE: To evaluate the clinical effectiveness and safety of laser lancing devices (LLDs) compared with an automatic incision device (AID) for heel puncture in preterm infants. STUDY DESIGN: A randomized crossover non-inferiority trial was conducted in 40 preterm infants between April and December 2021. Primary outcomes were procedural success rate, pain response assessed by the Premature Infant Pain Profile (PIPP), and skin penetration depth. RESULTS: LLD achieved a 75% first-attempt success rate, reaching 100% after a second attempt at a higher energy setting, whereas AID achieved 100% success on the first attempt. PIPP scores during the procedure were significantly lower with LLD than with AID (4.5 [3.0–6.0] vs. 6.5 [4.0–7.5]; P =0.014). Penetration depths were similar between devices (1.21±0.30 vs. 1.25±0.23 mm). CONCLUSIONS: LLD appears to be an effective and safe alternative to AID for heel puncture in preterm infants, with reduced procedure pain. CLINICAL TRIAL REGISTRATION: Clinical Research Information Service (Registration No. KCT0010932) Health sciences/Health care/Paediatrics Health sciences/Medical research/Biomarkers/Diagnostic markers Figures Figure 1 Figure 2 Introduction Automatic incision devices (AIDs) are widely recommended as the standard method in neonatal intensive care units (NICUs) for the heel puncture required for capillary blood collection [ 1 , 2 ]. However, their sharp blades can injure skin and cause pain, particularly in critically ill or preterm infants who frequently undergo repeated procedures [ 3 – 5 ]. Although non-pharmacological and pharmacological strategies are recommended to mitigate procedure pain [ 1 , 5 – 7 ], their applications remain limited in critically ill neonates. Recent nationwide surveys report that, despite their proven benefits, breastfeeding and skin-to-skin care are less frequently utilized in sick newborns than in healthy newborns during routine heel puncture [ 8 ]. In addition, intravenous analgesia is rarely used despite recent reports that indicate infants of lower gestational age and earlier postnatal age experience more pain and undergo more pain assessments [ 9 ]. Therefore, continued efforts are needed to reduce pain and injury associated with clinical procedures. Recently, a laser-lancing device (LLD) using a monopulse erbium:YAG laser was developed as an alternative for capillary blood collection, eliminating the need for a sharp blades. In adult populations, LLDs have been shown to significantly reduce puncture pain and improve patient compliance compared to conventional needle lancets [ 10 – 13 ]. Extending this evidence to neonatal populations, our previous study in full-term infants demonstrated that LLDs achieved success rates comparable to those of AIDs, while producing markedly smaller skin injuries (approximately 0.2 mm vs. 2.0 mm) [ 14 ]. This reduced tissue disruption provides robust evidence supporting a safety advantage of LLDs in neonates, for whom tissue fragility is a critical concern. However, preterm infants present unique challenges because of thinner, fragile skin, requiring the precise determination of penetration depth to avoid tissue injury [ 15 ]. In addition, the immature central nervous system necessitates careful monitoring of pain responses to prevent immediate and long-term adverse neurodevelopmental outcomes [ 16 – 18 ]. To address these concerns, we conducted a randomized crossover non-inferiority trial in preterm infants to evaluate whether an LLD might serve as a safer, less painful alternative than an AID in this high-risk population. Methods A prospective randomized crossover non-inferiority trial was conducted from April to December 2021 at Korea University Ansan Hospital. The study was approved by the Institutional Review Board (IRB No. 2021AS0089) and registered at the Clinical Research Information Service (Registration No. KCT0010932). Written informed consent was obtained from all parents at the time of enrollment. 1. Subjects Inclusion criteria were a clinically stable preterm infant with a gestational age of 1,500 g, who were clinically stable and undergoing heel puncture for capillary blood collection. Infants with congenital anomalies or severe respiratory distress requiring invasive ventilation were excluded, as unstable hemodynamics might influence capillary refill time. Forty-two infants were randomly and equally allocated to group A or B. Group A underwent heel blood sampling with the LLD on day 1 and the AID on day 2, whereas group B followed the reverse sequence (Fig. 1 ). Two infants were subsequently excluded (one was discharged after the first LLD procedure and another was transferred after the first AID procedure), and thus, 40 infants were included in the final analysis. All data were de-identified to protect personal information. 2. Procedures All infants receiving 1 mL of 10% glucose orally 2 minutes before puncture as a non-pharmacological pain control measure [ 16 ]. Blood collection was performed using an LLD (LMT-5000 HandyRay-Pro, Lameditech, Seoul, Korea) or an AID (BD Quikheel Preemie Lancet, depth 0.85 mm, width 1.75 mm) [ 19 ]. The LLD was set at energy level 4 (4,270 mJ) for the initial puncture and level 5 (5,320 mJ) for the second attempt if the volume obtained was insufficient. The initial AID puncture was performed using the Preemie Lancet, and using the BD Quikheel Infant Lancet (depth 1.00 mm, width 2.50 mm) for the second attempt if the volume obtained was insufficient. The second attempt was initiated after the infant had returned to a stable state following the first attempt. Success was defined as the collection of ≥ 100 µL after two attempts. For optimal blood collection, a milking motion was performed at the plantar surface, and the number of maneuvers was recorded as an indirect measure of procedural efficiency. Squeezing toward the heel was avoided [ 20 ]. 3. Assessment of pain response To assess pain response, all subjects were video recorded from before oral glucose administration through the procedure until pain subsided. Pain was independently scored by two blinded investigators using the Premature Infant Pain Profile (PIPP), a validated composite pain assessment tool [ 21 , 22 ]. Pain assessment was based on the attempt that achieved successful blood collection. 4. Measurement of heel penetration depth A Swept Source Optical Coherence Tomography system (SS-OCT; VEG220C1, Thorlabs Inc., USA) was used to measure heel penetration depth non-invasively. Imaging was performed immediately after heel puncture with standardized perpendicular probe positioning and fixed acquisition parameters. SS-OCT datasets were pre-processed using speckle noise reduction and contrast enhancement, followed by semi-automated segmentation using gradient- and graph-based methods to delineate tissue boundaries. Penetration depth was defined as the distance from the skin surface to the deepest disruption point. In addition, temporal changes in structure, reflectivity, and junction continuity were analyzed to evaluate healing dynamics and device-related differences. 5. Statistics For a crossover design, a sample size of 42 infants per sequence (total 84) achieves a power of 80.005% to detect a difference of 0.114 using a one-sided non-inferiority test against a bound of 0.21 with a significance level of 0.05, when the standard deviation of paired differences is 0.323 and the dropout rate is 15%. Values are expressed as numbers (%), means ± standard deviations, or medians [interquartile ranges]. Categorical variables were analyzed using the Chi-square (χ2) test. Fisher’s exact test was used when any expected cell count was < 5 or when the total sample size was insufficient to meet Chi-square assumptions. After checking for normality, continuous variables were analyzed using the Mann-Whitney test. IBM SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was used for the analysis, and P-values of < 0.05 were considered statistically significant. Results Forty preterm infants were included in the final analysis; their clinical characteristics are presented in Table 1 . Mean gestational age was 34.1 ± 1.6 weeks, and mean birth weight was 2,019 ± 433 g. Procedures were performed at a mean postnatal age of 10.0 ± 7.7 days when mean body weight was 2,053 ± 339 g. Table 1 Clinical characteristics of the studied preterm infants. N = 40 Gestational age (weeks) 34.1 ± 1.6 Birth weight (g) 2,019 ± 433 Male, n (%) 17 (42.5%) Cesarean section, n (%) 29 (72.5%) Apgar score at 1 min 8 [ 7 – 9 ] Apgar score at 5 min 9 [ 9 – 10 ] Postnatal age (day) 10.0 ± 7.7 Body weight (g) 2,053 ± 339 The effectiveness and safety of the LLD and AID arms are shown in Table 2 . The LLD arm achieved a 75% success rate (30/40) on the first attempt at an energy power level 4, with 10 failures. After increasing the power level to 5, all 10 remaining cases were successful, yielding an overall 100% success rate (40/40). On the other hand, the AID arm achieved a 100% success rate (40/40) on the first attempt. Furthermore, the mean number of milking was significantly lower in the AID arm than in the LLD arm (3 [ 2 – 4 ] vs 6 [ 4 – 9 ]; P < 0.01). Table 2 The comparison of effectiveness and safety in both arms. Laser Lancing Device (N = 40) Automatic Incision Device (N = 40) P value Number of successes (%) 40 (100%) 40 (100%) – Success on 1st attempt 30 (75%) 40 (100%) < 0.01 Number of milking 6 [ 4 – 9 ] 3 [ 2 – 4 ] < 0.01 PIPP score Before 2.0 [1.0–3.5] 2.5 [1.0–3.5] 0.436 During puncture 4.5 [3.0–6.0] 6.5 [4.0–7.5] 0.014 After 7.5 [4.0–9.0] 7.0 [3.5–10.5] 0.889 Penetration depth (mm) 1.21 ± 0.30 1.25 ± 0.23 0.455 Sustained bleeding 0 0 – Wound infection 0 0 – PIPP; premature infant pain profile PIPP scores changed significantly over time in both arms. Before capillary blood sampling, the mean PIPP scores were similar in the LLD and AID arms (2.0 [1.0–3.5] vs. 2.5 [1.0–3.5]; P = 0.436). However, during puncture, the mean PIPP score was significantly lower in LLD arm (4.5 [3.0–6.0] vs. 6.5 [4.0–7.5]; P = 0.014), though after puncture, there was no significant difference between the two arms (LLD 7.5 [4.0–9.0] vs. AID 7.0 [3.5–10.5]; P = 0.889). Mean heel penetration depths were similar in the LLD and AID arms (1.21 ± 0.30 mm vs. 1.25 ± 0.23 mm; P = 0.455. Representative visualizations of penetration depths measured using an optic scale bar are shown in Fig. 2 . No sustained bleeding or wound infection was observed in either arm. Analysis of vital signs before and after puncture showed no significant differences in respiratory rate (RR), blood pressure (BP), or peripheral oxygen saturation (SpO2) in the LLD or AID arm. However, heart rate (HR) increased significantly after puncture versus baseline in both arms (data not shown). Discussion This study demonstrates that LLD, which does not use a sharp blade, is an alternative to AID in terms of effectiveness and safety for heel puncture for capillary blood sampling in preterm infants. The overall success rates of the LLD and AID arms were comparable. At an energy power level of 4, the LLD arm achieved a 75% first-attempt success rate, and success was achieved in all remaining cases after increasing the power to level 5, which matched that achieved in the AID arm. These findings indicate that LLD is as effective as AID in preterm infants. Nevertheless, the number of milking required for successful collection was significantly higher in the LLD arm, indicating that, despite equivalent overall success rates, the LLD procedure required repeated milking motions. The lower first-attempt success rate of LLD may reflect the higher skin water content and immature skin barrier of preterm infants, which can increase light scatter during laser application. Moreover, the initial energy setting was chosen as level 4, that is, at the lowest anticipated effective level, to minimize the risk of adverse effects, and starting at level 5 would probably have improved first-attempt success. The smaller skin incision produced by LLD (0.2 ± 0.1 mm vs. 2.0 ± 0.47 mm for AID) may also have contributed to the higher number of milking needed to obtain adequate blood samples. These observations suggest that optimizing energy power levels during laser application could reduce repeated milking and improve procedural efficiency. Future studies should investigate optimal energy settings according to skin maturity and other clinical parameters in critically ill preterm infants. Despite initial concerns regarding the variable penetration depth of LLD, measured mean depth and standard deviation were comparable to those of AID (1.21 ± 0.30 mm vs. 1.25 ± 0.23 mm). Interestingly, although the preset penetration depth of AID using the Preemie Lancet was 0.85 mm, the actual measured depth was greater, probably because of the additional vertical compression applied during the procedure. These observations indicate that LLD maintains procedural safety and achieves penetration depths similar to AID in preterm infants. Importantly, the LLD arm had significantly lower PIPP scores during puncture, indicating that the immediate nociceptive response was attenuated compared to that in the AID arm. Given that AID is already recommended over needle lancets to minimize procedure pain [ 23 , 24 ], this additional reduction represents a clinically meaningful improvement, particularly in vulnerable preterm infants. The immature central nervous system of these infants requires careful monitoring of pain responses, and the lower nociceptive response induced by LLD suggests that it provides a safer and more tolerable alternative for capillary blood sampling and potentially improves overall care in this population. In adult populations, the use of LLDs for capillary blood sampling has been shown to significantly reduce puncture pain as compared to conventional needle lancets [ 10 – 13 ]. These studies adopted a similar step-up energy protocol, that is, an initial low-energy attempt followed by escalation when required and achieved high cumulative success while maintaining sampling adequacy. Additionally, no significant difference in bleeding time was observed between the LLD and needle lancet groups, despite allowing two attempts, whereas pain scores were significantly lower for LLD. Furthermore, this enhanced satisfaction and reduced discomfort resulted in improved patient compliance and procedural acceptance. Overall, adult data reinforce the clinical relevance of our findings and support the use of LLD as a clinically acceptable method for reducing procedure pain in vulnerable preterm infants. In addition to its clinical advantages, LLD may have economic and ecological benefits in neonatal care. For example, its blade-free, non-contact mechanism allows repeated use, potentially lowers the cost of capillary blood sampling, and reduces medical waste. These advantages suggest that LLD is a more sustainable and cost-effective alternative to disposable AID in routine neonatal practice. This study has several limitations. First, it was conducted at a single center on a relatively small sample, which may limit the generalizability of our findings. Second, only clinically stable preterm infants with a birth weight of > 1,500 g were included, and thus, our results cannot be extrapolated to more vulnerable populations, such as extremely low birth weight or clinically unstable infants. Third, although we used a randomized crossover design, the short interval between procedures may have introduced carryover effects, such as sensitization or habituation to repeated heel punctures. Fourth, pain assessment was based solely on PIPP scores, and although PIPP is a validated tool, it is subjective, and thus, scores may have been influenced by inter-observer variability. Finally, the study was limited to short-term outcomes; long-term safety data, including potential effects on skin integrity or infection risk from repeated heel punctures, were not evaluated. Conclusions For heel puncture during capillary blood sampling in preterm infants, LLD demonstrated non-inferior clinical effectiveness and safety compared to conventional AID, but provided the benefits of reduced procedure pain and minimal skin injury. These findings suggest that LLD is a clinically viable alternative for routine neonatal care, particularly for preterm infants requiring repeated painful procedures. Future studies should focus on validating these results in larger, multi-center trials across diverse neonatal populations that include extremely low birth weight infants and infants with hemodynamic instability. In addition, reference data are needed to guide individualized adjustment of energy settings to optimize first-attempt success safely. Declarations Conflict of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics approval and consent to participate This study was performed in accordance with the Declaration of Helsinki. This human study protocol was reviewed and approved by the Institutional Review Board of Korea University Ansan Hospital, approval number [2021AS0089]. And the clinical trial was registered at the Clinical Research Information Service (Registration No. KCT0010932). Written informed consent was obtained from all parents at the time of enrollment. Availability of Data and Materials The data that support the findings of this study are not publicly available due to personal data security but are available upon reasonable request from the corresponding author. Funding Sources This work was supported by a Korea University Ansan Hospital (Grant number: K2011011) and the Korea Medical Device Development Fund Grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711174303, RS-2020-KD000233). Author Contributions BMC, CKY, and HWC conceptualized and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and critically reviewed and revised the manuscript for important intellectual content. EKC, JK and HJK designed the data collection instruments, collected the data and carried out the initial analyses. BCP contributed to the study design and supervised data collection. All authors critically reviewed and approved the final manuscript as submitted and agree to be accountable for all aspects of the work. 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Pediatr Int 2020;62:357–62. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 25 Feb, 2026 Review # 1 received at journal 17 Feb, 2026 Reviewer # 1 agreed at journal 06 Feb, 2026 Reviewers invited by journal 20 Jan, 2026 Submission checks completed at journal 16 Jan, 2026 Editor assigned by journal 15 Jan, 2026 First submitted to journal 15 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8611028","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":577615714,"identity":"b186dba3-497a-4f88-a2b9-c9a9163cec8f","order_by":0,"name":"Byung Min 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07:04:42","extension":"pptx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38563,"visible":true,"origin":"","legend":"","description":"","filename":"Figure12026Jan15.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/5c75b0b839cc7f268fe9d50d.pptx"},{"id":100950350,"identity":"d0d6cb8d-6cfd-4ec0-ac54-25abf62292bb","added_by":"auto","created_at":"2026-01-23 07:07:46","extension":"pptx","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":244506,"visible":true,"origin":"","legend":"","description":"","filename":"Figure22026Jan15.pptx","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/17054504263777e198c77a6b.pptx"},{"id":100866353,"identity":"48b95db3-678f-4f19-882b-f0d54b639041","added_by":"auto","created_at":"2026-01-22 08:32:47","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69364,"visible":true,"origin":"","legend":"","description":"","filename":"260730structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/6323c8bee0350eaffaf22a4f.xml"},{"id":100950001,"identity":"0b476017-fd8a-4510-8e69-7b18c2ac2885","added_by":"auto","created_at":"2026-01-23 07:06:40","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":81613,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/71cc9806522726e88ab63f4d.html"},{"id":100949630,"identity":"05558332-f29b-4385-ba2d-6e66116582fa","added_by":"auto","created_at":"2026-01-23 07:04:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39669,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram of the randomized crossover trial in preterm infants\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/f7ae8338648755eeb1adb904.png"},{"id":100866347,"identity":"645915e2-1f44-4d20-a5af-d0c62f4e7e65","added_by":"auto","created_at":"2026-01-22 08:32:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":399919,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative visualization of skin penetration depth measured with an optical scale bar: (A) laser lancing device (LLD); (B) automatic incision device (AID)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/d5ee502f1da92ab8ba36b9de.png"},{"id":101298898,"identity":"6f884c90-8db0-492e-b93d-1f0ef60c6cba","added_by":"auto","created_at":"2026-01-28 09:37:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1034257,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8611028/v1/a8340917-e51e-45d0-b836-254211aa4be9.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Clinical Effectiveness and Safety of Laser Lancing for Heel Puncture in Preterm Infants: A Randomized Crossover Non-Inferiority Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutomatic incision devices (AIDs) are widely recommended as the standard method in neonatal intensive care units (NICUs) for the heel puncture required for capillary blood collection [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, their sharp blades can injure skin and cause pain, particularly in critically ill or preterm infants who frequently undergo repeated procedures [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough non-pharmacological and pharmacological strategies are recommended to mitigate procedure pain [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], their applications remain limited in critically ill neonates. Recent nationwide surveys report that, despite their proven benefits, breastfeeding and skin-to-skin care are less frequently utilized in sick newborns than in healthy newborns during routine heel puncture [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In addition, intravenous analgesia is rarely used despite recent reports that indicate infants of lower gestational age and earlier postnatal age experience more pain and undergo more pain assessments [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, continued efforts are needed to reduce pain and injury associated with clinical procedures.\u003c/p\u003e \u003cp\u003eRecently, a laser-lancing device (LLD) using a monopulse erbium:YAG laser was developed as an alternative for capillary blood collection, eliminating the need for a sharp blades. In adult populations, LLDs have been shown to significantly reduce puncture pain and improve patient compliance compared to conventional needle lancets [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExtending this evidence to neonatal populations, our previous study in full-term infants demonstrated that LLDs achieved success rates comparable to those of AIDs, while producing markedly smaller skin injuries (approximately 0.2 mm vs. 2.0 mm) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This reduced tissue disruption provides robust evidence supporting a safety advantage of LLDs in neonates, for whom tissue fragility is a critical concern.\u003c/p\u003e \u003cp\u003eHowever, preterm infants present unique challenges because of thinner, fragile skin, requiring the precise determination of penetration depth to avoid tissue injury [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, the immature central nervous system necessitates careful monitoring of pain responses to prevent immediate and long-term adverse neurodevelopmental outcomes [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address these concerns, we conducted a randomized crossover non-inferiority trial in preterm infants to evaluate whether an LLD might serve as a safer, less painful alternative than an AID in this high-risk population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA prospective randomized crossover non-inferiority trial was conducted from April to December 2021 at Korea University Ansan Hospital. The study was approved by the Institutional Review Board (IRB No. 2021AS0089) and registered at the Clinical Research Information Service (Registration No. KCT0010932). Written informed consent was obtained from all parents at the time of enrollment.\u003c/p\u003e \u003cp\u003e1. Subjects\u003c/p\u003e \u003cp\u003eInclusion criteria were a clinically stable preterm infant with a gestational age of \u0026lt;\u0026thinsp;37 weeks and a body weight of \u0026gt;\u0026thinsp;1,500 g, who were clinically stable and undergoing heel puncture for capillary blood collection. Infants with congenital anomalies or severe respiratory distress requiring invasive ventilation were excluded, as unstable hemodynamics might influence capillary refill time.\u003c/p\u003e \u003cp\u003eForty-two infants were randomly and equally allocated to group A or B. Group A underwent heel blood sampling with the LLD on day 1 and the AID on day 2, whereas group B followed the reverse sequence (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Two infants were subsequently excluded (one was discharged after the first LLD procedure and another was transferred after the first AID procedure), and thus, 40 infants were included in the final analysis. All data were de-identified to protect personal information.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e2. Procedures\u003c/p\u003e \u003cp\u003eAll infants receiving 1 mL of 10% glucose orally 2 minutes before puncture as a non-pharmacological pain control measure [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBlood collection was performed using an LLD (LMT-5000 HandyRay-Pro, Lameditech, Seoul, Korea) or an AID (BD Quikheel Preemie Lancet, depth 0.85 mm, width 1.75 mm) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The LLD was set at energy level 4 (4,270 mJ) for the initial puncture and level 5 (5,320 mJ) for the second attempt if the volume obtained was insufficient. The initial AID puncture was performed using the Preemie Lancet, and using the BD Quikheel Infant Lancet (depth 1.00 mm, width 2.50 mm) for the second attempt if the volume obtained was insufficient. The second attempt was initiated after the infant had returned to a stable state following the first attempt.\u003c/p\u003e \u003cp\u003eSuccess was defined as the collection of \u0026ge;\u0026thinsp;100 \u0026micro;L after two attempts. For optimal blood collection, a milking motion was performed at the plantar surface, and the number of maneuvers was recorded as an indirect measure of procedural efficiency. Squeezing toward the heel was avoided [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e3. Assessment of pain response\u003c/p\u003e \u003cp\u003eTo assess pain response, all subjects were video recorded from before oral glucose administration through the procedure until pain subsided. Pain was independently scored by two blinded investigators using the Premature Infant Pain Profile (PIPP), a validated composite pain assessment tool [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Pain assessment was based on the attempt that achieved successful blood collection.\u003c/p\u003e \u003cp\u003e4. Measurement of heel penetration depth\u003c/p\u003e \u003cp\u003eA Swept Source Optical Coherence Tomography system (SS-OCT; VEG220C1, Thorlabs Inc., USA) was used to measure heel penetration depth non-invasively. Imaging was performed immediately after heel puncture with standardized perpendicular probe positioning and fixed acquisition parameters. SS-OCT datasets were pre-processed using speckle noise reduction and contrast enhancement, followed by semi-automated segmentation using gradient- and graph-based methods to delineate tissue boundaries. Penetration depth was defined as the distance from the skin surface to the deepest disruption point. In addition, temporal changes in structure, reflectivity, and junction continuity were analyzed to evaluate healing dynamics and device-related differences.\u003c/p\u003e \u003cp\u003e5. Statistics\u003c/p\u003e \u003cp\u003eFor a crossover design, a sample size of 42 infants per sequence (total 84) achieves a power of 80.005% to detect a difference of 0.114 using a one-sided non-inferiority test against a bound of 0.21 with a significance level of 0.05, when the standard deviation of paired differences is 0.323 and the dropout rate is 15%.\u003c/p\u003e \u003cp\u003eValues are expressed as numbers (%), means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations, or medians [interquartile ranges]. Categorical variables were analyzed using the Chi-square (χ2) test. Fisher\u0026rsquo;s exact test was used when any expected cell count was \u0026lt;\u0026thinsp;5 or when the total sample size was insufficient to meet Chi-square assumptions. After checking for normality, continuous variables were analyzed using the Mann-Whitney test. IBM SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was used for the analysis, and P-values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eForty preterm infants were included in the final analysis; their clinical characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Mean gestational age was 34.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 weeks, and mean birth weight was 2,019\u0026thinsp;\u0026plusmn;\u0026thinsp;433 g. Procedures were performed at a mean postnatal age of 10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 days when mean body weight was 2,053\u0026thinsp;\u0026plusmn;\u0026thinsp;339 g.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of the studied preterm infants.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,019\u0026thinsp;\u0026plusmn;\u0026thinsp;433\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (42.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean section, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (72.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar score at 1 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar score at 5 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostnatal age (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,053\u0026thinsp;\u0026plusmn;\u0026thinsp;339\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe effectiveness and safety of the LLD and AID arms are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The LLD arm achieved a 75% success rate (30/40) on the first attempt at an energy power level 4, with 10 failures. After increasing the power level to 5, all 10 remaining cases were successful, yielding an overall 100% success rate (40/40). On the other hand, the AID arm achieved a 100% success rate (40/40) on the first attempt. Furthermore, the mean number of milking was significantly lower in the AID arm than in the LLD arm (3 [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] vs 6 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe comparison of effectiveness and safety in both arms.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLaser Lancing Device (N\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutomatic Incision Device (N\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of successes (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccess on 1st attempt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of milking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIPP score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0 [1.0\u0026ndash;3.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5 [1.0\u0026ndash;3.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.436\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuring puncture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.5 [3.0\u0026ndash;6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5 [4.0\u0026ndash;7.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5 [4.0\u0026ndash;9.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 [3.5\u0026ndash;10.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.889\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePenetration depth (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.455\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSustained bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePIPP; premature infant pain profile\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePIPP scores changed significantly over time in both arms. Before capillary blood sampling, the mean PIPP scores were similar in the LLD and AID arms (2.0 [1.0\u0026ndash;3.5] vs. 2.5 [1.0\u0026ndash;3.5]; P\u0026thinsp;=\u0026thinsp;0.436). However, during puncture, the mean PIPP score was significantly lower in LLD arm (4.5 [3.0\u0026ndash;6.0] vs. 6.5 [4.0\u0026ndash;7.5]; P\u0026thinsp;=\u0026thinsp;0.014), though after puncture, there was no significant difference between the two arms (LLD 7.5 [4.0\u0026ndash;9.0] vs. AID 7.0 [3.5\u0026ndash;10.5]; P\u0026thinsp;=\u0026thinsp;0.889).\u003c/p\u003e \u003cp\u003eMean heel penetration depths were similar in the LLD and AID arms (1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 mm vs. 1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 mm; P\u0026thinsp;=\u0026thinsp;0.455. Representative visualizations of penetration depths measured using an optic scale bar are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No sustained bleeding or wound infection was observed in either arm.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAnalysis of vital signs before and after puncture showed no significant differences in respiratory rate (RR), blood pressure (BP), or peripheral oxygen saturation (SpO2) in the LLD or AID arm. However, heart rate (HR) increased significantly after puncture versus baseline in both arms (data not shown).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrates that LLD, which does not use a sharp blade, is an alternative to AID in terms of effectiveness and safety for heel puncture for capillary blood sampling in preterm infants.\u003c/p\u003e \u003cp\u003eThe overall success rates of the LLD and AID arms were comparable. At an energy power level of 4, the LLD arm achieved a 75% first-attempt success rate, and success was achieved in all remaining cases after increasing the power to level 5, which matched that achieved in the AID arm. These findings indicate that LLD is as effective as AID in preterm infants. Nevertheless, the number of milking required for successful collection was significantly higher in the LLD arm, indicating that, despite equivalent overall success rates, the LLD procedure required repeated milking motions.\u003c/p\u003e \u003cp\u003eThe lower first-attempt success rate of LLD may reflect the higher skin water content and immature skin barrier of preterm infants, which can increase light scatter during laser application. Moreover, the initial energy setting was chosen as level 4, that is, at the lowest anticipated effective level, to minimize the risk of adverse effects, and starting at level 5 would probably have improved first-attempt success. The smaller skin incision produced by LLD (0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 mm vs. 2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 mm for AID) may also have contributed to the higher number of milking needed to obtain adequate blood samples. These observations suggest that optimizing energy power levels during laser application could reduce repeated milking and improve procedural efficiency. Future studies should investigate optimal energy settings according to skin maturity and other clinical parameters in critically ill preterm infants.\u003c/p\u003e \u003cp\u003eDespite initial concerns regarding the variable penetration depth of LLD, measured mean depth and standard deviation were comparable to those of AID (1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 mm vs. 1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 mm). Interestingly, although the preset penetration depth of AID using the Preemie Lancet was 0.85 mm, the actual measured depth was greater, probably because of the additional vertical compression applied during the procedure. These observations indicate that LLD maintains procedural safety and achieves penetration depths similar to AID in preterm infants.\u003c/p\u003e \u003cp\u003eImportantly, the LLD arm had significantly lower PIPP scores during puncture, indicating that the immediate nociceptive response was attenuated compared to that in the AID arm. Given that AID is already recommended over needle lancets to minimize procedure pain [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], this additional reduction represents a clinically meaningful improvement, particularly in vulnerable preterm infants. The immature central nervous system of these infants requires careful monitoring of pain responses, and the lower nociceptive response induced by LLD suggests that it provides a safer and more tolerable alternative for capillary blood sampling and potentially improves overall care in this population.\u003c/p\u003e \u003cp\u003eIn adult populations, the use of LLDs for capillary blood sampling has been shown to significantly reduce puncture pain as compared to conventional needle lancets [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These studies adopted a similar step-up energy protocol, that is, an initial low-energy attempt followed by escalation when required and achieved high cumulative success while maintaining sampling adequacy. Additionally, no significant difference in bleeding time was observed between the LLD and needle lancet groups, despite allowing two attempts, whereas pain scores were significantly lower for LLD. Furthermore, this enhanced satisfaction and reduced discomfort resulted in improved patient compliance and procedural acceptance. Overall, adult data reinforce the clinical relevance of our findings and support the use of LLD as a clinically acceptable method for reducing procedure pain in vulnerable preterm infants.\u003c/p\u003e \u003cp\u003eIn addition to its clinical advantages, LLD may have economic and ecological benefits in neonatal care. For example, its blade-free, non-contact mechanism allows repeated use, potentially lowers the cost of capillary blood sampling, and reduces medical waste. These advantages suggest that LLD is a more sustainable and cost-effective alternative to disposable AID in routine neonatal practice.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it was conducted at a single center on a relatively small sample, which may limit the generalizability of our findings. Second, only clinically stable preterm infants with a birth weight of \u0026gt;\u0026thinsp;1,500 g were included, and thus, our results cannot be extrapolated to more vulnerable populations, such as extremely low birth weight or clinically unstable infants. Third, although we used a randomized crossover design, the short interval between procedures may have introduced carryover effects, such as sensitization or habituation to repeated heel punctures. Fourth, pain assessment was based solely on PIPP scores, and although PIPP is a validated tool, it is subjective, and thus, scores may have been influenced by inter-observer variability. Finally, the study was limited to short-term outcomes; long-term safety data, including potential effects on skin integrity or infection risk from repeated heel punctures, were not evaluated.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFor heel puncture during capillary blood sampling in preterm infants, LLD demonstrated non-inferior clinical effectiveness and safety compared to conventional AID, but provided the benefits of reduced procedure pain and minimal skin injury. These findings suggest that LLD is a clinically viable alternative for routine neonatal care, particularly for preterm infants requiring repeated painful procedures.\u003c/p\u003e \u003cp\u003eFuture studies should focus on validating these results in larger, multi-center trials across diverse neonatal populations that include extremely low birth weight infants and infants with hemodynamic instability. In addition, reference data are needed to guide individualized adjustment of energy settings to optimize first-attempt success safely.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the Declaration of Helsinki. This human study protocol was reviewed and approved by the Institutional Review Board of Korea University Ansan Hospital, approval number [2021AS0089]. And the clinical trial was registered at the Clinical Research Information Service (Registration No. KCT0010932). Written informed consent was obtained from all parents at the time of enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not publicly available due to personal data security but are available upon reasonable request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a Korea University Ansan Hospital (Grant number: K2011011) and the Korea Medical Device Development Fund Grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health \u0026amp; Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711174303, RS-2020-KD000233).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBMC, CKY, and HWC conceptualized and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and critically reviewed and revised the manuscript for important intellectual content. EKC, JK and HJK designed the data collection instruments, collected the data and carried out the initial analyses. BCP contributed to the study design and supervised data collection.\u003c/p\u003e\n\u003cp\u003eAll authors critically reviewed and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to all the neonates and families participating in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEvans DL, Volsko TA, Capellari E, Strickland SL. AARC Clinical Practice Guidelines: Capillary Blood Gas Sampling for Neonatal and Pediatric Patients. Respir Care 2022;67:1190\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadiye D, Serap B. 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Arch Pediatr Adolesc Med 2003;157:1075\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJanes M, Pinelli J, Landry S, Downey S, Paes B. Comparison of capillary blood sampling using an automated incision device with and without warming the heel. J Perinatol 2002;22:154\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGanguly A, Bhadesia PJ, Phatak AG, Nimbalkar AS, Nimbalkar SM. Pain profile of premature infants during routine procedures in neonatal intensive care: An observational study. J Family Med Prim Care 2020;9:1517\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonnie JS, Sharyn G, Janet Y, Kimberley D, Grace L, Celeste J, et al. The premature infant pain profile-revised(PIIP-R) initial validation and feasibility. Clin J Pain 2014;30:238\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVertanen H, Fellman V, Brommels M, Viinikka L. An automatic incision device for obtaining blood samples from the heels of preterm infants causes less damage than a conventional manual lancet. Arch Dis Child Fetal Neonatal Ed 2001;84:F53\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoto T, Inoue T, Kamiya C, Kawabe H, Higuchi M, Suyama M, et al. Neonatal pain response to automatic lancet versus needle heel-prick blood sampling: A prospective randomized controlled clinical trial. Pediatr Int 2020;62:357\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8611028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8611028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eOBJECTIVE:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the clinical effectiveness and safety of laser lancing devices (LLDs) compared with an automatic incision device (AID) for heel puncture in preterm infants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTUDY DESIGN:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA randomized crossover non-inferiority trial was conducted in 40 preterm infants between April and December 2021. Primary outcomes were procedural success rate, pain response assessed by the Premature Infant Pain Profile (PIPP), and skin penetration depth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLLD achieved a 75% first-attempt success rate, reaching 100% after a second attempt at a higher energy setting, whereas AID achieved 100% success on the first attempt. PIPP scores during the procedure were significantly lower with LLD than with AID (4.5 [3.0–6.0] vs. 6.5 [4.0–7.5]; \u003cem\u003eP\u003c/em\u003e=0.014). Penetration depths were similar between devices (1.21±0.30 \u003cem\u003evs.\u003c/em\u003e 1.25±0.23 mm).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSIONS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLLD appears to be an effective and safe alternative to AID for heel puncture in preterm infants, with reduced procedure pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCLINICAL TRIAL REGISTRATION:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical Research Information Service (Registration No. KCT0010932)\u003c/p\u003e","manuscriptTitle":"Clinical Effectiveness and Safety of Laser Lancing for Heel Puncture in Preterm Infants: A Randomized Crossover Non-Inferiority Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 08:32:42","doi":"10.21203/rs.3.rs-8611028/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-02-25T11:24:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-17T13:05:55+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-06T22:55:32+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-01-20T15:42:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-16T11:08:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-15T13:36:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2026-01-15T13:36:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7a5f7db5-7df2-4c60-8312-8e77562f567b","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61453210,"name":"Health sciences/Health care/Paediatrics"},{"id":61453211,"name":"Health sciences/Medical research/Biomarkers/Diagnostic markers"}],"tags":[],"updatedAt":"2026-05-12T18:15:16+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-22 08:32:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8611028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8611028","identity":"rs-8611028","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}