United States

Introduction
Distal radius fractures are becoming increasing prevalent in our aging population. Locked volar plating remains the preferred surgical treatment. Prior studies investigating optimal locking plate constructs for fracture stability have predominantly used extra-articular fracture models. Many surgeons have adopted unicortical distal fixation to minimize risk of extensor tendon injury. This study aimed to determine the biomechanical effect of unicortical distal locking screws and pegs on stability in comminuted, intra-articular distal radius fracture cadavers. 

Methods
We applied volar-locking distal radius plates to 24 cadaveric radiuses. The radiuses were divided into 4 groups based on distal locking fixation: 100% length bicortical screws, 75% length screws, 100% length pegs, and 75% length pegs. Osteotomies simulated AO type 23 C2 dorsally comminuted, intra-articular fractures. We determined each construct’s stiffness under physiologic loads (axial compression, dorsal bending, and volar bending) before and after 1,000 cycles of axial conditioning and before axial load to clinical failure (2mm of displacement) and catastrophic failure. We used Analysis of Covariance (ANCOVA) to compare differences of means between groups and Tukey Honest Significant Difference (HSD) test for post-hoc analysis. 

Results 
There were no significant differences in age, weight, or bone mineral density (BMD) between groups. Stiffness to volar bending and dorsal bending were statistically equivalent between groups before and after cycling loading. Final stiffness under axial load was statistically equivalent for all groups. Force to clinical failure was statistically equivalent between 100% screw length (308N) and 75% screw length (351N) constructs, and equivalent between 100% peg length (127N) and 75% peg length (150N) constructs. Forces to clinical failure were significantly greater for 100% and 75% screw lengths compared to their peg counterparts (p=0.0253 and p=0.0125 respectively). Force to clinical failure was significantly greater for 75% screw lengths than 100% smooth pegs (p=0.005). Force to catastrophic failure was statistically equivalent between all groups. 

Conclusions 
We recommend the use of 75% length screws or pegs over their bicortical counterparts to prevent dorsal cortex penetration without compromising stability. Surgeons may consider using threaded locking screws over smooth pegs in treating more complex intra-articular distal radius fractures. 



AMA Research Challenge 2024 

Investigating the Effect of Distal Screw and Peg Length on Stability in Volar Plating of Comminuted, Intra-articular Distal Radius Fractures

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Background
The incidence of acute sport injuries in children is on the rise, with 2.6 annual million emergency room visits for sports-related injury. Concurrently, opioid prescribing practices have increased in recent decades, especially in pediatric populations. To help curb opioid usage, a multimodal pain management guideline should be instituted. Further investigation is needed on the precision of regional anesthetic in performing an adductor canal nerve block (ACB) in pediatric knee arthroscopy procedures. Variations in nerve locations within the thigh may impact postoperative pain and opioid usage. We are interested in studying the optimal location of ACB placement to reduce postoperative pain and consequently reduce opioid medication usage after pediatric knee arthroscopy.

Methods
A prospective, double-blinded randomized control trial consisting of 80 pediatric patients (ages 5-17) undergoing knee arthroscopy at St. Christopher’s Hospital for Children, approved by the Institutional Review Board. Enrolled patients are randomized to receive an ultrasound-guided placement of an ACB using 0.2% ropivacaine in one of three locations in the thigh: proximal, middle, distal, or control group with saline. The primary data collected are postoperative pain scores and amount of opioids taken, standardized to morphine milligram equivalents (MME), in the 24 and 48-hour postoperative period. Secondary outcomes included correlational assessment of pre and postoperative anxiety of patients and caregivers, correlation between patient anxiety and pain, and a postoperative dermatome sensation test. Data analysis performed with ANOVA test. Complete results including analysis of primary and secondary outcomes are shown in Tables 1 and 2.

Results
60 patients (mean age 15.5) have completed this actively enrolling study. This includes 14 in the proximal placement group, 15 in the middle placement group, and 16 in the distal placement group, and 15 in the control group. Primary outcomes analysis showed no significant difference in pain scores or opioids taken at 24 and 48-hours postoperatively among groups. Increased anxiety positively correlated with heightened postoperative pain.

Conclusion
ACB placement in proximal, middle, and distal thigh locations provided comparable 24 and 48-hour postoperative analgesia and opioid medication usage in our first 60 patients.

Adductor Canal Regional Anesthetic Placement in Pediatric Patients for Knee Arthroscopy: Defining the Optimal Location and Analysis of Other Trends

Background
Recent evidence has demonstrated that current hypertension (HTN) diagnosis using seated blood pressure (BP) measurements alone may omit supine HTN, a condition linked with mortality. Higher resting supine systolic BP (SBP) and maximal exercise SBP are associated with increased morbidity and mortality risk, but their relationship remains unexplored in cohorts including both men and women. This study aimed to assess potential sex differences in the change from resting supine BP to maximal exercise BP to predict all-cause mortality.

Methods
This sample included 2,269 apparently healthy, nonclinical adults (1176 men, 1093 women, mean age: 45.2 +- 13.0 yr) from the Ball State Adult Fitness Longitudinal Lifestyle Study (BALL ST) cohort. Participants underwent a maximal cardiopulmonary treadmill exercise test with resting supine and peak exercise SBP recorded. Descriptive statistics summarized participant characteristics including risk factors, ethnicity, and clinical measurements like baseline supine BP and changes to peak BP. Baseline differences among men and women were assessed using unpaired t-tests. Participants were categorized into four groups based on resting and peak SBP: supine HTN (SBP >140mmHg) with exaggerated peak BP (SBP >210mmHg for men, SBP >190mmHg for women), supine HTN with normal peak BP, normal supine BP with exaggerated peak BP, and normal supine BP with normal peak BP. Kaplan-Meier survival curve analysis with Bonferroni adjustment compared these groups.

Results
Women exhibited lower resting supine SBP (124.4 +- 15.5 vs 132.3 +- 14.6 mmHg), peak SBP (166.8 +- 21.7 vs 185.3 +- 22.2 mmHg), and change from supine to peak SBP (42.4 +- 16.6 vs 53.0 +- 19.1 mmHg) compared to men (P<0.05, all). Participants were followed for an average of 19.0 +- 9.4 yr for all-cause mortality, during which 238 died (163 men, 75 women). Kaplan-Meier analysis in the whole cohort revealed lower survival in the supine HTN, normal peak SBP and supine HTN, exaggerated peak SBP groups compared with normal supine, normal peak group (P<0.05, both). Sex-specific survival curve analyses demonstrated lower survival rates for the HTN, exaggerated peak SBP compared to the normal supine, normal peak group for men and women (P<0.05, both).

Conclusion
These findings demonstrate higher all-cause mortality in both men and women with supine HTN and exaggerated peak BP responses, compared to those with normal supine SBP and normal peak responses. This highlights the importance of screening for supine HTN and incorporating resting supine BP measurements with exercise treadmill stress tests to better predict all-cause mortality.

Supine Hypertension and Exaggerated Exercise Blood Pressure Response are Associated with All-Cause Mortality in Men and Women

Background
Brainstem cavernous malformations (BSCM) are challenging lesions to treat surgically due to their eloquent location and proximity to critical neurovascular structures. Safe entry zones (SEZs) have emerged as important corridors for accessing these lesions while minimizing morbidity. This systematic review and meta-analysis aims to provide a comprehensive analysis of the surgical management of pontine BSCM with a focus on SEZs, clinical presentation, lesion characteristics, surgical approach, and clinical outcomes.
Methods
A systematic literature search was performed in PubMed for articles published from 1986 to June 2024 reporting on the surgical management of pontine BSCM. Data were extracted on patient demographics, clinical presentation, BSCM characteristics, surgical approach, use of SEZs, and clinical outcomes. Statistical analyses were performed to identify factors associated with improved outcomes.
Results
Fifty-seven studies with a total of 490 patients were included. The cohort was 54% female with an average age of 33.42±17.7 years. The most common presenting symptoms varied by location. Symptoms associated with a particular anatomical distribution included hemiparesis (p=.0128), hemipaesthesia (p=.0125) and diplopia (p=.001) in basilar pons, CN V palsy (p=.0140) in peritrigeminal pons, CN VII (p=.0247), CN IX (p=.001), CN X (p=.001) and vertigo (p=.006) in the inferior peduncular pons and tetraspasticity (p=.001) in the rhomboid pons. The two most common BSCM locations were peritrigeminal (31.25%) and rhomboid (33.13%). The average major diameter of BSCM was 19.05±8.75 mm and 5.3% of BSCM were developmental venous anomalies. The most frequently used surgical approaches were the suboccipital telovelar approach (31.8%), the retrosigmoid approach (18.7%), and the transpetrosal approach (6.05%) and the most commonly utilized SEZ was the lateral pontine zone (LPZ) (34.1%). Average follow-up was 4.0±4.4 years. Overall, gross total resection was achieved in 65.6% of cases, in cases utilizing the LPZ gross total resection was achieved in 82.8% of cases. Good clinical outcome (follow-up mRS<2) was observed in 64.1% of patients, with an overall mortality rate of 1.0%. The use of SEZs for pontine BSCM was associated with improved clinical outcome (OR: 2.41, 95% CI: 1.279-4.546, p=.006). BSCM located in the middle peduncular pons were associated with an improved clinical outcome (OR: 6.759, 95% CI: 2.322-19.673, p=.0005), while BSCM located in the basilar pons were associated with a worse clinical outcome (OR:0.075, 95% CI: 0.010-0.584, p=.0133).
Conclusion
Surgical resection of pontine BSCM can be performed with low morbidity and mortality rates when utilizing SEZs and careful preoperative planning. The lateral pontine, supratrigeminal, and peritrigeminal SEZs are associated with high rates of complete resection and improved neurological outcomes. BSCM location dictates the choice of SEZ and surgical approach, emphasizing the importance of understanding the regional anatomy of the brainstem. Future studies with standardized reporting and longer follow-ups are needed to further refine surgical techniques, patient selection, and stratify outcomes based on anatomical distribution.


Surgical Management of Pontine Brainstem Cavernous Malformations: A Systematic Review and Meta-Analysis Emphasizing Safe Entry Zones and Clinical Outcomes

Abstract Title
The Role of Irreversible Electroporation for Pancreatic Cancer

Background
Pancreatic cancer is one of the most aggressive cancers in the world, representing the fourth most frequent tumor-related cause of death in the Western world and the seventh leading cause of cancer death worldwide. Surgical resection offers the only chance of long-term survival, but only 15-20% of patients have potentially resectable disease at primary diagnosis. Due to proximity to critical anatomical structures, patients with locally advanced pancreatic cancer (LAPC) may be unable to undergo surgical resection. Furthermore, many patients with LAPC are treated like metastatic disease with systemic palliative chemotherapy, resulting in poor response. The aim of the present review was to evaluate the role of irreversible electroporation (IRE) in borderline resectable pancreatic cancer and LAPC.

Methods
A comprehensive review was performed using PubMed, Embase (OvidSP), Library of Congress, Lista (EBSCO), and Web of Science Core Collection. The initial search was conducted using the terms “Pancreatic Cancer” or “Pancreatic Adenocarcinoma” and “Irreversible Electroporation” in the title field, yielding 165 results. 140 articles were excluded because they focused on cancers not pertinent to the study, weren’t exclusive to human studies, combined open and percutaneous IRE data, or didn’t pertain to the study. The remaining 25 articles were examined for quality reporting data related to key inclusion materials, and 15 articles’ survival outcomes, safety, and efficacy results were included. The data extracted focused on outcomes related to progression free survival (PFS) and overall survival (OS) relating to IRE therapy, safety and efficacy compared to other ablation techniques, and induction chemotherapy regimen type and intensity. The primary endpoint was to determine whether IRE could safely and effectively improve PFS and OS in patients with LAPC. 

Results
IRE has demonstrated encouraging survival and response outcomes when combined with induction chemotherapy versus patient populations that receive chemotherapy and/or chemoradiation alone. The use of IRE with targeted therapies may enhance antitumor immunity and possibly improve survival outcomes compared to historical controls. Additionally, the combination of IRE with multiagent therapy has been associated with a low rate of serious adverse events, complications, and infections. 

Conclusion
Irreversible electroporation could improve overall survival and progression free survival when combined with multiagent therapy in patients with LAPC. The optimal management of patients with LAPC is evolving with the advent of improved IRE implementation, newer chemotherapeutics and immunotherapy. IRE has demonstrated itself to be a viable surgical intervention for patients with borderline resectable pancreatic cancer and LAPC.


The Role of Irreversible Electroporation (IRE) for Pancreatic Cancer

Metformin is one of the most prescribed medications in the United States, mainly due to its utility in treating patients with diabetes. Continued research into metformin’s mechanisms have yielded interesting findings on its cancer suppressing abilities, including its actions in prostate cancer. With these mechanisms in mind, we sought to investigate the potential effects of metformin use on PSA levels in patients with prostate cancer. Using the TriNetX research network, we collected data forming two cohorts of patients with diabetes and same-stage prostate cancer, with and without metformin treatment, cohort A and cohort B respectively. We found a difference between PSA and metformin usage. The mean serum PSA level among patients with the diagnosis of prostate cancer and metformin use in Cohort A (N=45,145) was 20.1 ± 17.8 and the mean serum PSA level for patients with the diagnosis of prostate cancer and no metformin use (N=440,464) was 34.3 ± 31, p<0.0002. We identified a significant decrease in the mean PSA level in metformin users compared to non-metformin users. Further investigation on the effects of metformin on PSA levels is needed to clarify metformin-induced dampening of PSA in screening for prostate cancer diagnosis.

PSA Down, Metastasis at Bay: Metformin's Impact on Prostate Cancer and Implications for Screening

Background
Frailty indices are well-established metrics used to assess physiologic reserve and predict peri- and post-operative morbidity and mortality. While multiple frailty tools exist, there is limited consensus regarding the most effective risk assessment tool in orthopaedic trauma. Although there is literature supporting the utility of the 5-Item Modified Frailty Index (mFI-5) in the orthopaedic trauma population, the newer Revised Risk Analysis Index (RAI-Rev) has not been evaluated in this population. This study sought to determine the applicability of RAI-Rev in the orthopaedic trauma population and compare the predictive discrimination for the RAI-Rev and mFI-5 for 30-day postoperative outcomes.

Methods
The ACSNSQIP data were queried from 2015 to 2020 for patients ≥ 18 with operatively treated fractures of the forearm, humerus, pelvis, acetabulum, femur, tibia, and hindfoot. Outcomes included a composite of major complications (death, sepsis, pulmonary embolism, ventilator use greater than 48 hours, return to operating room, unplanned re-intubation, acute postoperative renal failure, cardiac arrest, myocardial infarction, cerebrovascular accident, and graft failure), mortality, readmission, and wound complications. Frailty scores were stratified into four cohorts based on frailty levels, utilizing previously described cutoff scores. Multivariate analysis was used to assess the predictive value of frailty. Receiver operating characteristics curve analysis was quantified with C-statistic for discriminatory accuracy. 

Results
In total, 206,352 patients met inclusion criteria. Median age was 69 years old, with 64.2% (n = 132,514) being female. Multivariate regression analysis showed that increasing frailty tiers in both RAI-Rev and mFI-5 were independent predictors of mortality, major complications, readmission, and wound complications. The cohort with the highest degree of frailty in both RAI-Rev and mFI-5 had the greatest risk of poor outcomes. RAI-Rev had significantly superior predictive discriminatory thresholds compared to mFI-5 for predicting 30-day mortality (C-statistic: RAI-Rev (0.84) and mFI-5 (0.67), p <0.001), major complications (C-statistic: RAI-Rev (0.73) and mFI-5 (0.65), p <0.001), and readmission (C-statistic: RAI-Rev (0.68) and mFI-5 (0.63), p <0.001). However, mFI-5 outperformed RAI-Rev when predicting wound complications (C-statistic: RAI-Rev (0.52) and mFI-5 (0.55), p <0.001). 

Conclusion
RAI-rev demonstrated superior predictability of postoperative morbidity, mortality, and readmission rates compared to mFI-5, but was less effective in predicting surgical site complications. These findings demonstrate the utility of RAI-Rev in anticipating postoperative complications in the setting of orthopaedic trauma, where optimizing surgical candidate selection is not always possible. Assessing the predicted morbidity and mortality through RAI-Rev may allow surgeons to mitigate postoperative complications in patients undergoing surgical fixation of traumatic injuries.


Comparison of Revised Risk Analysis Index and 5-Item Modified Frailty Index as Predictors of Mortality and Morbidity in Orthopaedic Trauma

Background
Mind-wandering is a pervasive human brain state and, when in excess, may promote negative affect and neuropsychiatric conditions. Mindfulness meditation may promote alternate brain states, improving affect and reducing stress. An understanding of the neural basis between these brain states could thus advance treatment of neuropsychiatric conditions. Patients with epilepsy suffer from high rates of neuropsychiatric conditions including anxiety and depression that may be mediated by mind-wandering and improved by mindfulness meditation. Patients with drug-resistant epilepsy routinely undergo intracranial recordings using stereo electroencephalography (sEEG) to locate and treat the anatomical origin of seizures. SEEG recordings over several days in these patients therefore afford a unique opportunity to study the effects of mind-wandering and mindfulness on the human brain. 

Methods
To explore the neural basis of mindfulness meditation versus mind-wandering, we enrolled eight patients in a trial of structured mindfulness meditation and open mind-wandering who underwent sEEG within the mesial temporal lobe for seizure localization. Electrophysiology was compared between mind-wandering and mindfulness separately for epileptic and non-epileptic tissue. Using fitting-one-over-f modeling, periodic components of electrophysiology were compared in canonical frequency bands of theta (4-8Hz), alpha (8-13Hz), beta (13-30Hz), and gamma (30-55Hz). Aperiodic components of the power spectra were assessed by the model offset, knee, and exponent. 

Results
We found a significant reduction in gamma power (30-55Hz) within the mesial temporal lobe during mindfulness meditation compared with mind-wandering in non-epileptic (p=1.20E-4) but not in epileptic brain (p=0.352).There was also a significant difference between epileptic versus non-epileptic brain in difference in gamma power between conditions (p=0.011). There were no significant changes in power across any frequency band within epileptic mesial temporal brain tissue between brain states. Conversely, there were significant differences between mind-wandering and mindfulness within epileptic brain in aperiodic components (offset, knee, and exponent, all p<0.05), while no differences in aperiodic components were seen in non-epileptic brain (all p>0.70). 

Conclusion
Intracranial electrophysiologic modulations between brain state (mind-wandering versus mindfulness) may differ between epileptic and non-epileptic brain tissue. Modulations in gamma activity in non-epileptic brain may represent functional changes in brain state, while aperiodic changes in epileptic brain may modulate propensity for seizures. 


Mesial Temporal Electrophysiology between Mind-Wandering and Mindfulness Meditation

Background
Glaucoma is defined by damage to the optic nerve that results in visual field (VF) loss widely considered to be irreversible. However, in a landmark clinical trial for glaucoma known as the Ocular Hypertension Treatment Study (OHTS)(1), reversal of VF loss was observed but assumed to be caused by artifact. We tested the assumption of whether vision loss is always irreversible.

Methods
Given the inherent variability of VF testing, a prevailing challenge is distinguishing true improvement from random noise. Permutation of pointwise linear regression (PoPLR)(2) is a statistical method that determines whether an observed VF trend is a true phenomenon. PoPLR determined the prevalence of eyes with VF outcome (improvement, deterioration, or stability) with the threshold for random variation at 5%. Archetypal analysis (AA)(3) is an unsupervised machine learning technique that decomposes an individual VF into patterns of glaucomatous defects. Longitudinal trends of glaucomatous defect were measured with linear regression. To assess whether learning effect is confounder for improvement, reliability indices including false positive rate (FPR), false negative rate (FNR), and fixation losses (FL) were compared across VF outcomes using one-way ANOVA. We also analyzed structural differences by comparing rates of significant thinning of retinal nerve fiber layer (RNFL) using Chi-Square analysis. A p-value less than 0.05 was considered statistically significant.

Results
This study isolated 886 eyes from 619 patients, of which 106 eyes (11.96%), 331 eyes (37.36%) and 449 eyes (50.68%) demonstrated VF improvement, deterioration, and stability, respectively. Eyes exhibiting VF improvement had significantly decreased representation of superior altitudinal defect (-0.05%/year, p<0.001), inferotemporal defect (-0.08%/year, p=0.013), and inferonasal defect (-0.12%/year, p<0.001). There was no significant difference in FPR (p=0.203), FNR (p=0.631), or FL (p=0.105) across VF outcomes. VF improvement was found to have a lower rate of significant RNFL thinning compared to VF deterioration (11.1% vs. 42.2%, p<0.001).

Conclusion
Reversal of glaucomatous vision loss is a true phenomenon as VF improvement occurred more often than random variation and was accompanied by a decrease in classic glaucomatous defects with preserved RNFLT integrity. Furthermore, learning effect was not a significant confounder for improvement. Future research will assess which treatments (medication vs. surgery) can optimize reversal of glaucomatous vision loss and therefore aid clinical decision-making.

References
1. Keltner JL, Johnson CA, Quigg JM, et al. Confirmation of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthal. 2000;118(9):1187-1194. https://jamanetwork.com/journals/jamaophthalmology/article-abstract/413586
2. O’Leary N, Chauhan BC, Artes PH. Visual field progression in glaucoma: estimating the overall significance of deterioration with permutation analyses of pointwise linear regression (PoPLR). Invest Ophthalmol Vis Sci. 2012;53(11):6776-6784. doi:10.1167/iovs.12-10049
3. Elze T, Pasquale LR, Shen LQ, Chen TC, Wiggs JL, Bex PJ. Patterns of functional vision loss in glaucoma determined with archetypal analysis. J R Soc Interface. 2015;12(103). doi:10.1098/rsif.2014.1118

Reversal of Glaucomatous Vision Loss Detected By Unsupervised Machine Learning

Abstract Title: Glioblastoma Multiforme Tumor Volume and Persistence of Chimeric Antigen Receptor T Cells Following Treatment

Background: Glioblastoma Multiforme (GBM) is one of the most common and aggressive high-grade primary brain tumors that arises from the glial cells of the central nervous system and occurs most often in the frontal and temporal lobes. Despite current treatment options, long-term prognosis of GBM remains low with no significant improvement rates. Chimeric antigen receptor (CAR)-expressing T cells target the B cell marker CD19 and have shown increased efficacy in B cell lymphomas, acute lymphoblastic leukemia, and chronic lymphocytic leukemia
suggesting benefits in GBM. B7-Homologue3 (B7-H3) is a type 1 transmembrane glycoprotein that shares homologous domains with PD-L1 and recently gained increased attention as an important immune checkpoint molecule. B7-H3 is highly expressed in GBM, contributing to tumor invasiveness, metastatic potential, and poor outcomes, making it an ideal target for immune therapies. This study aims to quantify the persistence of CAR-T cells in the context of GBM tumor volume following neurosurgical debulking procedure.

Methods: For imaging, a radiology software known as the mint Lesion was utilized to provide Tumor Response Assessment by Criteria (TRAC) reports that consist of volumetric measurements of the tumor lesions (target enhancing lesions, non-target enhancing lesions, and non-target non-enhancing lesions). The Response Assessment in Neuro-Oncology (RANO) criteria is used as a radiologic assessment of treatment response in high-grade gliomas. Fluorescence-activated cell sorting (FACS) is a type of flow cytometry technique that uses highly specific antibodies labeled with fluorescence conjugates. FACS analysis takes a sample
mixture of cells and sorts them into different populations based on their specific biomarkers and fluorescence characteristics and with the help of Cytek Aurora, separates the cells into various groups to provide a graphical representation.

Results: B7-H3 CAR-T cell persistence was increased in patients with a larger post-surgical tumor volume. CAR-T cells remained detectable till the end of the cycle (Day 28) for all subjects. This was reflected through the ratio of the percentage of CD8 CAR-T cells and the follow-up tumor volume. Increased B7-H3 CAR-T cell persistence was demonstrated with a larger ratio and reflected a larger post-surgical tumor volume.

Conclusion: To conclude, B7-H3 CAR-T cells are highly persistent in patients with a large post-surgical tumor volume making CAR-T cell therapy a more promising regimen in patients with the first recurrence of glioblastoma.

Glioblastoma Multiforme Tumor Volume and Persistence of Chimeric Antigen Receptor T Cells Following Neurosurgical Debulking

Abstract Title: Advancements in Nanomedicine: A Study on Lipid Nanoparticle Reliability and Formulation Optimization

Background: Lipid nanoparticles (LNP) have emerged as vital tools for delivering nucleic acids like messenger RNA (mRNA) and small interfering RNA (siRNA), playing a key role in the development of COVID-19 vaccines and RNA interference (RNAi)-based therapies for diseases including cancer and cardiovascular disorders. Despite their potential, inquiries into the comparative formulation efficiencies of LNPs when encapsulating siRNA versus mRNA payloads remain limited. Noteworthy challenges endure in optimizing LNP formulations, ensuring stability, scalability, and the mitigation of potential side effects. This study explores the encapsulation efficiency of LNPs for siRNA and mRNA, aiming to enhance the formulation of vaccines and gene therapies. We hypothesize that there is a difference in formulation efficiency and stability between siRNA and mRNA. Specific Aims: Aim 1: Compare the difference in formulation efficiency between siRNA and mRNA. Aim 2: Assess the stability of mRNA-LNP at room temperature.

Methods: Using siRNA targeting Firefly Luciferase and mRNA for NanoLuciferase, we prepared lipid formulations with ALC-0315, DSPC, cholesterol, and PEG-DMG. Following dialysis against PBS, we assessed cholesterol content, siRNA/mRNA concentration, and encapsulation efficiency through RiboGreen assays and determined particle size and polydispersity index (PDI) to evaluate stability. 
Results: In our experimental investigations, we have demonstrated the encapsulation formulation efficiencies for various components. Specifically, the encapsulation formulation efficiency for siRNA targeting Luciferase was found to be 85-95% (N=8, P<0.05), while that for mRNA encoding NanoLuciferase yielded a value of 80-90% (N=7, P<0.05). Furthermore, a comparative examination between siRNA and mRNA revealed distinct data regarding encapsulation formulation efficiency. Our findings also encompassed particle size measurements, indicating that siRNA-LNP had longer stability at room temperature compared to mRNA-LNP. mRNA-LNP had a significant increase in particle size compared to siRNA-LNP. The results pertaining to PDI showed that mRNA-LNP had a significant increase in PDI over a 12-hour time period.

Conclusion: These results provide valuable insights into the encapsulation properties and stability profiles of various components within lipid nanoparticles, contributing to the advancement of nanoparticle-based drug delivery systems. To further expand on these findings and advance research and therapeutic applications, future investigations may encompass evaluating encapsulation efficiency with plasmid DNA, exploring novel ionizable cationic lipids, and extending studies to encompass larger animal models.

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