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Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding β-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection, minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs. The generated β-cateninGOF mRNA encapsulated in SM-102 LNPs (SM-102-β-cateninGOF mRNA) showed bioactivity in vitro through upregulation of downstream canonical Wnt genes, axin2 and runx2. When testing SM-102-β-cateninGOF mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 μg concentration at 2 weeks post-fracture. μCT testing confirmed that SM-102-β-cateninGOF mRNA promoted bone formation in vivo, revealing significantly more bone volume over total volume in the 45 μg group. Thus, we generated a novel mRNA-based therapeutic encoding a β-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Myocardial recovery is characterized by a return toward normal structure and function of the heart after an injury. Mechanisms of myocardial recovery include restoration and/or adaptation of myocyte structure and function, mitochondrial activity and number, metabolic homeostasis, electrophysiological stability, extracellular matrix remodeling, and myocardial perfusion. Myocardial regeneration is an element of myocardial recovery that involves the generation of new myocardial tissue, a process which is limited in adult humans but may be therapeutically augmented. Understanding the mechanisms of myocardial recovery and myocardial regeneration will lead to novel therapies for heart failure. [ABSTRACT FROM AUTHOR]

Background and Aims In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium. Methods In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF ≤40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days. Results Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Δ from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P =.0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Δ from baseline to 360 days (127.5 m, SD 110.6) than patients in the Sham group (43.6 m, SD 172.1) (P =.028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P =.15). Two patients in the treatment group died for non-device-related reasons. Conclusions In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure. [ABSTRACT FROM AUTHOR]

The focus of current research work was to develop and validate size-exclusion chromatography method and develop and evaluate gel formulation of deferoxamine conjugated with PEGylated carbon nanoparticles (DEF-PEG-CNP) for topical delivery. Size-exclusion chromatography-based method was validated as per ICH guidelines. Effect of Carbopol® 974P and Transcutol® on the nanoparticles' permeation was studied by 3-level full factorial design of experiment. Gel formulations were characterized for viscosity, cohesive and adhesive force by texture analyzer, and drug permeation through pig ear and human skin. The analytical method was specific as no interference from solvent or excipients were observed and met preset criteria of validation with limit of quantification of 0.24 ± 0.00 μg/mL. The nanoparticles permeation, steady state flux, and retained drug were statistically (p < 0.05) affected by Carbopol® 974P and Transcutol® percentage in the gel formulations. The permeation, steady state flux, and retained nanoparticles from the gel formulations varied from 23.2 ± 2.5 % to 70.9 ± 113.3 %, 0.8 ± 0.3 to 6.6 ± 2.1 μg/cm 2 .h, and 5.6 ± 0.3 to 38.8 ± 8.8 µg/g, respectively. Permeation of the nanoparticles was 1.9 folds higher in pig skin compared to human skin. Immunofluorescence detected successful permeation of DEF-PEG-CNP particles into skin. In conclusion, the analytical method can quantify the nanoparticles from the gel formulation without interference, and gel formulation of the nanoparticles can permeate across the skin., Competing Interests: Declaration of competing 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., (Copyright © 2024. Published by Elsevier B.V.)