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In this study, we explored the use of lipid mesophases (LMPs) as a biocompatible and biodegradable material for sustained drug delivery. Our hypothesis centered on leveraging the high surface-to-volume ratio of LMP-based beads to enhance strength, stability, and surface interaction compared to the LMP bulk gel. To modulate drug release, we introduced antioxidant vitamin E into the beads, influencing mesophase topologies and controlling drug diffusion coefficients. Four drugs with distinct chemical properties and intended for three different pathologies and administration routes were successfully loaded into the beads with a drug entrapment efficiency exceeding 80 %. Notably, our findings revealed sustained drug release, irrespective of the drugs' chemical properties, culminating in the development of an injectable formulation. This formulation allows direct administration into the target site, minimizing systemic exposure, and thereby mitigating adverse effects. Our approach demonstrates the potential of LMP-based beads for tailored drug delivery systems with broad applications in diverse therapeutic scenarios., 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 Elsevier Inc. All rights reserved.)

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection., Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus., Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus., Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Arenas Hoyos, Helmer, Yerly, Lese, Hirsiger, Zhang, Casoni, Garcia, Petrucci, Hammer, Duckova, Banz, Montani, Constantinescu, Vögelin, Bordon, Aleandri, Prost, Taddeo, Luciani, Rieben, Sorvillo and Olariu.)

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a widespread joint condition affecting millions globally, presenting a growing socioeconomic burden thus making the development of more effective therapeutic strategies crucial. This review emphasizes recent advancements in lipid-based drug delivery systems (DDSs) for intra-articular administration of OA therapeutics, encompassing non-steroidal anti-inflammatory drugs, corticosteroids, small molecule disease-modifying OA drugs, and RNA therapeutics. Liposomes, lipid nanoparticles, lipidic mesophases, extracellular vesicles and composite systems exhibit enhanced stability, targeted delivery, and extended joint retention, which contribute to improved therapeutic outcomes and minimized systemic drug exposure. Although active targeting strategies hold promise, further research is needed to assess their targeting efficiency in physiologically relevant conditions. Simultaneously, multifunctional DDSs capable of delivering combinations of distinct therapeutic classes offer synergistic effects and superior OA treatment outcomes. The development of such long-acting systems that resist rapid clearance from the joint space is crucial, where particle size and targeting capabilities emerge as vital factors. Additionally, combining cartilage lubrication properties with sustained drug delivery has demonstrated potential in animal models, meriting further investigation in human clinical trials. This review highlights the crucial need for direct, head-to-head comparisons of novel DDSs with standard treatments, particularly within the same drug class. These comparisons are essential in accurately evaluating their effectiveness, safety, and clinical applicability, and are set to significantly shape the future of OA therapy., Competing Interests: Declaration of Competing Interest Gregor Bordon and Oliver Distler declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Francis Berenbaum is founder and CMO of 4Moving Biotech and has consulted for 4P Pharma, AstraZeneca, Cellprothera, Grunenthal, GSK, Medivir, Novartis, Pfizer, Lilly, Servier. Paola Luciani has consulted and received research funding from Lipoid GmbH, Sanofi-Aventis Deutschland and DSM Nutritional Products Ltd., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the last three calendar years: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Pfizer, Prometheus, Redxpharma, Roivant and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). PL has consulted and received research funding from Lipoid GmbH, Sanofi-Aventis Deutschland and DSM Nutritional Products Ltd., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Context: Several minimally invasive lumbar interbody fusion techniques may be used as a treatment for spondylolisthesis to alleviate back and leg pain, improve function and provide stability to the spine. Surgeons may choose an anterolateral or posterior approach for the surgery however, there remains a lack of real-world evidence from comparative, prospective studies on effectiveness and safety with relatively large, geographically diverse samples and involving multiple surgical approaches., Purpose: To test the hypothesis that anterolateral and posterior minimally invasive approaches are equally effective in treating patients with spondylolisthesis affecting one or two segments at 3-months follow-up and to report and compare patient reported outcomes and safety profiles between patients at 12-months post-surgery., Design: Prospective, multicenter, international, observational cohort study., Patient Sample: Patients with degenerative or isthmic spondylolisthesis who underwent 1- or 2-level minimally invasive lumbar interbody fusion., Outcome Measures: Patient reported outcomes assessing disability (ODI), back pain (VAS), leg pain (VAS) and quality of life (EuroQol 5D-3L) at 4-weeks, 3-months and 12-months follow-up; adverse events up to 12-months; and fusion status at 12-months post-surgery using X-ray and/or CT-scan. The primary study outcome is improvement in ODI score at 3-months., Methods: Eligible patients from 26 sites across Europe, Latin America and Asia were consecutively enrolled. Surgeons with experience in minimally invasive lumbar interbody fusion procedures used, according to clinical judgement, either an anterolateral (ie, ALIF, DLIF, OLIF) or posterior (MIDLF, PLIF, TLIF) approach. Mean improvement in disability (ODI) was compared between groups using ANCOVA with baseline ODI score used as a covariate. Paired t-tests were used to examine change from baseline in PRO for both surgical approaches at each timepoint after surgery. A secondary ANCOVA using a propensity score as a covariate was used to test the robustness of conclusions drawn from the between group comparison., Results: Participants receiving an anterolateral approach (n=114) compared to those receiving a posterior approach (n=112) were younger (56.9 vs 62.0 years, p <.001), more likely to be employed (49.1% vs 25.0%, p<.001), have isthmic spondylolisthesis (38.6% vs 16.1%, p<.001) and less likely to only have central or lateral recess stenosis (44.9% vs 68.4%, p=.004). There were no statistically significant differences between the groups for gender, BMI, tobacco use, duration of conservative care, grade of spondylolisthesis, or the presence of stenosis. At 3-months follow-up there was no difference in the amount of improvement in ODI between the anterolateral and posterior groups (23.2 ± 21.3 vs 25.8 ± 19.5, p=.521). There were no clinically meaningful differences between the groups on mean improvement for back- and leg-pain, disability, or quality of life until the 12-months follow-up. Fusion rates of those assessed (n=158; 70% of the sample), were equivalent between groups (anterolateral, 72/88 [81.8%] fused vs posterior, 61/70 [87.1%] fused; p=.390)., Conclusions: Patients with degenerative lumbar disease and spondylolisthesis who underwent minimally invasive lumbar interbody fusion presented statistically significant and clinically meaningful improvements from baseline up to 12-months follow-up. There were no clinically relevant differences between patients operated on using an anterolateral or posterior approach., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Latin America and Caribbean region exhibit some of the lowest undernutrition rates globally. Yet, disparities exist between and within countries and countries in the region increasingly face other pressing nutritional concerns, including overweight, micronutrient deficiencies and inadequate child feeding practices. This paper reports findings from a regional analysis to identify the determinants and drivers of children's diets, with a focus on the complementary feeding window between the age of 6-23 months. The analysis consists of a narrative review and descriptive data analysis, complemented with qualitative interviews with key informants in four countries: Guatemala, Paraguay, Peru and Uruguay. Findings indicate that poverty and inequality (disparities within countries by wealth and residence), unequal access to services, inadequate coverage of social programmes and lack of awareness on appropriate feeding practices are important drivers for inadequate diets. We conclude that countries in the region need to invest in policies to tackle overweight and micronutrient deficiencies in young children, considering inequalities between and within countries, enhance coverage of social protection programmes, improve coordination between sectors to improve children's diets and expand the coverage and intensity of awareness campaigns on feeding practices, using iterative programme designs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Gassmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To review the complications associated with the minimally invasive retropleural approach used in the anterior approach to the thoraco-lumbar spine., Material and Method: We present the MIS surgical technique and the evaluation of data collected prospectively from the initial series of 31 patients undergoing surgery. Pleural opening during the approach, lung complications derived, other surgical complications, time of intervention, intraoperative bleeding, need for transfusion and hospital stay are evaluated., Discussion: The mean age of the patients was 58years, the surgical time 225min, and the bleeding 274ml, with a 13% postoperative transfusion. Intraoperatively, pleural opening was detected in 8 cases, of which none had major pulmonary complications during the postoperative period. There were 3 cases of mild pleural effusion, all patients without pleural opening, and one case of haemopneumothorax due to intercostal vessel bleeding that required reoperation. The percentage of intercostal neuralgia was 3%. The mean hospital stay was 6.7days, and 24 of 31 patients were able to initiate early mobilization on the first postoperative day., Conclusions: The retropleural approach allows the surgical treatment of pathologies requiring anterior access to the thoraco-lumbar spine, with a low profile of pulmonary complications, and with the advantages of minimally invasive techniques in terms of less bleeding, early recovery and shorter hospital stay. Nevertheless the learning curve is long., (Copyright © 2018 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

OBJECTIVE Pedicle subtraction osteotomy (PSO) is a powerful but high-risk surgical technique for destabilizing the spine for deformity correction in both the sagittal and coronal planes. Numerous reports have demonstrated the benefits of this technique for realigning the spine in a physiological posture; however, the open surgical technique is associated with a high complication rate. In this report the authors review data obtained in a series of patients who underwent PSO through a less invasive approach. METHODS Sixteen patients with severe coronal- and/or sagittal-plane deformities were treated in this series. Conservative measures had failed in all cases and patients had undergone a single-level PSO or extended PSO at L-2 or L-3. Fixation was accomplished using percutaneous instrumentation and interbody or facet joint fusions were used at the remaining levels. None of the procedures were aborted or converted to a traditional open procedure. Standard clinical and radiographic measures were used to assess patient outcomes. RESULTS Mean age was 68.8 years and mean follow-up duration was 17.7 months. An average of 7.6 levels were fused, and 50% of the patients had bilateral iliac screw fixation, with all constructs crossing both the thoracolumbar and lumbosacral junctions. Operative time averaged 356 ± 50 minutes and there was a mean blood loss of 843 ± 339 ml. The leg visual analog scale score improved from a mean of 5.7 ± 2.7 to one of 1.3 ± 1.6, and the back visual analog scale score improved from a mean of 8.6 ± 1.3 to one of 2.4 ± 2.1. The Oswestry Disability Index score improved from a mean of 50.1 ± 14.4 to 16.4 ± 12.7, representing a mean reduction of 36.0 ± 16.9 points. The SF-36 physical component summary score changed from a mean of 43.4 ± 2.6 to one of 47.0 ± 4.3, and the SF-36 mental component summary score changed from a mean of 46.7 ± 3.6 to 46.30 ± 3.0. Coronal alignment improved from a mean of 27.9 ± 43.6 mm to 16.0 ± 17.2 mm. The lumbar Cobb angle improved from a mean of 41.2° ± 18.4° to 15.4° ± 9.6°, and lumbar lordosis improved from 23.1° ± 15.9° to 48.6° ± 11.7°. Pelvic tilt improved from a mean of 33.7° ± 8.6° to 24.4° ± 6.5°, and the sagittal vertical axis improved from 102.4 ± 73.4 mm to 42.2 ± 39.9 mm. The final lumbar lordosis-pelvic incidence difference averaged 8.4° ± 12.1°. There were 4 patients who failed to achieve less than or equal to a 10° mismatch on this parameter. Ten of the 16 patients underwent delayed postoperative CT, and 8 of these had developed a solid arthrodesis at all levels treated. A total of 6 complications occurred in this series. There were no cases of symptomatic proximal junction kyphosis. CONCLUSIONS Advancements in minimally invasive technique have resulted in the ability to manage increasingly complex deformities with hybrid approaches. In this limited series, the authors describe the results of utilizing a tissue-sparing mini-open PSO to correct severe spinal deformities. This method was technically feasible in all cases with acceptable radiographic outcomes similar to open surgery. However, high complication rates associated with these deformity corrections remain problematic.

Problem: Thoracic disc disease with radicular pain and myelopathic symptoms can have serious neurological sequelae. The authors present a relevant treatment option., Methods: Data of patients with single level symptomatic thoracic disc herniation treated with thoracoscopic microdiscectomy were prospectively collected over a period of 10 years. Data collection included the preoperative status and the follow-up status was 6, 12 and 24 months after surgery for every patient., Results: A total of 167 single level thorascoscopic discectomies without previous surgery on the level of the procedure were included in this study. The average preoperative duration of pain symptoms was 14.3 months, myelopathic symptoms were present for an average of 16.7 months before surgery. After the procedure pain scores measured with visual analog scale (VAS) decreased by 4.4 points and the muscle strength improved by a mean of 4.6 points (American Spinal Injury Association ASIA motor score). After 2 years, 79% of the patients reported a excellent or good outcome for pain and 80% of the patients reported a excellent or good outcome for motor function. The overall complication rate was 15.6%., Conclusions: Thoracoscopic microdiscectomy for single level symptomatic disc herniation is a highly effective and reliable technique, it can be performed safely with low complication rate.