Dynamic topology optimization of 3D-Printed transtibial orthopedic implant using tunable isotropic porous metamaterials.

In this paper, we introduce the design and manufacturing process of a transtibial orthopedic implant. We used medical-grade polyurethane polymer resin to fabricate a 3D porous architected implant with tunable isotropy, employing a high-speed printing method known as Continuous Liquid Interface Production (CLIP). Our objective is to enhance the weight-bearing capabilities of the bone structures in the residual limb, thereby circumventing the traditional reliance on a natural bridge. To achieve a custom-made design, we acquire the topology and morphology of the residual limb as well as the bone structure of the tibia and fibula, utilizing computed tomography (CT) and high-resolution 3D scanning. We employed a dynamic topological optimization method, informed by gait cycle data, to effectively reduce the mass of the implant. This approach, which differs from conventional static methods, enables the quantification of variations in applied forces over time. Using the Euler-Lagrange energy approach, we propose the equations of motion for a homologous multibody model with three degrees of freedom. The versatility of the Solid Isotropic Material with Penalization (SIMP) method facilitates the integration of homogenization methods for microscale porous architectures into the optimized domain. The design of these porous architectures is based on a bias-driven tuning symmetry isotropy of a Triply Periodic Minimal Surface (Schwarz Primitive surface). The internal porosity of the structure significantly reduces weight without compromising the isotropic behavior of the implant.

Lipid nanoparticle-mediated mRNA delivery in lung fibrosis.

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.

Endovascular Treatment of Transplant Renal Artery Stenosis: A Systematic Review and Meta-analysis.

OBJECTIVE: Endovascular treatment through either percutaneous transluminal angioplasty (PTA) alone or stenting has been previously used as a treatment for transplant renal artery stenosis (TRAS). This review aimed to investigate the results of endovascular treatment for renal artery stenosis in transplanted kidneys as compared with the outcomes of interventions, medical management, and graft survival in non-TRAS patients. METHODS: A systematic review of PubMed, Google Scholar, Cochrane, and Scopus was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in which studies that reported outcomes of the treatment of TRAS via the endoluminal approach were identified, and their results were meta-analyzed. RESULTS: Fifty-four studies with a total of 1522 patients were included. A significant reduction of serum creatinine level was found, favoring the stenting group, with a mean difference of 0.68 mg/dL (95% confidence interval (CI), 0.17-1.19; Z=2.60, p=0.0009). Comparison of pre- and post-intervention values of any intervention revealed a significant decrease in overall serum creatinine level (0.65 mg/dL; 95% CI, 0.40-0.90; Z=5.09, p=0.00001), overall blood pressure, with a mean difference of 11.12 mmHg (95% CI, 7.29-14.95; Z=5.59, p=0.00001), mean difference in the use of medications (0.77; 95% CI, 0.29-1.24; p=0.002), and peak systolic velocity (190.05; 95% CI, 128.41-251.69; p<0.00001). The comparison of serum creatinine level between endovascular interventions and best medical therapy favored endovascular intervention, with a mean difference of 0.23 mg/dL (95% CI, 0.14-0.32; Z=5.07, p<0.00001). Graft survival was similar between the treated patients and those without TRAS (hazard ratio, 0.98; 95% CI, 0.75-1.28; p=0.091). The overall pooled success rate was 89%, and the overall complication rate was 10.4%, with the most prevalent complication being arterial dissection. CONCLUSION: The endovascular treatment of TRAS improves graft preservation and renal function and hemodynamic parameters. PTA + stenting appears to be a more effective option to PTA alone in the stabilization of renal function, with additional benefits from decreased restenosis rates. Further high-quality studies could expand on these findings.

Characterization of Porous Scaffolds Fabricated by Joining Stacking Based Laser Micro-Spot Welding (JS-LMSW) for Tissue Engineering Applications.

A novel manufacturing approach was used to fabricate metallic scaffolds. A calibration of the laser cutting process was performed using the kerf width compensation in the calculations of the tool trajectory. Welding defects were studied through X-ray microtomography. Penetration depth and width resulted in relative errors of 9.4%, 1.0%, respectively. Microhardness was also measured, and the microstructure was studied in the base material. The microhardness values obtained were 400 HV, 237 HV, and 215 HV for the base material, HAZ, and fusion zone, respectively. No significant difference was found between the microhardness measurement along with different height positions of the scaffold. The scaffolds' dimensions and porosity were measured, their internal architecture was observed with micro-computed tomography. The results indicated that geometries with dimensions under 500 µm with different shapes resulted in relative errors of ~2.7%. The fabricated scaffolds presented an average compressive modulus ~13.15 GPa, which is close to cortical bone properties. The proposed methodology showed a promising future in bone tissue engineering applications.

Shortening in the Tp-e/QTc ratio after angioplasty in patients with acute coronary syndrome. / Acortamiento en la relación Tp-f/QTc tras angioplastia en pacientes con síndrome isquémico coronario agudo.

Objetivo: La dispersión transmural de la repolarización ventricular (DTMRV) es un factor de riesgo para muerte en pacientes con síndrome isquémico coronario agudo (SICA). Con el objetivo de conocer el efecto de la realización de angioplastia sobre la DTMRV, se estudió la relación Tp-f/QTc en pacientes con SICA sometidos a angioplastia. Método: Se diseñó un estudio observacional, retrospectivo y descriptivo. Se incluyeron 150 pacientes (N = 150) con diagnóstico de SICA. Se valoró la relación Tp-f/QTc inicial y se evaluó su acortamiento posangioplastia. Como objetivo secundario, se comparó la asociación de dichos cambios en la relación Tp-f/QTc con la mortalidad cardiovascular y los eventos adversos cardiovasculares. Resultados: El promedio en la relación Tp-f/QTc inicial fue de 0.2529, mientras que posangioplastia fue de 0.2397. Por medio de prueba de rangos de Wilcoxon se evidenció un descenso significativo en la relación Tp-f/QTc posterior a la angioplastia, con un valor Z de -2.051 y una p < 0.04. En el análisis secundario se encontró que una Tp-f/QTc ≥ 0.29 posangioplastia es factor de riesgo para presentación de los siguientes eventos adversos: muerte intrahospitalaria (7.4 vs 0%; p < 0.003), nuevo SICA en seguimiento a 1 año (25.9 vs. 18.5%; p < 0.006) y reintervención en seguimiento a 1 año (29.6 vs. 15.0%; p < 0.002). Conclusiones: Existe un acortamiento significativo en la relación Tp-f/QTc posangioplastia en pacientes con SICA. Esta medida de la DTMRV puede servir como un predictor de muerte intrahospitalaria, eventos cardiovasculares y reintervención a 1 año en pacientes con SICA tratados con angioplastia. Objective: Transmural Dispersion of Repolarization (TDR) is a Risk factor for Death in patients with Acute Coronary ­Syndrome (ACS). In order to know the effect of angioplasty on TDR, the Tp-e/QTc ratio was studied in patients with ACS undergoing angioplasty. Method: An observational, retrospective and descriptive study was designed. 150 patients (N = 150) with diagnosis of ACS were included. The initial Tp-e/QTc ratio was assessed and then its post-angioplasty shortening was evaluated. As a secondary objective, we compared the association of these Tp-e/QTc ratio changes with cardiovascular mortality and cardiovascular adverse events. Results: The average in the initial Tp-e/QTc ratio was 0.2529, while post-angioplasty was 0.2397. Through a Wilcoxon rage test, a significant decrease in the Tp-e/QTc ratio after angioplasty was observed, with a Z value of −2.051 and p < 0.04. In the secondary analysis, it was found that a Tp-e/QTc ≥ 0.29 post-angioplasty is a risk factor for presenting the following adverse events: in-hospital death (7.4 vs. 0%; p < 0.003), new ACS in 1-year follow-up (25.9 vs. 18.5%; p < 0.006), and reintervention in 1-year follow up (29.6 vs. 15%; p < 0.002). Conclusions: There is a significant shortening in the Tp-e/QTc ratio post-angioplasty in patients with ACS. This measure of TDR can serve as a predictor of in-hospital death, cardiovascular events and 1-year reintervention in patients with ACS treated initially by angioplasty.

LAPKaans: Tool-Motion Tracking and Gripping Force-Sensing Modular Smart Laparoscopic Training System.

Laparoscopic surgery demands highly skilled surgeons. Traditionally, a surgeon's knowledge is acquired by operating under a mentor-trainee method. In recent years, laparoscopic simulators have gained ground as tools in skill acquisition. Despite the wide range of laparoscopic simulators available, few provide objective feedback to the trainee. Those systems with quantitative feedback tend to be high-end solutions with limited availability due to cost. A modular smart trainer was developed, combining tool-tracking and force-using employing commercially available sensors. Additionally, a force training system based on polydimethylsiloxane (PDMS) phantoms for sample stiffness differentiation is presented. This prototype was tested with 39 subjects, between novices (13), intermediates (13), and experts (13), evaluating execution differences among groups in training exercises. The estimated cost is USD $200 (components only), not including laparoscopic instruments. The motion system was tested for noise reduction and position validation with a mean error of 0.94 mm. Grasping force approximation showed a correlation of 0.9975. Furthermore, differences in phantoms stiffness effectively reflected user manipulation. Subject groups showed significant differences in execution time, accumulated distance, and mean and maximum applied grasping force. Accurate information was obtained regarding motion and force. The developed force-sensing tool can easily be transferred to a clinical setting. Further work will consist on a validation of the simulator on a wider range of tasks and a larger sample of volunteers.

Acortamiento en la relación Tp-f/QTc tras angioplastia en pacientes con síndrome isquémico coronario agudo / Shortening in the Tp-e/QTc ratio after angioplasty in patients with acute coronary syndrome

Resumen Objetivo: La dispersión transmural de la repolarización ventricular (DTMRV) es un factor de riesgo para muerte en pacientes con síndrome isquémico coronario agudo (SICA). Con el objetivo de conocer el efecto de la realización de angioplastia sobre la DTMRV, se estudió la relación Tp-f/QTc en pacientes con SICA sometidos a angioplastia. Método: Se diseñó un estudio observacional, retrospectivo y descriptivo. Se incluyeron 150 pacientes (N = 150) con diagnóstico de SICA. Se valoró la relación Tp-f/QTc inicial y se evaluó su acortamiento posangioplastia. Como objetivo secundario, se comparó la asociación de dichos cambios en la relación Tp-f/QTc con la mortalidad cardiovascular y los eventos adversos cardiovasculares. Resultados: El promedio en la relación Tp-f/QTc inicial fue de 0.2529, mientras que posangioplastia fue de 0.2397. Por medio de prueba de rangos de Wilcoxon se evidenció un descenso significativo en la relación Tp-f/QTc posterior a la angioplastia, con un valor Z de −2.051 y una p < 0.04. En el análisis secundario se encontró que una Tp-f/QTc ≥ 0.29 posangioplastia es factor de riesgo para presentación de los siguientes eventos adversos: muerte intrahospitalaria (7.4 vs 0%; p < 0.003), nuevo SICA en seguimiento a 1 año (25.9 vs. 18.5%; p < 0.006) y reintervención en seguimiento a 1 año (29.6 vs. 15.0%; p < 0.002). Conclusiones: Existe un acortamiento significativo en la relación Tp-f/QTc posangioplastia en pacientes con SICA. Esta medida de la DTMRV puede servir como un predictor de muerte intrahospitalaria, eventos cardiovasculares y reintervención a 1 año en pacientes con SICA tratados con angioplastia.

Abstract Objective: Transmural Dispersion of Repolarization (TDR) is a Risk factor for Death in patients with Acute Coronary Syndrome (ACS). In order to know the effect of angioplasty on TDR, the Tp-e/QTc ratio was studied in patients with ACS undergoing angioplasty. Method: An observational, retrospective and descriptive study was designed. 150 patients (N = 150) with diagnosis of ACS were included. The initial Tp-e/QTc ratio was assessed and then its post-angioplasty shortening was evaluated. As a secondary objective, we compared the association of these Tp-e/QTc ratio changes with cardiovascular mortality and cardiovascular adverse events. Results: The average in the initial Tp-e/QTc ratio was 0.2529, while post-angioplasty was 0.2397. Through a Wilcoxon rage test, a significant decrease in the Tp-e/QTc ratio after angioplasty was observed, with a Z value of −2.051 and p < 0.04. In the secondary analysis, it was found that a Tp-e/QTc ≥ 0.29 post-angioplasty is a risk factor for presenting the following adverse events: in-hospital death (7.4 vs. 0%; p < 0.003), new ACS in 1-year follow-up (25.9 vs. 18.5%; p < 0.006), and reintervention in 1-year follow up (29.6 vs. 15%; p < 0.002). Conclusions: There is a significant shortening in the Tp-e/QTc ratio post-angioplasty in patients with ACS. This measure of TDR can serve as a predictor of in-hospital death, cardiovascular events and 1-year reintervention in patients with ACS treated initially by angioplasty.

Effect of Surgical Expertise on Biomechanical Properties of Sutures After Abdominal Wall Closure.

BACKGROUND: Despite preventive methods and careful surgical technique, surgical site infection and incisional hernias are of main concern after the closure of surgical incisions and keep haunting abdominal wall wound healing. The aim of this study is to find how surgical expertise level modifies biomechanical properties of sutures commonly used in abdominal wall fascial closure (polypropylene, polyglactin 910, polydioxanone). MATERIALS AND METHODS: Surgery residents with different experience levels performed abdominal wall fascial closure in swine models with the previously mentioned suture materials. A standardized technique was used. Sutures were removed, and a tensile stress test was performed on the removed sutures. A total of 81 abdominal fascial closures were achieved. Time, extension, maximum tensile force (Ftmax), and maximum stress were measured and analyzed. RESULTS: The results of the polydioxanone stress test present a trend in three variables: extension, tensile force, and stress. The trend shows higher medians in the expert group and lower medians in the novice group. While using polypropylene sutures, medians in the expert group are the highest; however, a trend is not observed. Polyglactin 910 sutures have nonspecific behavior among the different experience groups and variables. Polypropylene is the material with the lowest Ftmax tested and fails at 42.64 (IQR 40.98-44.89) N. Regarding the elastic properties of the material, polyglactin demonstrates the least extension of all sutures tested, with a 14 (IQR 13.33-14.83) mm extension. This study demonstrates that polydioxanone has a superior Ftmax compared with polypropylene and has a superior extension at failure properties compared with polyglactin, confirming that polydioxanone could be the suture of choice used for abdominal wall fascial closure. CONCLUSIONS: Study results do not show statistically significant differences regarding the impact of the experience level of different general surgery residents in the biomechanical properties of sutures used in abdominal wall fascial closure.

Functionalization of endovascular devices with superparamagnetic iron oxide nanoparticles for interventional cardiovascular magnetic resonance imaging.

Presently, cardiovascular interventions such as stent deployment and balloon angioplasty are performed under x-ray guidance. However, x-ray fluoroscopy has poor soft tissue contrast and is limited by imaging in a single plane, resulting in imprecise navigation of endovascular instruments. Moreover, x-ray fluoroscopy exposes patients to ionizing radiation and iodinated contrast agents. Magnetic resonance imaging (MRI) is a safe and enabling modality for cardiovascular interventions. Interventional cardiovascular MR (iCMR) is a promising approach that is in stark contrast with x-ray fluoroscopy, offering high-resolution anatomic and physiologic information and imaging in multiple planes for enhanced navigational accuracy of catheter-based devices, all in an environment free of radiation and its deleterious effects. While iCMR has immense potential, its translation into the clinical arena is hindered by the limited availability of MRI-visible catheters, wire guides, angioplasty balloons, and stents. Herein, we aimed to create application-specific, devices suitable for iCMR, and demonstrate the potential of iCMR by performing cardiovascular catheterization procedures using these devices. Tools, including catheters, wire guides, stents, and angioplasty balloons, for endovascular interventions were functionalized with a polymer coating consisting of poly(lactide-co-glycolide) (PLGA) and superparamagnetic iron oxide (SPIO) nanoparticles, followed by endovascular deployment in the pig. Findings from this study highlight the ability to image and properly navigate SPIO-functionalized devices, enabling interventions such as successful stent deployment under MRI guidance. This study demonstrates proof-of-concept for rapid prototyping of iCMR-specific endovascular interventional devices that can take advantage of the capabilities of iCMR.

Nanotherapeutics for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating and fatal chronic lung disease. While current pharmacotherapies have improved patient quality of life, PAH drugs suffer from limitations in the form of short-term pharmacokinetics, instability, and poor organ specificity. Traditionally, nanotechnology-based delivery strategies have proven advantageous at increasing both circulation lifetimes of chemotherapeutics and accumulation in tumors due to enhanced permeability through fenestrated vasculature. Importantly, increased nanoparticle (NP) accumulation in diseased tissues has been observed pre-clinically in pathologies characterized by endothelial dysfunction and remodeled vasculature, including myocardial infarction and heart failure. Recently, this phenomenon has also been observed in preclinical models of PAH, leading to the exploration of NP-based drug delivery as a therapeutic modality in PAH. Herein, we discussed the advantages of NPs for efficacious treatment of PAH, including heightened therapeutic delivery to diseased lungs for increased drug bioavailability, as well as highlighted innovative nanotherapeutic approaches for PAH.

Polymer Functionalization of Isolated Mitochondria for Cellular Transplantation and Metabolic Phenotype Alteration.

Aberrant mitochondrial energy transfer underlies prevalent chronic health conditions, including cancer, cardiovascular, and neurodegenerative diseases. Mitochondrial transplantation represents an innovative strategy aimed at restoring favorable metabolic phenotypes in cells with dysfunctional energy metabolism. While promising, significant barriers to in vivo translation of this approach abound, including limited cellular uptake and recognition of mitochondria as foreign. The objective is to functionalize isolated mitochondria with a biocompatible polymer to enhance cellular transplantation and eventual in vivo applications. Herein, it is demonstrated that grafting of a polymer conjugate composed of dextran with triphenylphosphonium onto isolated mitochondria protects the organelles and facilitates cellular internalization compared with uncoated mitochondria. Importantly, mitochondrial transplantation into cancer and cardiovascular cells has profound effects on respiration, mediating a shift toward improved oxidative phosphorylation, and reduced glycolysis. These findings represent the first demonstration of polymer functionalization of isolated mitochondria, highlighting a viable strategy for enabling clinical applications of mitochondrial transplantation.

Nanoparticles administered intrapericardially enhance payload myocardial distribution and retention.

Pharmacological therapies for cardiovascular diseases are limited by short-term pharmacokinetics and extra-cardiac adverse effects. Improving delivery selectivity specifically to the heart, wherein therapeutic drug levels can be maintained over time, is highly desirable. Nanoparticle (NP)-based pericardial drug delivery could provide a strategy to concentrate therapeutics within a unique, cardiac-restricted compartment to allow sustained drug penetration into the myocardium. Our objective was to explore the kinetics of myocardial penetration and retention after pericardial NP drug delivery. Fluorescently-tagged poly(lactic-co-glycolic acid) (PLGA) NPs were loaded with BODIPY, a fluorophore, and percutaneously administered into the pericardium via subxiphoid puncture in rabbits. At distinct timepoints hearts were examined for presence of NPs and BODIPY. PLGA NPs were found non-uniformly distributed on the epicardium following pericardial administration, displaying a half-life of ~2.5days in the heart. While NPs were mostly confined to epicardial layers, BODIPY was capable of penetrating into the myocardium, resulting in a transmural gradient. The distinct architecture and physiology of the different regions of the heart influenced BODIPY distribution, with fluorophore penetrating more readily into atria than ventricles. BODIPY proved to have a long-term presence within the heart, with a half-life of ~7days. Our findings demonstrate the potential of utilizing the pericardial space as a sustained drug-eluting reservoir through the application of nanoparticle-based drug delivery, opening several exciting avenues for selective and prolonged cardiac therapeutics.

Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.

Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.

Nucleic Acid Delivery for Endothelial Dysfunction in Cardiovascular Diseases.

Endothelial dysfunction has been implicated in the pathophysiology of multiple cardiovascular diseases and involves components of both innate and acquired immune mechanisms. Identifying signature patterns and targets associated with endothelial dysfunction can help in the development of novel nanotherapeutic platforms for treatment of vascular diseases. This review discusses nucleic acid-based regulation of endothelial function and the different nucleic acid-based nanotherapeutic approaches designed to target endothelial dysfunction in cardiovascular disorders.

An injectable nanoparticle generator enhances delivery of cancer therapeutics.

The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG-pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice.

A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics.

AIMS: Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. METHODS AND RESULTS: In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. CONCLUSIONS: Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure.

Adjuvant cationic liposomes presenting MPL and IL-12 induce cell death, suppress tumor growth, and alter the cellular phenotype of tumors in a murine model of breast cancer.

Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1ß and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1ß, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80(+) macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response.

The physiology of cardiovascular disease and innovative liposomal platforms for therapy.

Heart disease remains the major cause of death in males and females, emphasizing the need for novel strategies to improve patient treatment and survival. A therapeutic approach, still in its infancy, is the development of site-specific drug-delivery systems. Nanoparticle-based delivery systems, such as liposomes, have evolved into robust platforms for site-specific delivery of therapeutics. In this review, the clinical impact of cardiovascular disease and the pathophysiology of different subsets of the disease are described. Potential pathological targets for therapy are introduced, and promising advances in nanotherapeutic cardiovascular applications involving liposomal platforms are presented.