scholarly journals 708 Application of a novel mSENS drug delivery technology for mRNA therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A750-A750
Author(s):  
Sojin Lee ◽  
Joon Young Park ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Minhyuk Yun ◽  
...  
Keyword(s):  
Particle Size ◽  
Protein Expression ◽  
Cancer Vaccine ◽  
Encapsulation Efficiency ◽  
Tumor Model ◽  
Cell Responses ◽  
Delivery Platform ◽  
Mrna Therapeutics

BackgroundSuccessful clinical translation of mRNA therapeutics requires an appropriate delivery strategy to overcome instability of mRNA and facilitate cellular uptake into the cells.1 Several lipid based nanoparticle approaches that encapsulate mRNA, notably lipid nanoparticle (LNP), have been developed, but their efficiency for delivery to certain target tissues and toxicity profiles still have room for improvement. The application of a novel polymer based nanoparticle technology platform, so called Stability Enhanced Nano Shells (SENS) for mRNA (mSENS) as a mRNA delivery platform for a cancer vaccine was demonstrated.MethodsThe physicochemical properties of mSENS formulation, particle size and encapsulation efficiency, were characterized using dynamic light scattering (DLS) and gel retardation assay. Using luciferase-encoding mRNA, the protein expression levels in vitro and in vivo were evaluated by luciferase assay or bioluminescence imaging (BLI), respectively. For cancer vaccine studies, antigen (tyrosinase-related protein 2 (Trp-2))-specific T cell responses were assessed by immunophenotyping mouse splenocytes using flow cytometry and by the enzyme-linked immunosorbent spot (ELISPOT) assay. The anti-tumor efficacy was studied in B16F10 lung tumor model in C57BL/6 mice. Liver and systemic toxicity of mSENS treated mice was evaluated through blood chemistry and complete blood count (CBC) tests.ResultsA library of mSENS formulations complexed with luciferase-encoding mRNA, were characterized for their particle size, surface charge, encapsulation efficiency, colloidal stability, and in vitro and in vivo luciferase protein expression level. Upon systemic administration in mice, varying biodistribution profiles were observed, implicating the potential for tailored delivery to target tissues. Particularly, cancer vaccine application was further developed leveraging the formulation with preferential spleen delivery. Following vaccination with Trp-2 mRNA encapsulated with mSENS (Trp-2 mRNA-mSENS) in B16F10 tumor bearing mice, strong Trp-2 antigen-specific IFN-γ T-cell responses were observed. Generated anti-tumor immunity also marked suppression of B16F10 lung tumors were observed in Trp-2-mSENS immunized mice compared to non-immunized controls, demonstrating the potential of mSENS as a mRNA delivery platform for the application for vaccine.ConclusionsProprietary biodegradable polymer based-mSENS platform offers an attractive delivery strategy for mRNA by tailoring to specific therapeutic applications. Depending on the application, whether it’s a vaccine or protein replacement, a rationally designed mSENS formulation can efficiently distribute mRNA to specific tissues. In particular, application of a splenic mSENS formulation for a cancer vaccine has been demonstrated in murine tumor model. In summary, mRNA delivery through mSENS platform is expected to provide significant opportunities in clinical development for mRNA therapeutics.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals’ IACUC (Institutional Animal Care and Use Committee), approval number SYAU-2027.ReferencePiotr S. Kowalski, Arnab Rudra, Lei Miao, and Daniel G. Anderson, delivering the messenger: advances in technologies for therapeutic mRNA delivery. Molecular Therapy Vol. 27 No 4 April 2019.

scholarly journals FORMULATION AND EVALUATION OF CURCUMIN LOADED LIPOSOME AND ITS BIO-ENHANCEMENT

2019 ◽  
Vol 9 (4-A) ◽  
pp. 425-437
Author(s):  
Khushboo Verma ◽  
Jhakeshwar Prasad ◽  
Suman Saha ◽  
Surabhi Sahu
Keyword(s):  
Thin Film ◽  
Particle Size ◽  
Drug Release ◽  
Zeta Potential ◽  
High Performance ◽  
Encapsulation Efficiency ◽  
Mean Particle Size ◽  
Liposome Formulation

The aim of this work was to develop and evaluate curcumin loaded liposome and its bio- enhancement. Curcumin was selected as a natural drug for liposome formulation. Curcumin show variety of biological activity but it also shows poor bioavailability due to low aqueous solubility (1 µg/ml), poor absorption and rapid metabolism so that piperine was selected as bio enhancer to improve curcumin bioavailability. Soy lecithin and cholesterol were used to prepared curcumin and curcumin-piperine loaded liposome at different ratio by thin film hydration method because of easy to perform, and high encapsulation rates of lipid. The all liposome formulations (F1-F5) were evaluated by mean particle size, polydispersity index, zeta potential, encapsulation efficiency and drug release. Bioavailability was also determined on rat. Blood samples were collected at specific intervals, and plasma was separated by ultracentrifugation. Plasma was analyzed by high-performance liquid chromatography at 425 nm taking acetonitrile: water (75:25 v/v) acidified with 2% acetic acid as a mobile phase at a flow rate of 0.5 ml/min using C18 column. The mean particle size was found in the range between 800-1100 that indicate liposome are large unilamellar vesical types. By zeta potential study its conform that the all formulation was stable. The encapsulation efficiency of all liposome formulation are varied between 59-67%. In vitro drug release was analyse in 7.4 pH phosphate buffer, the maximum %CDR observed at the 12 hrs., and formulation are follow sustained release thus they reduce metabolism, good absorption rate which improve bioavailability of drug. From in-vivo study, it is clear that curcumin-piperine liposomal formulation, increases Cmax, area under the curve, and mean residence time significantly as compared to pure curcumin and pure curcumin liposome. Keywords: liposome; Curcumin; Piperine, Thin film hydration method; Bioavailability

scholarly journals Formulation and evaluation of carvedilol microcapsules using Eudragit NE30D and sodium alginate

2013 ◽  
Vol 49 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Trishna Bal ◽  
Shubhranshu Sengupta ◽  
Padala Narasimha Murthy
Keyword(s):  
Particle Size ◽  
Drug Release ◽  
Sodium Alginate ◽  
Encapsulation Efficiency ◽  
In Vitro Release ◽  
Kinetic Equations ◽  
Oral Feeding ◽  
Primary Role

Inclusion complexes of carvedilol(CR) with hydroxyl propyl beta-cyclodextrin (HPBCD) was prepared using co-grinding technique. Then, the inclusion complex was microencapsulated using combinations of Eudragit NE30D (EU) and sodium alginate (SA) utilizing orifice gelation technique. The formulations were analysed by using Scanning electron microscopy (SEM), Fourier Transform Infrared spectroscopy (FTIR), Differential scanning Calorimetry (DSC) and X-ray diffractometer (XRD) and also evaluated for particle size, encapsulation efficiency, production yield, swelling capacity, mucoadhesive properties, zeta potential and drug release. The microcapsules were smooth and showed no visible cracks and extended drug release of 55.2006% up to 12 hours in phosphate buffer of pH 6.8, showing particle size within the range of 264.5-358.5 µm, and encapsulation efficiency of 99.337±0.0100-66.2753±0.0014%.The in vitro release data of optimized batch of microcapsules were plotted in various kinetic equations to understand the mechanisms and kinetics of drug release, which followed first order kinetics, value of "n" is calculated to be 0.459 and drug release was diffusion controlled. The mice were fed with diet for inducing high blood pressure and the in vivo antihypertensive activity of formulations was carried out administering the optimized formulations and pure drug separately by oral feeding and measured by B.P Monwin IITC Life Science instrument and the results indicated that the bioavailability of carvedilol was increased both in vitro and in vivo with the mucoadhesive polymers showing primary role in retarding the drug release.

scholarly journals Preparation of pegylated nano-liposomal formulation containing SN-38: In vitro characterization and in vivo biodistribution in mice

2009 ◽  
Vol 59 (2) ◽  
pp. 133-144 ◽  
Author(s):  
Fatemeh Atyabi ◽  
Anahita Farkhondehfai ◽  
Farnaz Esmaeili ◽  
Rassoul Dinarvand
Keyword(s):  
Particle Size ◽  
Encapsulation Efficiency ◽  
Liposomal Formulation ◽  
Pegylated Liposomes ◽  
In Vivo Biodistribution ◽  
In Vitro Characterization ◽  
Poorly Soluble ◽  
Low Toxicity

Preparation of pegylated nano-liposomal formulation containing SN-38:In vitrocharacterization andin vivobiodistribution in mice7-Ethyl-10-hydroxy-camptothecin (SN-38), a metabolite of irinotecan x HCl, is poorly soluble in aqueous solutions and practically insoluble in most physiologically compatible and pharmaceutically acceptable solvents. Formulation of SN-38 in concentrated pharmaceutical delivery systems for parenteral administration is thus very difficult. Due to their biocompatibility and low toxicity, liposomes were considered for the delivery of SN-38. In this study, pegylated liposomes with distearoylphosphatidylcholine, distearoylphosphatidylethanolamine containing SN-38 were prepared and their characteristics, such as particle size, encapsulation efficiency,in vitrodrug release and biodistribution, were investigated. The particle size of liposomes was in the range of 150--200 nm. The encapsulation efficiency andin vitrorelease rate of pegylated liposomes was higher than those of non-pegylated liposomes. As expected, the distribution of pegylated liposomes in body organs such as liver, kidney, spleen and lung was considerably lower than that of non-pegylated liposomes. Also, their blood concentration was at least 50 % higher than that of non-pegylated liposomes.

Formulation and Evaluation of Nanosuspension of Simvastatin

2015 ◽  
Vol 8 (2) ◽  
pp. 2858-2873
Author(s):  
Rupali L. Shid ◽  
Shashikant N. Dhole ◽  
Nilesh Kulkarni ◽  
Santosh L Shid
Keyword(s):  
Particle Size ◽  
Zeta Potential ◽  
Factorial Design ◽  
Dissolution Rate ◽  
In Vitro Dissolution ◽  
Total Drug ◽  
23 Factorial Design ◽  
Rate Of Dissolution

Poor water solubility and slow dissolution rate are issues for the majority of upcoming and existing biologically active compounds. Simvastatin is poorly water-soluble drug and its bioavailability is very low from its crystalline form. The purpose of this study wasto increase the solubility and dissolution rate of simvastatin by the  preparation of nanosuspension by emulsification solvent diffusion method at laboratory scale. Prepared nanosus-pension was evaluated for its particle size and in vitro dissolution study and characterized by zeta potential,differential scanning calorimetry (DSC) and X-Ray diffractometry (XRD), motic digital microscopy, entrapment efficiency, total drug content, saturated solubility study and in vivo study. A 23 factorial design was employed to study the effect of independent variables, amount of SLS (X1), amount of PVPK-30 (X2) and poloxamer-188 (X3) and dependent variables are total drug content and polydispersity Index. The obtained results showed that particle size (nm) and rate of dissolution has been improved when nanosuspension prepared with the higherconcentration of PVPK-30 with the higher concentration of PVP K-30 and Poloxamer-188 and lower concentration of SLS. The particle size and zeta potential of optimized formulation was found to be 258.3 nm and 23.43. The rate of dissolution of the optimized nanosuspension was enhanced (90% in 60min), relative to plain simvastatin  (21% in 60 min), mainly due to the formation of nanosized particles. These results indicate the suitability of 23 factorial  design for preparation of simvastatin loaded nano-suspension significantly improved in vitro dissolution rate and thus possibly enhance fast onset of therapeutic drug effect. In vivo study shows increase in bioavailability in nanosuspension formulation than the plain simvastatin drug.

Optimization and Characterization of Aqueous Micellar Formulations for Ocular Delivery of an Antifungal Drug, Posaconazole

2020 ◽  
Vol 26 (14) ◽  
pp. 1543-1555 ◽  
Author(s):  
Meltem E. Durgun ◽  
Emine Kahraman ◽  
Sevgi Güngör ◽  
Yıldız Özsoy
Keyword(s):  
Particle Size ◽  
Zeta Potential ◽  
Size Distribution ◽  
Encapsulation Efficiency ◽  
Fungal Infections ◽  
In Vitro Release ◽  
Pluronic F127 ◽  
Glycol Succinate ◽  
Vitro Release

Background: Topical therapy is preferred for the management of ocular fungal infections due to its superiorities which include overcoming potential systemic side effects risk of drugs, and targeting of drugs to the site of disease. However, the optimization of effective ocular formulations has always been a major challenge due to restrictions of ocular barriers and physiological conditions. Posaconazole, an antifungal and highly lipophilic agent with broad-spectrum, has been used topically as off-label in the treatment of ocular fungal infections due to its highly lipophilic character. Micellar carriers have the potential to improve the solubility of lipophilic drugs and, overcome ocular barriers. Objective: In the current study, it was aimed optimization of posaconazole loaded micellar formulations to improve aqueous solubility of posaconazole and to characterize the formulations and to investigate the physical stability of these formulations at room temperature (25°C, 60% RH), and accelerated stability (40°C, 75% RH) conditions. Method: Micelles were prepared using a thin-film hydration method. Pre-formulation studies were firstly performed to optimize polymer/surfactant type and to determine their concentration in the formulations. Then, particle size, size distribution, and zeta potential of the micellar formulations were measured by ZetaSizer Nano-ZS. The drug encapsulation efficiency of the micelles was quantified by HPLC. The morphology of the micelles was depicted by AFM. The stability of optimized micelles was evaluated in terms of particle size, size distribution, zeta potential, drug amount and pH for 180 days. In vitro release studies were performed using Franz diffusion cells. Results: Pre-formulation studies indicated that single D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), a combination of it and Pluronic F127/Pluronic F68 are capable of formation of posaconazole loaded micelles at specific concentrations. Optimized micelles with high encapsulation efficiency were less than 20 nm, approximately neutral, stable, and in aspherical shape. Additionally, in vitro release data showed that the release of posaconazole from the micelles was higher than that of suspension. Conclusion: The results revealed that the optimized micellar formulation of posaconazole offers a potential approach for topical ocular administration.

scholarly journals Upregulation of ETV2 Expression Promotes Endothelial Differentiation of Human Dental Pulp Stem Cells

2021 ◽  
Vol 30 ◽  
pp. 096368972097873
Author(s):  
Jing Li ◽  
Youming Zhu ◽  
Na Li ◽  
Tao Wu ◽  
Xianyu Zheng ◽  
...  
Keyword(s):  
Protein Expression ◽  
Dental Pulp ◽  
Tube Formation ◽  
Endothelial Differentiation ◽  
Cell Source ◽  
Lentiviral Infection ◽  
Mrna And Protein Expression ◽  
Human Dental Pulp

The lack of vasculogenesis often hampers the survivability and integration of newly engineered tissue grafts within the host. Autologous endothelial cells (ECs) are an ideal cell source for neovascularization, but they are limited by their scarcity, lack of proliferative capacity, and donor site morbidity upon isolation. The objective of this study was to determine whether differentiation of human dental pulp stem cells (DPSCs) into the endothelial lineage can be enhanced by recombinant ETV2 overexpression. DPSCs were extracted from fresh dental pulp tissues. ETV2 overexpression in DPSCs was achieved by lentiviral infection and cellular morphological changes were evaluated. The mRNA and protein expression levels of endothelial-specific markers were assessed through quantitative real-time polymerase chain reaction, western blot, immunofluorescence staining, and flow cytometry. The tube formation assay and Matrigel plug assay were also performed to evaluate the angiogenic potential of the ETV2-transduced cells in vitro and in vivo, respectively. Additionally, proteomic analysis was performed to analyze global changes in protein expression following ETV2 overexpression. After lentiviral infection, ETV2-overexpressing DPSCs showed endothelial-like morphology. Compared with control DPSCs, significantly higher mRNA and protein expression levels of endothelial-specific genes, including CD31, VE-Cadherin, VEGFR1, and VEGFR2, were detected in ETV2-overexpressing DPSCs. Moreover, ETV2 overexpression enhanced capillary-like tube formation on Matrigel in vitro, as well as neovascularization in vivo. In addition, comparative proteomic profiling showed that ETV2 overexpression upregulated the expression of vascular endothelial growth factor (VEGF) receptors, which was indicative of increased VEGF signaling. Taken together, our results indicate that ETV2 overexpression significantly enhanced the endothelial differentiation of DPSCs. Thus, this study shows that DPSCs can be a promising candidate cell source for tissue engineering applications.

scholarly journals Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 308
Author(s):  
Ying-Ray Lee ◽  
Chia-Ming Chang ◽  
Yuan-Chieh Yeh ◽  
Chi-Ying F. Huang ◽  
Feng-Mao Lin ◽  
...  
Keyword(s):  
Protein Expression ◽  
Western Blotting ◽  
Expression Profiles ◽  
Plaque Assay ◽  
Virus Titer ◽  
Enterovirus 71 ◽  
Luciferase Reporter ◽  
Pathogen Invasion

Honeysuckle (Lonicera japonica Thunb) is a traditional Chinese medicine (TCM) with an antipathogenic activity. MicroRNAs (miRNAs) are small non-coding RNA molecules that are ubiquitously expressed in cells. Endogenous miRNA may function as an innate response to block pathogen invasion. The miRNA expression profiles of both mice and humans after the ingestion of honeysuckle were obtained. Fifteen overexpressed miRNAs overlapped and were predicted to be capable of targeting three viruses: dengue virus (DENV), enterovirus 71 (EV71) and SARS-CoV-2. Among them, let-7a was examined to be capable of targeting the EV71 RNA genome by reporter assay and Western blotting. Moreover, honeysuckle-induced let-7a suppression of EV71 RNA and protein expression as well as viral replication were investigated both in vitro and in vivo. We demonstrated that let-7a targeted EV71 at the predicted sequences using luciferase reporter plasmids as well as two infectious replicons (pMP4-y-5 and pTOPO-4643). The suppression of EV71 replication and viral load was demonstrated in two cell lines by luciferase activity, RT-PCR, real-time PCR, Western blotting and plaque assay. Furthermore, EV71-infected suckling mice fed honeysuckle extract or inoculated with let-7a showed decreased clinical scores and a prolonged survival time accompanied with decreased viral RNA, protein expression and virus titer. The ingestion of honeysuckle attenuates EV71 replication and related pathogenesis partially through the upregulation of let-7a expression both in vitro and in vivo. Our previous report and the current findings imply that both honeysuckle and upregulated let-7a can execute a suppressive function against the replication of DENV and EV71. Taken together, this evidence indicates that honeysuckle can induce the expression of let-7a and that this miRNA as well as 11 other miRNAs have great potential to prevent and suppress EV71 replication.

scholarly journals Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Farnaz Dabbagh Moghaddam ◽  
Iman Akbarzadeh ◽  
Ehsan Marzbankia ◽  
Mahsa Farid ◽  
Leila khaledi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cell Lines ◽  
Encapsulation Efficiency ◽  
Inbred Mice ◽  
Breast Cancer Treatment ◽  
Anticancer Effect ◽  
Anti Cancer

Abstract Background Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done. Results This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2, MMP2, and MMP9 genes while they up-regulate the expression of Bax, Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups. Conclusions Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.

scholarly journals Survival and Proliferation under Severely Hypoxic Microenvironments Using Cell-Laden Oxygenating Hydrogels

2021 ◽  
Vol 12 (2) ◽  
pp. 30
Author(s):  
Shabir Hassan ◽  
Berivan Cecen ◽  
Ramon Peña-Garcia ◽  
Fernanda Roberta Marciano ◽  
Amir K. Miri ◽  
...  
Keyword(s):  
Prolonged Release ◽  
Therapeutic Approaches ◽  
Encapsulated Cells ◽  
Hypoxic Conditions ◽  
Skeletal Myoblasts ◽  
Artificial Tissue ◽  
Delivery Platform ◽  
Living Tissues

Different strategies have been employed to provide adequate nutrients for engineered living tissues. These have mainly revolved around providing oxygen to alleviate the effects of chronic hypoxia or anoxia that result in necrosis or weak neovascularization, leading to failure of artificial tissue implants and hence poor clinical outcome. While different biomaterials have been used as oxygen generators for in vitro as well as in vivo applications, certain problems have hampered their wide application. Among these are the generation and the rate at which oxygen is produced together with the production of the reaction intermediates in the form of reactive oxygen species (ROS). Both these factors can be detrimental for cell survival and can severely affect the outcome of such studies. Here we present calcium peroxide (CPO) encapsulated in polycaprolactone as oxygen releasing microparticles (OMPs). While CPO releases oxygen upon hydrolysis, PCL encapsulation ensures that hydrolysis takes place slowly, thereby sustaining prolonged release of oxygen without the stress the bulk release can endow on the encapsulated cells. We used gelatin methacryloyl (GelMA) hydrogels containing these OMPs to stimulate survival and proliferation of encapsulated skeletal myoblasts and optimized the OMP concentration for sustained oxygen delivery over more than a week. The oxygen releasing and delivery platform described in this study opens up opportunities for cell-based therapeutic approaches to treat diseases resulting from ischemic conditions and enhance survival of implants under severe hypoxic conditions for successful clinical translation.

scholarly journals A therapeutic vascular conduit to support in vivo cell-secreted therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Edward X. Han ◽  
Hong Qian ◽  
Bo Jiang ◽  
Maria Figetakis ◽  
Natalia Kosyakova ◽  
...  
Keyword(s):  
Vascular Graft ◽  
Large Scale ◽  
Biological Effects ◽  
Therapeutic Protein ◽  
Close Proximity ◽  
Delivery Platform ◽  
Stage Renal Disease ◽  
End Stage

AbstractA significant barrier to implementation of cell-based therapies is providing adequate vascularization to provide oxygen and nutrients. Here we describe an approach for cell transplantation termed the Therapeutic Vascular Conduit (TVC), which uses an acellular vessel as a scaffold for a hydrogel sheath containing cells designed to secrete a therapeutic protein. The TVC can be directly anastomosed as a vascular graft. Modeling supports the concept that the TVC allows oxygenated blood to flow in close proximity to the transplanted cells to prevent hypoxia. As a proof-of-principle study, we used erythropoietin (EPO) as a model therapeutic protein. If implanted as an arteriovenous vascular graft, such a construct could serve a dual role as an EPO delivery platform and hemodialysis access for patients with end-stage renal disease. When implanted into nude rats, TVCs containing EPO-secreting fibroblasts were able to increase serum EPO and hemoglobin levels for up to 4 weeks. However, constitutive EPO expression resulted in macrophage infiltration and luminal obstruction of the TVC, thus limiting longer-term efficacy. Follow-up in vitro studies support the hypothesis that EPO also functions to recruit macrophages. The TVC is a promising approach to cell-based therapeutic delivery that has the potential to overcome the oxygenation barrier to large-scale cellular implantation and could thus be used for a myriad of clinical disorders. However, a complete understanding of the biological effects of the selected therapeutic is absolutely essential.

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