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146条结果
  • 机译 发行信息–目录
    • 作者:
    • 刊名:Bioengineering Translational Medicine
    • 2019年第3期
    摘要:
  • 机译 发行信息–目录
    • 作者:
    • 刊名:Bioengineering Translational Medicine
    • 2019年第1期
    摘要:
  • 机译 BioTM Buzz第4卷,第3期
    • 作者:Aaron C. Anselmo
    • 刊名:Bioengineering Translational Medicine
    • 2019年第3期
    摘要:
  • 机译 临床中的纳米颗粒:最新进展
    摘要:Nanoparticle drug delivery systems have been used in the clinic since the early 1990's. Since that time, the field of nanomedicine has evolved alongside growing technological needs to improve the delivery of various therapeutics. Over these past decades, newer generations of nanoparticles have emerged that are capable of performing additional delivery functions that can enable treatment via new therapeutic modalities. In the current clinical landscape, many of these new generation nanoparticles have reached clinical trials and have been approved for various indications. In the first issue of Bioengineering & Translational Medicine in 2016, we reviewed the history, current clinical landscape, and clinical challenges of nanoparticle delivery systems. Here, we provide a 3 year update on the current clinical landscape of nanoparticle drug delivery systems and highlight newly approved nanomedicines, provide a status update on previous clinical trials, and highlight new technologies that have recently entered the clinic.
  • 机译 编辑委员会成员简介:Mark R. Prausnitz教授
    • 作者:Harvinder S. Gill
    • 刊名:Bioengineering Translational Medicine
    • 2019年第3期
    摘要:
  • 机译 社论:生物工程与转化医学的启动阶段
    • 作者:Samir Mitragotri
    • 刊名:Bioengineering Translational Medicine
    • 2019年第3期
    摘要:
  • 机译 工程组织特异性血管
    摘要:Vascular diversity among organs has recently become widely recognized. Several studies using mouse and human fetal tissues revealed distinct characteristics of organ‐specific vasculature in molecular and functional levels. Thorough understanding of vascular heterogeneities in human adult tissues is significant for developing novel strategies for targeted drug delivery and tissue regeneration. Recent advancements in microfabrication techniques, biomaterials, and differentiation protocols allowed for incorporation of microvasculature into engineered organs. Such vascularized organ models represent physiologically relevant platforms that may offer innovative tools for dissecting the effects of the organ microenvironment on vascular development and expand our present knowledge on organ‐specific human vasculature. In this article, we provide an overview of the current structural and molecular evidence on microvascular diversity, bioengineering methods used to recapitulate the microenvironmental cues, and recent vascularized three‐dimensional organ models from the perspective of tissue‐specific vasculature.
  • 机译 了解光反射对比度以实时表征上皮前体病变
    摘要:Detecting early‐stage epithelial cancers and their precursor lesions are challenging as lesions could be subtle and focally or heterogeneously distributed over large mucosal areas. Optical coherence tomography (OCT) that enables wide‐field imaging of subsurface microstructures in vivo is a promising screening tool for epithelial diseases. However, its diagnostic capability has not been fully appreciated since the optical reflectance contrast is poorly understood. We investigated the back‐scattered intensities from clustered or packed nanometer scale intracellular scatterers using finite‐difference time‐domain method and 1‐μm resolution form of OCT, and uncovered that there existed correlations between the reflectance contrasts and the ultrastructural clustering or packing states of these scatterers, which allows us to interpret the physiological state of the cells. Specifically, both polarized goblet cells and foveolar cells exhibited asymmetric reflectance contrast, but they could be differentiated by the optical intensity of the mucin cup due to the different ultrastructural make‐ups of the mucin granules; keratinocytes could demonstrate varied cytoplasmic intensity and their cytoplasmic contrast was closely correlated with the packing state of keratin filaments. Further preliminary study demonstrated that these new understandings of OCT image contrast enables the characterization of precancerous lesions, which could complement the current morphology‐based criteria in realizing “virtual histology” and would have a profound impact for the screening and surveillance of epithelial cancers.
  • 机译 EGFR定位和聚类诱导角质形成细胞集体迁移过程中的前导细胞PLCγ1激活
    摘要:Re‐epithelialization is a critical step in wound healing and results from the collective migration of keratinocytes. Previous work demonstrated that immobilized, but not soluble, epidermal growth factor (EGF) resulted in leader cell‐specific activation of phospholipase C gamma 1 (PLCγ1) in HaCaT keratinocytes, and that this PLCγ1 activation was necessary to drive persistent cell migration. To determine the mechanism responsible for wound edge‐localized PLCγ1 activation, we examined differences in cell area, cell–cell interactions, and EGF receptor (EGFR) localization between wound edge and bulk cells treated with vehicle, soluble EGF, or immobilized EGF. Our results support a multistep mechanism where EGFR translocation from the lateral membrane to the basolateral/basal membrane allows clustering in response to immobilized EGF. This analysis of factors regulating PLCγ1 activation is a crucial step toward developing therapies or wound dressings capable of modulating this signal and, consequently, cell migration.
  • 机译 通过干扰选择性核孔屏障来促进质粒核传递
    摘要:Nuclear pore complexes (NPCs) are sophisticated transporters assembled from diverse proteins termed nucleoporins (Nups). They control all nucleocytoplasmic transport and form a stringent barrier between the cytosol and the nucleus. While selective receptor‐mediated transport enables translocation of macromolecules up to striking sizes approaching megadalton‐scale, the upper cutoff for diffusion is at 40 kDa. Raising the cutoff is of particular importance for nuclear delivery of therapeutic nanoparticles, for example, gene and chemotherapy. In this work, we set out to present compounds capable of raising the cutoff to an extent enabling nuclear delivery of 6 kbp pDNA (150 kDa) in cultured human vascular endothelial cells. Of all tested compounds one is singled out, 1,6‐hexanediol (1,6‐HD). Our observations reveal that 1,6‐HD facilitates nuclear delivery of pDNA in up to 10–20% of the tested cells, compared to no delivery at all in control conditions. It acts by interfering with bonds between Nups that occupy the NPC channel and confer transport selectivity. It also largely maintains cell viability even at high concentrations. We envisage that 1,6‐HD may serve as a lead substance and usher in the design of potent new strategies to increase nuclear delivery of therapeutic nanoparticles.
  • 机译 新型纳米级顺铂和PARP抑制剂的层状纳米颗粒用于卵巢癌铂类药物耐药性治疗
    摘要:Advanced staged high‐grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5‐year survival rates of only 25–30% due to late‐stage diagnosis and the shortcomings of platinum‐based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP‐ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum‐based therapy by developing a targeted delivery approach. Novel electrostatic layer‐by‐layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP‐encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44‐expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half‐life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.
  • 机译 协同作用和免疫刺激在化学疗法组合设计中的作用:阿霉素和喜树碱的分析
    摘要:Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near‐their maximum tolerated doses (MTDs), elevating the risk of dose‐related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low‐dose treatment option for breast cancer. DOX‐CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA‐MB‐231). This combination led to excellent long‐term survival of mice bearing MDA‐MB‐231 tumors at doses roughly five‐fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX‐CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.
  • 机译 BioTM Buzz第4卷,第2期
    • 作者:Aaron C. Anselmo
    • 刊名:Bioengineering Translational Medicine
    • 2019年第2期
    摘要:
  • 机译 单次注射抗VEGF控释水凝胶对非人类灵长类动物眼的长期治疗作用
    摘要:Wet age‐related macular degeneration (wet‐AMD) is a leading cause of irreversible blindness. Current treatment of AMD requires monthly intravitreal injection, which is difficult to be implemented in many parts of the world. In recent years, controlled release of anti‐vascular endothelial growth factor (VEGF) therapeutics has attracted intense research interest aiming to reduce the injection frequency to one or two times per year. In this study, we evaluated the in vivo pharmacokinetics and the long‐term therapeutic efficacy of an in situ hydrogel encapsulating an anti‐VEGF antibody in nonhuman primates. We show that after a single injection of anti‐VEGF controlled release hydrogel, a relatively constant concentration of drug can be maintained in the monkey eye for at least 5 months and the dose was sufficient for the treatment of recurrent choroidal neovascularization induced by repeat laser photocoagulation in monkeys. Our result suggested that when formulated into a controlled release formulation, a single dose of anti‐VEGF may be sufficient for a half‐year treatment and controlled release may be a suitable strategy to reduce the injection frequency in the treatment of AMD in human.
  • 机译 用于评估血脑屏障的人脑微流模型(μHuB)
    摘要:Microfluidic cellular models, commonly referred to as “organs‐on‐chips,” continue to advance the field of bioengineering via the development of accurate and higher throughput models, captivating the essence of living human organs. This class of models can mimic key in vivo features, including shear stresses and cellular architectures, in ways that cannot be realized by traditional two‐dimensional in vitro models. Despite such progress, current organ‐on‐a‐chip models are often overly complex, require highly specialized setups and equipment, and lack the ability to easily ascertain temporal and spatial differences in the transport kinetics of compounds translocating across cellular barriers. To address this challenge, we report the development of a three‐dimensional human blood brain barrier (BBB) microfluidic model (μHuB) using human cerebral microvascular endothelial cells (hCMEC/D3) and primary human astrocytes within a commercially available microfluidic platform. Within μHuB, hCMEC/D3 monolayers withstood physiologically relevant shear stresses (2.73 dyn/cm2) over a period of 24 hr and formed a complete inner lumen, resembling in vivo blood capillaries. Monolayers within μHuB expressed phenotypical tight junction markers (Claudin‐5 and ZO‐1), which increased expression after the presence of hemodynamic‐like shear stress. Negligible cell injury was observed when the monolayers were cultured statically, conditioned to shear stress, and subjected to nonfluorescent dextran (70 kDa) transport studies. μHuB experienced size‐selective permeability of 10 and 70 kDa dextrans similar to other BBB models. However, with the ability to probe temporal and spatial evolution of solute distribution, μHuBs possess the ability to capture the true variability in permeability across a cellular monolayer over time and allow for evaluation of the full breadth of permeabilities that would otherwise be lost using traditional end‐point sampling techniques. Overall, the μHuB platform provides a simplified, easy‐to‐use model to further investigate the complexities of the human BBB in real‐time and can be readily adapted to incorporate additional cell types of the neurovascular unit and beyond.
  • 机译 BioTM Buzz(第4卷,第1期)
    • 作者:Aaron C. Anselmo
    • 刊名:Bioengineering Translational Medicine
    • 2019年第1期
    摘要:
  • 机译 用于3D细胞培养和组织工程的明胶-多糖复合支架:走向天然疗法
    摘要:Gelatin is a promising material as scaffold with therapeutic and regenerative characteristics due to its chemical similarities to the extracellular matrix (ECM) in the native tissues, biocompatibility, biodegradability, low antigenicity, cost‐effectiveness, abundance, and accessible functional groups that allow facile chemical modifications with other biomaterials or biomolecules. Despite the advantages of gelatin, poor mechanical properties, sensitivity to enzymatic degradation, high viscosity, and reduced solubility in concentrated aqueous media have limited its applications and encouraged the development of gelatin‐based composite hydrogels. The drawbacks of gelatin may be surmounted by synergistically combining it with a wide range of polysaccharides. The addition of polysaccharides to gelatin is advantageous in mimicking the ECM, which largely contains proteoglycans or glycoproteins. Moreover, gelatin–polysaccharide biomaterials benefit from mechanical resilience, high stability, low thermal expansion, improved hydrophilicity, biocompatibility, antimicrobial and anti‐inflammatory properties, and wound healing potential. Here, we discuss how combining gelatin and polysaccharides provides a promising approach for developing superior therapeutic biomaterials. We review gelatin–polysaccharides scaffolds and their applications in cell culture and tissue engineering, providing an outlook for the future of this family of biomaterials as advanced natural therapeutics.
  • 机译 纳米晶体:转化研究和临床研究的视角
    摘要:Poorly soluble small molecules typically pose translational hurdles owing to their low solubility, low bioavailability, and formulation challenges. Nanocrystallization is a versatile method for salvaging poorly soluble drugs with the added benefit of a carrier‐free delivery system. In this review, we provide a comprehensive analysis of nanocrystals with emphasis on their clinical translation. Additionally, the review sheds light on clinically approved nanocrystal drug products as well as those in development.
  • 机译 脂质纳米颗粒沉默肿瘤坏死因子α以改善糖尿病小鼠的伤口愈合
    摘要:Diabetes mellitus is a mounting concern in the United States, as are the mortality and morbidity that result from its complications. Of particular concern, diabetes patients frequently suffer from impaired wound healing and resultant nonhealing diabetic foot ulcers. These ulcers overproduce tumor necrosis factor α (TNFα), which reduces wound bed cell migration and proliferation while encouraging apoptosis. Herein, we describe the use of siRNA‐loaded lipid nanoparticles (LNPs) as a potential wound treatment to combat an overzealous immune response and facilitate wound closure. LNPs were formulated with an ionizable, degradable lipidoid and siRNA specific for TNFα. Topical application of nanoparticles reduced TNFα mRNA expression in the wound by 40–55% in diabetic and nondiabetic mice. In diabetic mice, this TNFα knockdown accelerated wound healing compared to untreated controls. Together, these results serve as proof‐of‐concept that RNA interference therapy using LNPs can reduce the severity and duration of chronic diabetic wounds.
  • 机译 膜不稳定阳离子纳米凝胶对细胞内药物输送的吸收和功能
    摘要:The design of intracellular drug delivery vehicles demands an in‐depth understanding of their internalization and function upon entering the cell to tailor the physicochemical characteristics of these platforms and achieve efficacious treatments. Polymeric cationic systems have been broadly accepted to be membrane disruptive thus being beneficial for drug delivery inside the cell. However, if excessive destabilization takes place, it can lead to adverse effects. One of the strategies used to modulate the cationic charge is the incorporation of hydrophobic moieties, thus increasing the hydrophobic content. We have demonstrated the successful synthesis of nanogels based on diethylaminoethyl methacrylate and poly(ethylene glycol) methyl ether methacrylate. Addition of the hydrophobic monomers tert‐butyl methacrylate or 2‐(tert‐butylamino)ethyl methacrylate shows improved polymer hydrophobicity and modulation of the critical swelling pH. Here, we evaluate the cytocompatibility, uptake, and function of these membrane‐destabilizing cationic methacrylated nanogels using in vitro models. The obtained results suggest that the incorporation of hydrophobic monomers decreases the cytotoxicity of the nanogels to epithelial colorectal adenocarcinoma cells. Furthermore, analysis of the internalization pathways of these vehicles using inhibitors and imaging flow cytometry showed a significant decrease in uptake when macropinocytosis/phagocytosis inhibitors were present. The membrane‐disruptive abilities of the cationic polymeric nanogels were confirmed using three different models. They demonstrated to cause hemolysis in sheep erythrocytes, lactate dehydrogenase leakage from a model cell line, and disrupt giant unilamellar vesicles. These findings provide new insights of the potential of polymeric nanoformulations for intracellular delivery.

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