Prospects for Microtechnology and Nanotechnology in Bioengineering of Replacement Microvessels

Archives of Pathology & Laboratory Medicine. Mar, 2002  |  Pubmed ID: 11860307

Due to its anticipated curative potential, therapeutic angiogenesis recently became a major preoccupation for the biomedical research community. Most of the related work reported to date employs either biochemical or genetic tools.

Noninvasive Diagnosis of Incomplete Endovascular Aneurysm Repair: D-dimer Assay to Detect Type I Endoleaks and Nonshrinking Aneurysms

Journal of Endovascular Therapy : an Official Journal of the International Society of Endovascular Specialists. Feb, 2002  |  Pubmed ID: 11958331

To test the hypothesis that D-dimer (D-D), a cross-linked fibrin degradation product of an ongoing thrombotic event, could be a marker for incomplete aneurysm exclusion after endovascular abdominal aortic aneurysm (AAA) repair.

Biotechnology Apprenticeship for Secondary-level Students: Teaching Advanced Cell Culture Techniques for Research

Cell Biology Education. 2002  |  Pubmed ID: 12587031

The purpose of this article is to discuss small-group apprenticeships (SGAs) as a method to instruct cell culture techniques to high school participants. The study aimed to teach cell culture practices and to introduce advanced imaging techniques to solve various biomedical engineering problems. Participants designed and completed experiments using both flow cytometry and laser scanning cytometry during the 1-month summer apprenticeship. In addition to effectively and efficiently teaching cell biology laboratory techniques, this course design provided an opportunity for research training, career exploration, and mentoring. Students participated in active research projects, working with a skilled interdisciplinary team of researchers in a large research institution with access to state-of-the-art instrumentation. The instructors, composed of graduate students, laboratory managers, and principal investigators, worked well together to present a real and worthwhile research experience. The students enjoyed learning cell culture techniques while contributing to active research projects. The institution's researchers were equally enthusiastic to instruct and serve as mentors. In this article, we clarify and illuminate the value of small-group laboratory apprenticeships to the institution and the students by presenting the results and experiences of seven middle and high school participants and their instructors.

Mechanical Spectral Signatures of Malignant Disease? A Small-sample, Comparative Study of Continuum Vs. Nano-biomechanical Data Analyses

Disease Markers. 2002  |  Pubmed ID: 12590171

Thin sections from human breast biopsies were employed to perform a differential analysis of the ultrasound spectral responses from invasive ductal carcinoma and normal tissue. A non-destructive testing methodology was employed, yielding the reflection coefficients as function of frequency in the clinical ultrasound range. The spectral responses were simulated both in the context of continuum and nano-biomechanics, with the objective of quantifying the physical properties that determine the differences in the spectral signature of normal vs. malignant tissue. The properties that were employed for the theoretical reconstruction of the spectra were: the density, the continuum and the nanomechanical elastic constants, and the nanomechanical theory internodal distance. The latter is a measure of the depth-of-penetration of mechanical actions between contiguous tissue elements. Together with vectorial descriptors of the tissue spatial arrangement, the internodal distance variable affords the quantitative incorporation of tissue architectural data in the theoretical model. In this paper, the validity of the nanomechanical approach to tissue characterization is discussed, and its potential extensions to biomolecular marker-based cancer diagnostics and therapeutics are considered.

Interstitial Stress and Fluid Pressure Within a Growing Tumor

Annals of Biomedical Engineering. Mar, 2003  |  Pubmed ID: 12680730

A solid tumor is composed of a population of cells that is expanding as a result of cell division. With dense cell packing, the solid matrix of the interstitial tissue is subject to residual stress. In addition, elevated interstitial fluid pressure (IFP) has been reported by researchers for a number of solid tumors. These features were incorporated into a mathematical model that predicts the mechanical response of a solid tumor within its host environment. A theoretical framework accounting for volumetric expansion, transvascular exchange and extravascular transport of fluids was developed using poroelastic theory, and applied to a spherical, vascularized, alymphatic tumor undergoing small growth increments. Simulations of tumor IFP were similar to those predicted by Jain and Baxter, showing elevated IFP that is driven by microvascular fluid pressure. Tumor growth, tissue stiffness, and IFP contribute to the compressive stresses predicted in the solid tumor interior. Tensile and compressive stresses were predicted in adjacent host tissues corresponding to radial and circumferential directions, respectively. An application of this model includes a solid stress-based framework for predicting regions of vascular collapse within the tumor interior.

Evaluation of the Proximal Aortic Neck Enlargement Following Endovascular Repair of Abdominal Aortic Aneurysm: 3-years Experience

European Radiology. Aug, 2003  |  Pubmed ID: 12692676

The aim of this study was to evaluate incidence, potential risk factors and effects on stent-graft migration of proximal neck dilatation after endoluminal repair of abdominal aortic aneurysm (EVAR), and the role of ultrasound (US) in detecting neck enlargement. From November 1998 to October 2001, 90 patients underwent EVAR. On follow-up, US and CT angiography (CTA) were performed, and diameters of the suprarenal and infrarenal aortic necks were monitored. Incidence of significant neck enlargement (> or =2.5 mm) and distal stent-graft migration (>10 mm) was calculated. Several factors were evaluated as predictive of neck enlargement. Ultrasound and CTA measurements were compared. The US and CTA examinations were available in 68, 39, and 11 patients at 1, 2, and 3 years follow-up (mean follow-up 15 months). Incidence of significant neck dilatation was 21.8% at the infrarenal level (13, 33, and 36% at 1, 2, and 3 years follow-up) and 13.8% at the suprarenal level (9, 18, and 27% at 1, 2, and 3 years follow-up). Significant stent-graft migration occurred in 14 of 87 patients (16%) and was associated with neck dilatation in 8 (2 suprarenal and 6 infrarenal). No risk factors were identified. Ultrasound was less accurate than CT in measuring neck diameter, in particular at the suprarenal level. Proximal aortic neck enlargement occurs in up to 30% of patients after EVAR and represents the main risk factor for stent-graft migration. The risk of infrarenal neck dilatation is higher at 2 years follow-up, whereas the suprarenal neck enlarges later. Ultrasound is not useful in monitoring neck diameter.

T Helper Type 1 Lymphocytes Drive Inflammation in Human Atherosclerotic Lesions

Proceedings of the National Academy of Sciences of the United States of America. May, 2003  |  Pubmed ID: 12740434

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.

Clinical Proteomics: Written in Blood

Nature. Oct, 2003  |  Pubmed ID: 14586448

Recommendations of the National Heart, Lung, and Blood Institute Nanotechnology Working Group

Circulation. Dec, 2003  |  Pubmed ID: 14656908

Recent rapid advances in nanotechnology and nanoscience offer a wealth of new opportunities for diagnosis and therapy of cardiovascular, pulmonary, and hematologic diseases and sleep disorders. To review the challenges and opportunities offered by these nascent fields, the National Heart, Lung, and Blood Institute convened a Working Group on Nanotechnology. Working Group participants discussed the various aspects of nanotechnology and its applications to heart, lung, blood, and sleep (HLBS) diseases. This report summarizes their discussions according to scientific opportunities, perceived needs and barriers, specific disease examples, and recommendations on facilitating research in the field. An overarching recommendation of the Working Group was to focus on translational applications of nanotechnology to solve clinical problems. The Working Group recommended the creation of multidisciplinary research centers capable of developing applications of nanotechnology and nanoscience to HLBS research and medicine. Centers would also disseminate technology, materials, and resources and train new investigators. Individual investigators outside these centers should be encouraged to conduct research on the application of nanotechnology to biological and clinical problems. Pilot programs and developmental research are needed to attract new investigators and to stimulate creative, high-impact research. Finally, encouragement of small businesses to develop nanotechnology-based approaches to clinical problems was considered important.

Micropatterning of Endothelial Cells by Guided Stimulation with Angiogenic Factors

Biosensors & Bioelectronics. Jun, 2004  |  Pubmed ID: 15093211

Micropatterning technology holds significant promise in the development of micro/nanomedical devices. The precise control of cell position and migration is important in several applications. For example, the optimal design of implantable devices depends on the implant material's micro-and nano-texture, which influences the response of nearby tissue, including the microvessels. Therefore, we were interested in endothelial cell positioning and colonization on specific surface domains in the size range of microvasculature. To this end, endothelial cells were seeded in microfabricated grooves and exposed to vascular endothelial growth factor (VEGF), which plays a key role in the angiogenic response. Patterned silicon wafers with grooves of 50 microm width and depth and 150 microm groove spacing were used. Each patterned region had two semicircular ports at either end, one of which was used to seed human retinal endothelial cells (HREC) and the other to house VEGF embedded in Matrigel. After 1 week, cells were fixed and analyzed by laser scanning cytometry (LSC). Our results shows that we can control HREC seeding and positioning in surface grooves and that the speed of colonization of the grooves can be manipulated by local VEGF application. We were able to quantify this effect, showing that HREC relocate inside the grooves twice as fast in response to VEGF stimulation, compared to control conditions, at a speed of 3.14 +/- 0.01 and 1.55 +/- 0.01 microm/min, respectively. Our approach could be used towards the fabrication of "designer" substrates or devices that not only allow patterned cell growth, but also permit dynamic cell repositioning.

Object-oriented Design Tools for Supramolecular Devices and Biomedical Nanotechnology

Annals of the New York Academy of Sciences. May, 2004  |  Pubmed ID: 15194610

Nanotechnology provides multifunctional agents for in vivo use that increasingly blur the distinction between pharmaceuticals and medical devices. Realization of such therapeutic nanodevices requires multidisciplinary effort that is difficult for individual device developers to sustain, and identification of appropriate collaborations outside ones own field can itself be challenging. Further, as in vivo nanodevices become increasingly complex, their design will increasingly demand systems level thinking. System engineering tools such as object-oriented analysis, object-oriented design (OOA/D) and unified modeling language (UML) are applicable to nanodevices built from biological components, help logically manage the knowledge needed to design them, and help identify useful collaborative relationships for device designers. We demonstrate the utility of these systems engineering tools by reverse engineering an existing molecular device (the bacmid molecular cloning system) using them, and illustrate how object-oriented approaches identify fungible components (objects) in nanodevices in a way that facilitates design of families of related devices, rather than single inventions. We also explore the utility of object-oriented approaches for design of another class of therapeutic nanodevices, vaccines. While they are useful for design of current nanodevices, the power of systems design tools for biomedical nanotechnology will become increasingly apparent as the complexity and sophistication of in vivo nanosystems increases. The nested, hierarchical nature of object-oriented approaches allows treatment of devices as objects in higher-order structures, and so will facilitate concatenation of multiple devices into higher-order, higher-function nanosystems.

Adhesion of Microfabricated Particles on Vascular Endothelium: a Parametric Analysis

Annals of Biomedical Engineering. Jun, 2004  |  Pubmed ID: 15255210

"Smart" drug delivery systems should be selective and effective to ensure drug administration at the right time, at the right dosage, and anywhere in the body. Among the several administration routes and delivery systems that have been proposed, one of the most effective and promising is based on microfabricated particles injected directly into the blood stream. The shape, size, and material properties of the particles can be designed and optimized depending on the specific applications and targets (cell, tissue, or circulating virus). Since the binding affinity of particles to cells is affected by both the binding force and its growth rate with time, it is of great importance to consider the viscous response of the system. In this work, a parametric analysis is presented where the probability of adhesion of a microfabricated particle on the endothelium is expressed as a function of (i) the hemodynamic conditions, (ii) the viscoelastic properties of the particle and targeted cell, and (iii) density of ligands grafted over the particle. Criteria for the optimal design of particles are proposed.

Opportunities for Nanotechnology-based Innovation in Tissue Proteomics

Biomedical Microdevices. Sep, 2004  |  Pubmed ID: 15377833

Within this review we discuss two methodologies used in tissue proteomics, namely mass-spectrometry (MS)-based protein pattern diagnostics and protein microarrays. Further, we describe current goals within the field of tissue proteomics and suggest points of departure for designing nanotechnology-based tools that will enhance the role of molecularly based diagnostics and therapeutics development in clinical medicine.

Abdominal Aortic Aneurysm: Contrast-enhanced US for Missed Endoleaks After Endoluminal Repair

Radiology. Oct, 2004  |  Pubmed ID: 15454621

To evaluate contrast material-enhanced ultrasonography (US) for depiction of endoleaks after endovascular abdominal aortic aneurysm repair (or endovascular aneurysm repair [EVAR]) in patients with aneurysm enlargement and no evidence of endoleak.

Nanotechnology and Tumor Imaging: Seizing an Opportunity

Molecular Imaging. Oct, 2004  |  Pubmed ID: 15802054

Nanoparticles, labeled with a signaling moiety for in vivo imaging, and one or more ligands for molecularly targeted specificity, hold considerable promise in oncology. Nanoparticles can serve as modular platforms, from which a wide variety of highly sensitive and specific imaging agents can be created. For example, many hundreds or thousands of atoms that provide imaging signals, such as radioisotopes, lanthanides, or fluorophores, can be attached to each nanoparticle, to form imaging agents that would provide higher sensitivity that can be obtained from agents based on small molecules. Similarly, many copies of targeted ligands can be attached to nanoparticles to markedly increase specific binding. Drugs or therapeutic isotopes can be added to create multifunctional nanoparticles. Appropriately labeled and targeted nanoparticles could lead to a paradigm change in which cancer detection, diagnosis, and therapy are combined in a single molecular complex.

Allelic Genes Involved in Artery Compliance and Susceptibility to Sporadic Abdominal Aortic Aneurysm

The Journal of Steroid Biochemistry and Molecular Biology. Dec, 2004  |  Pubmed ID: 15698546

Vascular smooth muscle cells (VSMCs) synthesize elastin (ELN), major protein of aortic tunica media which confers strength and elasticity to aortic wall. Protein loss or distortion is typical in aneurysm tunica media. Transforming growth factor beta1 (TGFbeta1) inhibits growth and connective protein expression of abdominal VSMCs cultures. Also, in atherogenic studies, estrogen (but not estrogen plus progestin) treatments inhibit aortic collagen accumulation and elastic loss, risk factors to subsequent aortic enlargement. Therefore, polymorphisms of ELN, estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor (PR) and TGFbeta1 genes and their products may be involved in the abdominal aortic aneurysm (AAA) development. Using PCR-RFLP method, we analyzed ELN RmaI (exon 16), ERalphaPvuII-XbaI (intron 1), ERbetaAluI (exon 8), PR TaqI (intron 7) and TGFbeta1 Bsu36I (-509 bp, promoter) polymorphisms in 324 Caucasian male subjects: 225 healthy controls (mean age 71.20 +/- 6.85 years) and 99 unrelated AAA patients (mean age 69.8 +/- 7.1 years). No difference in ELN, ERalpha, PR and TGFbeta1 allele frequencies was observed in AAA patients versus controls (P > 0.05). However, because possessing at least an ERbetaAluI restriction site was statistically associated to AAA onset (chi(2) = 5.220; OR = 1.82, P < 0.05), ERbeta polymorphism was proposed as genetic determinant in the AAA susceptibility.

Cancer Nanotechnology: Opportunities and Challenges

Nature Reviews. Cancer. Mar, 2005  |  Pubmed ID: 15738981

Nanotechnology is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biology, physics and chemistry. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biological fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer.

Dynamic Model of Biomolecular Diffusion Through Two-dimensional Nanochannels

The Journal of Physical Chemistry. B. Apr, 2005  |  Pubmed ID: 16851842

The molecular diffusion dynamics in unconstrained cases has been studied thoroughly during the last two centuries, leading to the well-known Fick's diffusion laws and Stokes-Einstein equation. More recently, a new impulse to the study of this topic has been provided by the necessity of understanding the behavior of solute particles in the presence of environmental constraints of size comparable to the molecular dimensions. In this work, we investigate the diffusion kinetics of biomolecules, such as bovine serum albumin, interferon, and lysozyme, through microfabricated silicon membranes, having pores of nanometric size in only one dimension, in the range from few to tens of nanometers (the other dimensions are in the mum range). Experimental results show that the diffusion profiles, in some cases, deviate substantially from those predicted by Fick's laws. In light of these results, a new diffusion mathematical model is proposed, which can reasonably explain the phenomenon and, at the same time, recovers the classical diffusion laws in the unconstrained case. Moreover, a physical description, derived from van der Waals equation of state, is presented, and it is compared with the results obtained by the mathematical model.

Release of Biologically Functional Interferon-alpha from a Nanochannel Delivery System

Biomedical Microdevices. Mar, 2005  |  Pubmed ID: 15834523

Metastatic melanoma lesions often are unresectable due to their size and/or location near critical structures. These lesions represent a significant challenge for the oncologist, because radiation therapy and chemotherapy are infrequently successful in halting tumor growth. Of primary concern is the fact that these lesions are usually painful and present a cosmetic dilemma. We hypothesized that the development of a silicon-based nano-device capable of delivering antitumor compounds (e.g. immune modulators), locally, at a constant rate, to the tumor microenvironment could avoid the toxicity of systemic administration and the inconvenience of frequent clinic visits for local injections. Because of its diminutive size, such a device could be implanted using a minimally invasive procedure in close proximity to unresectable melanoma lesions. The current report uses interferon alpha-2b (IFN-alpha) as a model antitumor agent, since it is commonly used in the treatment of malignant melanoma and metastatic renal cell carcinoma. In this system, IFN-alpha is delivered directly to the tumor microenvironment by a novel nanochannel delivery system (nDS) that is capable of zero order release of small molecules. We have demonstrated that the IFN-alpha released from the nDS is functionally active on both host immune cells and a human melanoma cell line in vitro. This drug delivery platform could be used to develop alternative strategies for the treatment of unresectable tumors.

Nanovector Therapeutics

Current Opinion in Chemical Biology. Aug, 2005  |  Pubmed ID: 15967706

An ideal injected therapeutic drug would travel through the vasculature, reach the intended target at full concentration, and there act selectively on diseased cells and tissues only, without creating undesired side effects. Unfortunately, even the best current therapies fail to attain this ideal behavior, by a wide margin. A primary reason is the fact that the target recognition abilities of the current therapeutics molecules are quite limited. Furthermore, the natural defenses of the body present a sequence of formidable obstacles on the drug's pathway to the intended lesion. Requiring any molecule to have sufficient therapeutic efficacy, target recognition specificity, as well as all of the tools required to bypass multiple biological barriers is probably unrealistic. A different approach is to decouple the problem (i.e. employ the drug molecules for their therapeutic action only, and deliver them to the intended site by vectors that can be preferentially concentrated at desired body locations through the concurrent action of multiple targeting mechanisms). These vectors must also be large enough to comprise all the requirements for the evasion of the body defenses, while still sufficiently small so as not to create undesired blockages of even the smallest of blood vessels - and thus, by definition, nanotechnological.

Endovascular Repair of Abdominal Aortic Aneurysms: Analysis of Aneurysm Volumetric Changes at Mid-term Follow-up

Cardiovascular and Interventional Radiology. Jul-Aug, 2005  |  Pubmed ID: 16010509

To evaluate the volumetric changes in abdominal aortic aneurysms (AAA) after endovascular AAA repair (EVAR) in 24 months of follow-up.

Transcutaneous Gases Determination in Diabetic Critical Limb Ischemia

Diabetes Care. Aug, 2005  |  Pubmed ID: 16043766

Endovascular Repair of an Aorto-left Renal Vein Fistula Due to a Ruptured Abdominal Aortic Aneurysm After EVAR

Journal of Endovascular Therapy : an Official Journal of the International Society of Endovascular Specialists. Aug, 2005  |  Pubmed ID: 16048385

To report an unusual late complication of endovascular aneurysm repair: an arteriovenous fistula between the aneurysm sac and a retro-aortic left renal vein following sac expansion due to a type III endoleak.

Medical Nanotechnology: Shortening Clinical Trials and Regulatory Pathways?

BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy. 2005  |  Pubmed ID: 16128604

Nanotechnology, the science of creating structures, devices, and systems with a length scale of approximately 1-100 nanometers, is poised to have a revolutionary effect on biomedical research and clinical science. By operating at the same scale as most biomacromolecules, nanoscale devices can afford a detailed view of the molecules and events that drive cellular systems and that lie at the heart of disease, and thus, nanotechnology can impact the drug discovery, development, and clinical testing of novel pharmaceuticals. Already, nanoscale drug delivery vehicles are in clinical use, but those successes represent just one way in which nanotechnology will prove useful. One promising nanoscale technology under development may provide real-time, in vivo measurements of apoptosis, and thus may afford an early signal of therapeutic efficacy, both in human clinical trials and in preclinical screening. Microfluidic systems, built of nanoscale components, can enable a host of rapid, massively parallel, high-throughput screening systems, while nanoscale sensors in a wide variety of formats are ready to provide multiplexed biochemical and genetic measurements in living systems. These advances could be utilized to shave time and expense from multiple stages of the drug discovery and development effort.

Morphologic Instability and Cancer Invasion

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Oct, 2005  |  Pubmed ID: 16203763

A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue.

The Molecular Analysis of Breast Cancer Utilizing Targeted Nanoparticle Based Ultrasound Contrast Agents

Technology in Cancer Research & Treatment. Dec, 2005  |  Pubmed ID: 16292882

This study was structured to challenge the hypothesis that nano-sized particulates could be molecularly targeted and bound to the prognostic and predictive HER-2/neu cell membrane receptor to elicit detectable changes in ultrasound response from human breast cancer cells. SKBR-3 human breast cancer cells were enlisted to test the efficacy of the particle conjugation strategy used in this study and ultimately, to provide conclusive remarks regarding the validity of the stated hypothesis. A characterization-mode ultrasound (CMUS) system was used to apply a continuum mechanics based, two-step inversion algorithm to reconstruct the mechanical material properties of four cell/agarose test conditions upon three independent test samples. The four test conditions include: Herceptin conjugated iron oxide nanoparticles bound to cells (HER-con), Herceptin bound to cells (HER), iso-type matched antibody conjugated iron oxide nanoparticles bound to cells (ISO-con), and Cold Flow Buffer mixed with agarose (CFB). The statistical analysis of these ultrasound results supported the ability to differentiate between HER-2/neu positive SKBR-3 cells that have been successfully tagged with Herceptin(R) conjugated iron oxide particles to those that have not demonstrated particle binding. These findings serve as promising proof-of-concept data for the development of a quantitative histopathologic evaluation tool directed towards both in situ and in vivo applications. The ultimate goal of this research is to exploit the molecular expression of the HER-2/neu protein to offer rapid, quantitative ultrasound information concerning the malignancy rating of human breast tissue employing tumor targeting nanoparticle based ultrasound contrast agents. When fully developed, this could potentially help 32,000-63,000 women efficiently find their proper treatment strategy to fight and win their battle against breast cancer.

Tailoring Width of Microfabricated Nanochannels to Solute Size Can Be Used to Control Diffusion Kinetics

Journal of Controlled Release : Official Journal of the Controlled Release Society. Jan, 2005  |  Pubmed ID: 15653139

Top-down microfabrication techniques were used to create silicon-based membranes consisting of arrays of uniform channels having a width as small as 7 nm. The measurement of diffusion kinetics of solutes across these membranes under sink conditions reveals non-Fickian behavior as the nanopore width approaches the hydrodynamic diameter of the solute. Zero-order diffusion of interferon is observed at channel width of 20 nm, and the same phenomenon occurs with albumin and 13-nm-wide channels, whereas Fickian diffusion kinetics is seen at 26 nm and larger pore sizes. A prototypical drug delivery device is described that is fitted with a 13-nm nanopore membrane and loaded with radio-labeled BSA. Following subcutaneous implantation in rats, diffusion from the device provided prolonged levels of BSA in the blood. Such a nonmechanical device offers important advantages in drug delivery applications, including zero-order release and high loading capacity.

Type II Lumbar Endoleaks: Hemodynamic Differentiation by Contrast-enhanced Ultrasound Scanning and Influence on Aneurysm Enlargement After Endovascular Aneurysm Repair

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Jan, 2005  |  Pubmed ID: 15696037

The objective of this study was to differentiate type II lumbar endoleaks on the basis of dynamic features identified by contrast-enhanced ultrasound scanning (CUS) and to evaluate the role of this differentiation in detecting abdominal aortic aneurysm (AAA) enlargement > or =1 mL/mo.

Nanotechnology-enabled Medicine

Discovery Medicine. Aug, 2005  |  Pubmed ID: 20704873

Extract: Approximately one person a minute dies of cancer in the United States. Normalized per population size, this corresponds to a current mortality rate that is essentially identical to what it was in 1950 -- a very counterintuitive finding, given the exceptional progress recorded in the fundamental scientific understanding of malignant disease in the last 50 years. Dominant among the reasons for the unsatisfactory progress in the treatment of cancer is our general inability to treat metastatic colonies, when surgical intervention and radiation therapy are no longer available options. Systemic injection with chemical and biological agents is then the choice, with the yet-unsolved problem of selectivity in the intervention on cancer cell population, or the ability to kill cancer without causing intolerable levels of unwanted collateral effects on the patient. This treatment selectivity problem breaks down into three major, related components: the ability for the therapeutic substances to reach the cancer lesion, to recognize it as the target of its action, and to perform the therapeutic intervention solely at the site of the lesion. Many approaches have been developed to address these questions, and have met with different degrees of success. Particularly promising are the recent clinical advances recorded in the field of the so-called molecularly targeted therapies, which intervene in an exquisitely selective fashion on cancer-associated biological features, such as mutations in the receptor of epidermal growth factor in cancers of epithelial origin, or the activation of the BCR-ABL tyrosine kinase pathway in chronic myelogenous leukemia.

Nanotechnologies for Biomolecular Detection and Medical Diagnostics

Current Opinion in Chemical Biology. Feb, 2006  |  Pubmed ID: 16418011

Nanotechnology-based platforms for the high-throughput, multiplexed detection of proteins and nucleic acids in heretofore unattainable abundance ranges promise to bring substantial advances in molecular medicine. The emerging approaches reviewed in this article, with reference to their diagnostic potential, include nanotextured surfaces for proteomics, a two-particle sandwich assay for the biological amplification of low-concentration biomolecular signals, and silicon-based nanostructures for the transduction of molecular binding into electrical and mechanical signals, respectively.

Duodenal Duplication Cyst Causing Severe Pancreatitis: Imaging Findings and Pathological Correlation

World Journal of Gastroenterology : WJG. Mar, 2006  |  Pubmed ID: 16570360

We here report a case of a 18-year-old man with a history of recurrent abdominal pain and a previous episode of severe acute pancreatitis. Abdominal ultrasonography, contrast enhanced multislice computer tomography, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography and magnetic resonance imaging demonstrated a cystic mass lesion. Only on delayed phase magnetic resonance images after Gadolinium-BOPTA injection, it was possible to demonstrate the lesionos relationship with the biliary tree, differentiating the lesion from intraluminal duodenal diverticulum, and to achieve the diagnosis of duodenal duplication cyst, a recognized rare cause of acute pancreatitis. The diagnosis was confirmed by histology.

Laparoscopy-assisted Abdominal Aortic Aneurysm Repair: Early and Middle-term Results of a Consecutive Series of 122 Cases

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Apr, 2006  |  Pubmed ID: 16616222

Endoaneurysmorrhaphy with intraluminal graft placement, described by Creech, is the gold standard for abdominal aortic aneurysm (AAA) repair. Endovascular aneurysm repair has gained popularity for its minimal invasiveness and satisfying short-term results, but there are still many concerns about the long-term success of the procedure. Since 1998, laparoscopic surgery has been proposed for AAA treatment. The potential benefits of a minimally invasive procedure reproducing the endoaneurysmorrhaphy results over time have been advocated. In our experience, hand-assisted laparoscopic surgery (HALS) has been routinely used for the open-surgery transperitoneal/retroperitoneal approach and for endovascular aneurysm repair. After 4 years, we are able to define the early and middle-term results of such laparoscopic-assisted treatment.

Controlled-release Microchips

Expert Opinion on Drug Delivery. May, 2006  |  Pubmed ID: 16640498

Efficient drug delivery remains an important challenge in medicine: continuous release of therapeutic agents over extended time periods in accordance with a predetermined temporal profile; local delivery at a constant rate to the tumour microenvironment to overcome much of the systemic toxicity and to improve antitumour efficacy; improved ease of administration, and increasing patient compliance required are some of the unmet needs of the present drug delivery technology. Microfabrication technology has enabled the development of novel controlled-release microchips with capabilities not present in the current treatment modalities. In this review, the current status and future prospects of different types of controlled-release microchips are summarised and analysed with reference to microneedle-based microchips, as well as providing an in-depth focus on microreservoir-based and nanoporous microchips.

Selective Binding and Enrichment for Low-molecular Weight Biomarker Molecules in Human Plasma After Exposure to Nanoporous Silica Particles

Proteomics. Jun, 2006  |  Pubmed ID: 16645983

The present manuscript describes a biomarker capturing strategy based on nanoporous silica particles. The method is shown to enrich the yield of species in the low-molecular weight proteome (LMWP), allowing detection of small peptides in the low-nanomolar range. Plasma samples were exposed to the silica particles, and the captured molecular species were profiled using MALDI-TOF. Mass spectra of the silica-treated human plasma samples showed a significant enrichment in MALDI-TOF protein profiles in the LMWP. Preliminary results indicated good level of reproducibility in plasma profiles with CVs on peak heights ranging from 6.3 to 14.7%. The MALDI-TOF signature changed significantly when the characteristics of the nanoporous silica were altered. The facile sample pretreatment before MS analysis, coupled to the potential for tailoring the surface properties of silica supports, hold promise for improving the recovery of low-abundance serum biomarkers.

Nanoporous Surfaces As Harvesting Agents for Mass Spectrometric Analysis of Peptides in Human Plasma

Journal of Proteome Research. May, 2006  |  Pubmed ID: 16674117

Silica-based nanoporous surfaces have been developed in order to capture low molecular weight peptides from human plasma. Harvested peptides were subjected to mass spectrometric analysis by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as a means of detecting and assessing the bound molecules. Peptide profiles consisting of about 70 peaks in the range 800-10,000 m/z were generated. The method could allow detection of small peptides at ng/mL concentration levels, either in standard solutions or in plasma. The same molecular cutoff effect was observed for mixtures of standard proteins and peptides incubated with silicon-based nanoporous surfaces.

Fractionation of Serum Components Using Nanoporous Substrates

Bioconjugate Chemistry. May-Jun, 2006  |  Pubmed ID: 16704202

Numerous previously uncharacterized molecules resident within the low molecular weight circulatory proteome may provide a picture of the ongoing pathophysiology of an organism. Recently, proteomic signatures composed of low molecular weight molecules have been identified using mass spectrometry combined with bioinformatic algorithms. Attempts to sequence and identify the molecules that underpin the fingerprints are currently underway. The finding that many of these low molecular weight molecules may exist bound to circulating carrier proteins affords a new opportunity for fractionation and separation techniques prior to mass spectrometry-based analysis. In this study we demonstrate a method whereby nanoporous substrates may be used for the facile and reproducible fractionation and selective binding of the serum-based biomarker material, including subcellular proteins found within the serum. Aminopropyl-coated nanoporous silicon, when exposed to serum, can deplete serum of proteins and yield a serum with a distinct, altered MS profile. Additionally, aminopropyl-coated, nanoporous controlled-pore glass beads are able to bind a subset of serum proteins and release them with stringent elution. The eluted proteins have distinct MS profiles, gel electrophoresis profiles, and differential peptide sequence identities, which vary based on the size of the nanopores. These material surfaces could be employed in strategies for the harvesting and preservation of labile and carrier-protein-bound molecules in the blood.

Transcutaneous Oxygen and Carbon Dioxide Levels with Iloprost Administration in Diabetic Critical Limb Ischemia

Vascular and Endovascular Surgery. Aug-Sep, 2006  |  Pubmed ID: 16959724

Iloprost, a prostacyclin analogue, is a treatment option for surgically unsuitable diabetic chronic critical limb ischemia (CLI), although its outcome is difficult to be anticipated clinically. Whether transcutaneous (tc) oxygen tension (PO2) predicts the response to iloprost in diabetic CLI is unclear at this point and, in that same context, the prognostic role of tc carbon dioxide tension (PCO2), another ischemia-sensitive parameter, is unknown. Supine and dependent tcPO2 and tcPCO2 were measured at baseline and after 4 weeks of iloprost treatment in 31 limbs of 26 type-2 diabetic angiopathies with CLI not amenable to surgery. Success was defined as pain relief and significant reduction of analgesics. Clinical outcome was stratified by baseline tcPO2 and tcPCO2 tertiles, and likelihood ratios (LR) quantified the increase from pretest chances given a certain result. Iloprost succeeded in 16 (52%) and failed in 15 limbs (48%) and post-treatment tcPO2 followed a parallel course. Failures increased by ascending baseline tcPCO2 and descending tcPO2 tertiles; successes behaved specularly. Predictions of failure based on elevated tcPCO2 (>53 mm Hg) were more efficient than relying on depressed tcPO2 (LR 10.7 vs 3.6); success was almost certain when tcPO2 was >23 mm Hg (LR = 17.8). Dependent determinations were less useful than supine measurements for prognostic use. Elevated tcPCO2 predicted failure efficiently and high tcPO2 was a useful prognostic tool for success of iloprost, suggesting that their combined use may allow better prognostic stratification and improve the therapeutic approach to diabetic CLI.

Nan'o.tech.nol'o.gy N

Nature Nanotechnology. Oct, 2006  |  Pubmed ID: 18654128

Multiscale Modeling of Protein Transport in Silicon Membrane Nanochannels. Part 2. From Molecular Parameters to a Predictive Continuum Diffusion Model

Biomedical Microdevices. Dec, 2006  |  Pubmed ID: 17003963

Transport and surface interactions of proteins in nanopore membranes play a key role in many processes of biomedical importance. Although the use of porous materials provides a large surface-to-volume ratio, the efficiency of the operations is often determined by transport behavior, and this is complicated by the fact that transport paths (i.e., the pores) are frequently of molecular dimensions. Under these conditions, a protein diffusion can be slower than predicted from Fick law. The main contribution of this paper is the development of a mathematical model of this phenomenon, whose parameters are computed via molecular modeling, as described Part 1. Our multiscale modeling methodology, validated by using experimental results related to the diffusion of lysozyme molecules, constitutes an "ab initio" recipe, for which no experimental data are needed to predict the protein release, and can be tailored in principle to match any different protein and any different surface, thus filling gap between the nano and the macroscale.

Multiscale Modeling of Protein Transport in Silicon Membrane Nanochannels. Part 1. Derivation of Molecular Parameters from Computer Simulations

Biomedical Microdevices. Dec, 2006  |  Pubmed ID: 17003964

We report in this account our efforts in the development of a novel multiscale simulation tool for integrated nanosystem design, analysis and optimization based on a three-tiered modeling approach consisting of (i) molecular models, (ii) atomistic molecular dynamics simulations, and (iii) dynamical models of protein transport at the continuum scale. In this work we used molecular simulations for the analysis of lysozyme adsorption on a pure silicon surface. The molecular modeling procedures adopted allowed (a) to elucidate the specific mechanisms of interaction between the biopolymer and the silicon surface, and (b) to derive molecular energetic and structural parameters to be employed in the formulation of a mathematical model of diffusion through silicon-based nanochannel membranes, thus filling the existing gap between the nano--and the macroscale.

Mathematical Modeling of Cancer Progression and Response to Chemotherapy

Expert Review of Anticancer Therapy. Oct, 2006  |  Pubmed ID: 17069522

The complex, constantly evolving and multifaceted nature of cancer has made it difficult to identify unique molecular and pathophysiological signatures for each disease variant, consequently hindering development of effective therapies. Mathematical modeling and computer simulation are tools that can provide a robust framework to better understand cancer progression and response to chemotherapy. Successful therapeutic agents must overcome biological barriers occurring at multiple space and time scales and still reach targets at sufficient concentrations. A multiscale computer simulator founded on the integration of experimental data and mathematical models can provide valuable insights into these processes and establish a technology platform for analyzing the effectiveness of chemotherapeutic drugs, with the potential to cost-effectively and efficiently screen drug candidates during the drug-development process.

Polymorphic Analysis of the Matrix Metalloproteinase-9 Gene and Susceptibility to Sporadic Abdominal Aortic Aneurysm

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. Jun, 2007  |  Pubmed ID: 17223007

Abdominal aortic aneurysm (AAA) has a multifactorial aetiology and the importance of genetic components is getting increasing interest. Alteration in the structure of the vascular extracellular matrix has been described in AAA. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins which alter the vessel wall stability. We evaluated two different polymorphisms, a CA repeat and a cytosine to thymidine transition in the promoter sequence of MMP-9 gene for frequency in 146 patients with AAA. We compared the results with those of 156 healthy subjects. No difference was found in the allelic distribution of either polymorphisms. We therefore found no evidence that MMP-9 is a marker of susceptibility for AAA.

Cyclooxygenase-2 Directly Induces MCF-7 Breast Tumor Cells to Develop into Exponentially Growing, Highly Angiogenic and Regionally Invasive Human Ductal Carcinoma Xenografts

Anticancer Research. Mar-Apr, 2007  |  Pubmed ID: 17465194

Based on our studies demonstrating first time evidence that the cyclooxygenase-2 (Cox-2) enzyme is abundant within invasive human breast tumors, we developed a clonally derived human breast tumor cell clone designated as MCF-7/Cox-2 Clone 10 by transfection of human Cox-2 cDNA into slow growing, Cox-2 null, non-metastatic MCF-7 human breast tumor cells. The present studies evaluated the biological characteristics of the MCF-7/Cox-2 Clone 10 human breast tumors compared to the characteristics of MCF-7/empty vector control tumors when grown in vivo following injection of 5x10(6) tumor cells into mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice implanted with slow release 17-beta estradiol pellets. At 60 days after tumor cell injection, MCF-7/Cox-2 Clone 10 human breast tumors were 4-fold greater (p < 0.01) in volume than MCF-7/empty vector control tumors. MCF-7/Cox-2 Clone 10 human breast tumor xenografts were highly angiogenic based on histological observation of large-bore blood vessels, which was confirmed by immunohistochemical staining with anti-CD-31 antibody and quantitation of mean vessel density. MCF-7/Cox-2 Clone 10 human breast tumor cells were present within regional lymph nodes adjacent to mammary fat pads with their local invasion confirmed by Western blotting of Cox-2-protein. This unique Cox-2-dependent breast tumor model rapidly produces large, angiogenic, locally invasive human breast tumor xenografts in mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice at 42-60 days which recapitulate human breast ductal carcinomas. This unique model may be invaluable as a means to evaluate preclinical safety and efficacy of novel adjuvant therapies for women with metastastic breast cancer including prostanoid receptor antagonists, newly developed anti-angiogenic therapies, as well as other novel approaches for targeting and destruction of human breast tumors and their vasculature.

Localization to Atherosclerotic Plaque and Biodistribution of Biochemically Derivatized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) Contrast Particles for Magnetic Resonance Imaging (MRI)

Biomedical Microdevices. Oct, 2007  |  Pubmed ID: 17562181

Annexin V recognizes apoptotic cells by specific molecular interaction with phosphatidyl serine, a lipid that is normally sequestered in the inner leaflet of the cell membrane, but is translocated to the outer leaflet in apoptotic cells, such as foam cells of atherosclerotic plaque. Annexin V could potentially deliver carried materials (such as superparamagnetic contrast agents for magnetic resonance imaging) to sites containing apoptotic cells, such as high grade atherosclerotic lesions, so we administered biochemically-derivatized (annexin V) superparmagnetic iron oxide particles (SPIONs) parenterally to two related rabbit models of human atherosclerosis. We observe development of negative magnetic resonance imaging (MRI) contrast in atheromatous lesions and but not in healthy artery. Vascular targeting by annexin V SPIONs is atheroma-specific (i.e., does not occur in healthy control rabbits) and requires active annexin V decorating the SPION surface. Targeted SPIONs produce negative contrast at doses that are 2,000-fold lower than reported for non-specific atheroma uptake of untargeted superparamagnetic nanoparticles in plaque in the same animal model. Occlusive and mural plaques are differentiable. While most of the dose accumulates in liver, spleen, kidneys and bladder, annexin V SPIONs also partition rapidly and deeply into early apoptotic foamy macrophages in plaque. Contrast in plaque decays within 2 months, allowing MRI images to be replicated with a subsequent, identical dose of annexin V SPIONs. Thus, biologically targeted superparamagnetic contrast agents can contribute to non-invasive evaluation of cardiovascular lesions by simultaneously extracting morphological and biochemical data from them.

Antibiological Barrier Nanovector Technology for Cancer Applications

Expert Opinion on Drug Delivery. Jul, 2007  |  Pubmed ID: 17683250

The advent of sophisticated drug delivery strategies for cancer applications has inundated the scientific and clinical community with new tactics and approaches such as molecular targeting, nanotechnology-based methods and personalized therapies. Unfortunately, the clinical impact has been moderate at best, falling significantly short from revolutionizing existing chemotherapeutic methodologies. To this day, a cancer patient has a higher probability of receiving traditional systemically administered drugs than a more sophisticated targeted or nanotechnology-based therapeutic. This is not a reflection upon the novelty or quality of the technologies, but an indication of opportunity for a new approach that offers the realisation of the full potential of these scientific advances. This approach acknowledges the significance of the numerous biological barriers presented in the human body and their sequential nature. It is then recommended that computational mathematical tools are used to predict which nanovectors, surface modifications, therapeutic agents and penetration enhancers to use for a multi-stage drug delivery strategy. An approach where several stages of micro-/nano-vectors are nested within each other and delivered to overcome specific biological barriers to ultimately release a concentrated dose of a therapeutic payload at the intended lesion site. This novel, multi-stage strategy enables efficient localised delivery of chemotoxic drugs that may lead to significant improvements in therapy efficacy, reduced systemic toxicity and decreased total amount of injected drugs.

Biomedical Nanotechnology for Cancer

The Medical Clinics of North America. Sep, 2007  |  Pubmed ID: 17826110

Nanotechnology may hold the key to controlling many devastating diseases. In the fight against the pain, suffering, and death due to cancer, nanotechnology will allow earlier diagnosis and even prevention of malignancy at premalignant stages, in addition to providing multimodality treatment not possible with current conventional techniques. This review discusses nanotechnology already used in diagnostic and therapeutic applications for cancer. Also addressed are theoretic and evolving uses of nanotechnology, including multifunctional nanoparticles for imaging and therapy, nanochannel implants for controlled release of drugs, nanoscale devices for evaluation of proteomics and genomics, and diagnostic techniques that take advantage of physical changes in diseased tissue.

Osmotic Pressure Beyond Concentration Restrictions

The Journal of Physical Chemistry. B. Oct, 2007  |  Pubmed ID: 17880133

Osmosis is a fundamental physical process that involves the transit of solvent molecules across a membrane separating two liquid solutions. Osmosis plays a role in many biological processes such as fluid exchange in animal cells (Cell Biochem. Biophys. 2005, 42, 277-345;1 J. Periodontol. 2007, 78, 757-7632) and water transport in plants. It is also involved in many technological applications such as drug delivery systems (Crit. Rev. Ther. Drug. 2004, 21, 477-520;3 J. Micro-Electromech. Syst. 2004, 13, 75-824) and water purification. Extensive attention has been dedicated in the past to the modeling of osmosis, starting with the classical theories of van't Hoff and Morse. These are predictive, in the sense that they do not involve adjustable parameters; however, they are directly applicable only to limited regimes of dilute solute concentrations. Extensions beyond the domains of validity of these classical theories have required recourse to fitting parameters, transitioning therefore to semiempirical, or nonpredictive models. A novel approach was presented by Granik et al., which is not a priori restricted in concentration domains, presents no adjustable parameters, and is mechanistic, in the sense that it is based on a coupled diffusion model. In this work, we examine the validity of predictive theories of osmosis, by comparison with our new experimental results, and a meta-analysis of literature data.

Physicochemically Modified Silicon As a Substrate for Protein Microarrays

Biomaterials. Jan, 2007  |  Pubmed ID: 16987550

Reverse phase protein microarrays (RPMA) enable high throughput screening of posttranslational modifications of important signaling proteins within diseased cells. One limitation of protein-based molecular profiling is the lack of a PCR-like intrinsic amplification system for proteins. Enhancement of protein microarray sensitivities is an important goal, especially because many molecular targets within patient tissues are of low abundance. The ideal array substrate will have a high protein-binding affinity and low intrinsic signal. To date, nitrocellulose-coated glass has provided an effective substrate for protein binding in the microarray format when using chromogenic detection systems. As fluorescent systems, such as quantum dots, are explored as potential reporter agents, the intrinsic fluorescent properties of nitrocellulose-coated glass slides limit the ability to image microarrays for extended periods of time where increases in net sensitivity can be attained. Silicon, with low intrinsic autofluorescence, is being explored as a potential microarray surface. Native silicon has low binding potential. Through titrated reactive ion etching (RIE), varying surface areas have been created on silicon in order to enhance protein binding. Further, via chemical modification, reactive groups have been added to the surfaces for comparison of relative protein binding. Using this combinatorial method of surface roughening and surface coating, 3-aminopropyltriethoxysilane (APTES) and mercaptopropyltrimethoxysilane (MPTMS) treatments were shown to transform native silicon into a protein-binding substrate comparable to nitrocellulose.

Nanogeometry: Beyond Drug Delivery

Nature Nanotechnology. Mar, 2008  |  Pubmed ID: 18654480

Mesoporous Silicon Particles As a Multistage Delivery System for Imaging and Therapeutic Applications

Nature Nanotechnology. Mar, 2008  |  Pubmed ID: 18654487

Many nanosized particulate systems are being developed as intravascular carriers to increase the levels of therapeutic agents delivered to targets, with the fewest side effects. The surface of these carriers is often functionalized with biological recognition molecules for specific, targeted delivery. However, there are a series of biological barriers in the body that prevent these carriers from localizing at their targets at sufficiently high therapeutic concentrations. Here we show a multistage delivery system that can carry, release over time and deliver two types of nanoparticles into primary endothelial cells. The multistage delivery system is based on biodegradable and biocompatible mesoporous silicon particles that have well-controlled shapes, sizes and pores. The use of this system is envisioned to open new avenues for avoiding biological barriers and delivering more than one therapeutic agent to the target at a time, in a time-controlled fashion.

Seven Challenges for Nanomedicine

Nature Nanotechnology. May, 2008  |  Pubmed ID: 18654511

Design Maps for Nanoparticles Targeting the Diseased Microvasculature

Biomaterials. Jan, 2008  |  Pubmed ID: 17936897

Systemically administered ligand-coated nanoparticles have been proved to recognize biological targets in-vivo. This can provide breakthrough solutions for the early detection, imaging and cure of diseases. In cardiovascular applications, nanoparticles have been targeted directly to the diseased vasculature, and such delivery approach is becoming increasingly popular even in cancer research, supported by the growing body of evidences on the biological differences between normal and tumor vasculature. This work focuses on the optimal design of nanoparticles for vascular targeting throughout mathematical modeling. Such nanoparticles should be engineered so as to recognize specifically and adhere firmly to the diseased vessel walls withstanding the hydrodynamic dislodging forces and control uptake by the endothelial cells. A stochastic approach for predicting the adhesion strength of nanoparticles to a cell layer under flow has been coupled to a mathematical model for the receptor-mediated endocytosis of nanoparticles. The main geometrical, biophysical and biological parameters governing both events have been identified and their relative importance highlighted. Three different states for the particle/cell system have been predicted, namely no adhesion, adhesion with no endocytosis and adhesion with endocytosis, based upon the geometrical and biophysical properties of the particle and the biological conditions at the site of adhesion. Design maps have been generated to be used as a preliminary reference for choosing the properties of the nanoparticle as a function of physiological parameters, as the wall shear stress and the receptors surface density, at the site of desired adhesion within the target vasculature.

The Mathematical Engines of Nanomedicine

Small (Weinheim an Der Bergstrasse, Germany). Jan, 2008  |  Pubmed ID: 18165947

The Transport of Nanoparticles in Blood Vessels: the Effect of Vessel Permeability and Blood Rheology

Annals of Biomedical Engineering. Feb, 2008  |  Pubmed ID: 18172768

The longitudinal transport of nanoparticles in blood vessels has been analyzed with blood described as a Casson fluid. Starting from the celebrated Taylor and Aris theory, an explicit expression has been derived for the effective longitudinal diffusion (Deff) depending non-linearly on the rheological parameter xi(c), the ratio between the plug and the vessel radii; and on the permeability parameters pi and omega, related to the hydraulic conductivity and pressure drop across the vessel wall, respectively. An increase of xi(c) or pi has the effect of reducing Deff, and thus both the rheology of blood and the permeability of the vessels may constitute a physiological barrier to the intravascular delivery of nanoparticles.

Fast Membrane Osmometer As Alternative to Freezing Point and Vapor Pressure Osmometry

Analytical Chemistry. Apr, 2008  |  Pubmed ID: 18315010

Osmometry is an essential technique for solution analysis and the investigation of chemical and biological phenomena. Commercially available osmometers rely on the measurements of freezing point, vapor pressure, and osmotic pressure of solutions. Although vapor pressure osmometry (VPO) and freezing point osmometry (FPO) can perform rapid and inexpensive measurements, they are indirect techniques, which rely on thermodynamic assumptions, which limit their applicability. While membrane osmometry (MO) provides a potentially unlimited direct measurement of osmotic pressure and solution osmolality, the conventional technique is often time-consuming and difficult to operate. In the present work, a novel membrane osmometer is presented. The instrument significantly reduces the conventional MO measurement time and is not subject to the limitations of VPO and FPO. For this paper, the osmotic pressure of aqueous sucrose solutions was collected in a molality range 0-5.5, by way of demonstration of the new instrument. When compared with data found in the literature, the experimental data were generally in good agreement. However, differences among results from the three techniques were observed.

Nanoncology

Tumori. Mar-Apr, 2008  |  Pubmed ID: 18564607

Evaluation of Serial Changes of Pancreatic Branch Duct Intraductal Papillary Mucinous Neoplasms by Follow-up with Magnetic Resonance Imaging

Cancer Imaging : the Official Publication of the International Cancer Imaging Society. 2008  |  Pubmed ID: 19042176

The purpose of this study was to clarify the biological behaviour of branch duct type intraductal papillary mucinous neoplasm (IPMN) by evaluating serial changes at magnetic resonance cholangiopancreatography (MRCP). Fifty-two patients with a diagnosis of branch duct IPMN based on either endoscopic retrograde cholangiopancreatography (ERCP) (9/52) and/or MRCP examination (43/52), were followed up over a mean period of 31.2 months (range 12-108). All imaging data were retrospectively reviewed by two radiologists in order to evaluate serial changes in the maximum diameter of the cystic lesion, in the presence of main pancreatic duct dilatation (MPD), and filling defects within the lesion. Statistical analysis was performed using the Fisher exact probability test. Serial MRCP proved growth in seven cases. In two cases the size decreased; in the remaining 43 there was no change in size. Lesions greater than 3 cm at presentation and the presence of MPD dilatation or filling defects at imaging were most likely to grow. Only 2/37 cystic lesions less than 3 cm in diameter grew in size over the period of observation. No cystic lesion showed changes in morphology and structure. Branch duct IPMNs smaller than 3 cm, without associated filling defects, tend to be stable, making 'watch and wait' management possible.

The Margination Propensity of Spherical Particles for Vascular Targeting in the Microcirculation

Journal of Nanobiotechnology. 2008  |  Pubmed ID: 18702833

ABSTRACT: The propensity of circulating particles to drift laterally towards the vessel walls (margination) in the microcirculation has been experimentally studied using a parallel plate flow chamber. Fluorescent polystyrene particles, with a relative density to water of just 50 g/cm3comparable with that of liposomal or polymeric nanoparticles used in drug delivery and bio-imaging, have been used with a diameter spanning over three order of magnitudes from 50 nm up to 10 mum. The number n approximately s MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafmOvayLbaGaadaWgaaWcbaGaem4Camhabeaaaaa@2EB4@ of particles marginating per unit surface have been measured through confocal fluorescent microscopy for a horizontal chamber, and the corresponding total volume V approximately s MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafmOvayLbaGaadaWgaaWcbaGaem4Camhabeaaaaa@2EB4@ of particles has been calculated. Scaling laws have been derived as a function of the particle diameter d. In horizontal capillaries, margination is mainly due to the gravitational force for particles with d > 200 nm and V approximately s MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafmOvayLbaGaadaWgaaWcbaGaem4Camhabeaaaaa@2EB4@ increases with d4; whereas for smaller particles V approximately s MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafmOvayLbaGaadaWgaaWcbaGaem4Camhabeaaaaa@2EB4@ increases with d3. In vertical capillaries, since the particles are heavier than the fluid they would tend to marginate towards the walls in downward flows and towards the center in upward flows, with V approximately s MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGafmOvayLbaGaadaWgaaWcbaGaem4Camhabeaaaaa@2EB4@ increasing with d9/2. However, the margination in vertical capillaries is predicted to be much smaller than in horizontal capillaries. These results suggest that, for particles circulating in an external field of volume forces (gravitation or magnetic), the strategy of using larger particles designed to marginate and adhere firmly to the vascular walls under flow could be more effective than that of using particles sufficiently small (d < 200 nm) to hopefully cross a discontinuous endothelium.

Multistage Mesoporous Silicon-based Nanocarriers: Biocompatibility with Immune Cells and Controlled Degradation in Physiological Fluids

Controlled Release Newsletter / Controlled Release Society. Jan, 2008  |  Pubmed ID: 21853161

Mitotic Trafficking of Silicon Microparticles

Nanoscale. Nov, 2009  |  Pubmed ID: 20644846

Multistage carriers were recently introduced by our laboratory, with the concurrent objectives of co-localized delivery of multiple therapeutic agents, the "theranostic" integration of bioactive moieties with imaging contrast, and the selective, potentially personalized bypassing of the multiplicity of biological barriers that adversely impact biodistribution of vascularly injected particulates. Mesoporous ("nanoporous") silicon microparticles were selected as primary carriers in multi-stage devices, with targets including vascular endothelia at pathological lesions. The objective of this study was to evaluate biocompatibility of mesoporous silicon microparticles with endothelial cells using in vitro assays with an emphasis on microparticle compatibility with mitotic events. We observed that vascular endothelial cells, following internalization of silicon microparticles, maintain cellular integrity, as demonstrated by cellular morphology, viability and intact mitotic trafficking of vesicles bearing silicon microparticles. The presence of gold or iron oxide nanoparticles within the porous matrix did not alter the cellular uptake of particles or the viability of endothelial cells subsequent to engulfment of microparticles. Endothelial cells maintained basal levels of IL-6 and IL-8 release in the presence of silicon microparticles. This is the first study that demonstrates polarized, ordered partitioning of endosomes based on tracking microparticles. The finding that mitotic sorting of endosomes is unencumbered by the presence of nanoporous silicon microparticles advocates the use of silicon microparticles for biomedical applications.

Intravascular Delivery of Particulate Systems: Does Geometry Really Matter?

Pharmaceutical Research. Jan, 2009  |  Pubmed ID: 18712584

In cancer therapy and imaging, the systemic passive delivery of particulate systems has relied on the enhanced permeability and retention (EPR) effect: sufficiently small particles can cross the endothelial fenestrations and accumulate in the tumor parenchyma. The vast majority of man-made particulates exhibit a spherical shape as a result of surface energy minimization during their synthesis. The advent of phage display libraries, which are revealing the extraordinary molecular diversity of endothelial cells, and the development of processes for fabricating particles with shapes other than spherical are opening the path to new design solutions for systemically administered targeted particulates. In this paper, the role of particle geometry (i.e., size and shape) is discussed at the tissue and cellular scales. Emphasis is placed on how the synergistic effect of particle geometry and molecular targeting can enhance the specificity of delivery. The intravascular delivery process has been broken into three events: margination, firm adhesion and control of internalization. Predictions from mathematical models and observations from in-vitro experiments were used to show the relevance of particle geometry in systemic delivery. Rational design of particulate systems should consider, beside the physico-chemical properties of the surface coatings, geometrical features as size and shape. The integration of mathematical modeling with in-vitro and in-vivo testing provides the tools for establishing a rational design of nanoparticles.

Predicting Drug Pharmacokinetics and Effect in Vascularized Tumors Using Computer Simulation

Journal of Mathematical Biology. Apr, 2009  |  Pubmed ID: 18781304

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC(50) concentration). For doxorubicin the effect of hypoxia and hypoglycemia ("nutrient effect") is isolated and shown to further increase cell inhibition heterogeneity and double the IC(50), both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment.

Laparoscopic-assisted Treatment of Abdominal Aortic Aneurysm Requiring Suprarenal Cross-clamping

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Nov, 2009  |  Pubmed ID: 19878783

Hand-assisted laparoscopic surgery (HALS) was previously employed to treat patients with infrarenal abdominal aortic aneurysm (IAAA). The use of HALS for juxtarenal abdominal aortic aneurysm (JAAA) has never been validated. In this study, we report our experience with this technique to demonstrate its feasibility and prove its safety in dealing with JAAA.

Nanomedicine--challenge and Perspectives

Angewandte Chemie (International Ed. in English). 2009  |  Pubmed ID: 19142939

The application of nanotechnology concepts to medicine joins two large cross-disciplinary fields with an unprecedented societal and economical potential arising from the natural combination of specific achievements in the respective fields. The common basis evolves from the molecular-scale properties relevant to the two fields. Local probes and molecular imaging techniques allow surface and interface properties to be characterized on a nanometer scale at predefined locations, while chemical approaches offer the opportunity to elaborate and address surfaces, for example, for targeted drug delivery, enhanced biocompatibility, and neuroprosthetic purposes. However, concerns arise in this cross-disciplinary area about toxicological aspects and ethical implications. This Review gives an overview of selected recent developments and applications of nanomedicine.

Application of Physicochemically Modified Silicon Substrates As Reverse-phase Protein Microarrays

Journal of Proteome Research. Mar, 2009  |  Pubmed ID: 19170514

Physicochemically modified silicon substrates can provide a high quality alternative to nitrocellulose-coated glass slides for use in reverse-phase protein microarrays. Enhancement of protein microarray sensitivities is an important goal, especially because molecular targets within patient tissues exist in low abundance. The ideal array substrate has a high protein binding affinity and low intrinsic background signal. Silicon, which has low intrinsic autofluorescence, is being explored as a potential microarray surface. In a previous paper ( Nijdam , A. J. ; Cheng , M. M.-C. ; Fedele , R. ; Geho , D. H. ; Herrmann , P. ; Killian , K. ; Espina , V. ; Petricoin , E. F. ; Liotta , L. A. ; Ferrari , M. Physicochemically Modified Silicon as Substrate for Protein Microarrays . Biomaterials 2007 , 28 , 550 - 558 ), it is shown that physicochemical modification of silicon substrates increases the binding of protein to silicon to a level comparable with that of nitrocellulose. Here, we apply such substrates in a reverse-phase protein microarray setting in two model systems.

The Association of Silicon Microparticles with Endothelial Cells in Drug Delivery to the Vasculature

Biomaterials. May, 2009  |  Pubmed ID: 19215978

Endothelial targeting is an approach evolving for drug delivery to the vasculature of pathological lesions. Nano-porous silicon-based multi-functional particles are of particular interest, since they can be manufactured in essentially any size and shape, employing methods of photolithography, to optimize their ability to localize on target endothelia. In this study we tested the impact of surface charge, serum opsonization, and inflammation on the ability of vascular endothelial cells to associate with nano-porous silicon microparticles. Vascular endothelial cells were capable of rapidly internalizing both positive and negative silicon microparticles by an actin-dependent mechanism involving both phagocytosis and macropinocytosis. However, following serum opsonization, internalization was selective for APTES (originally positive) modified microparticles, despite the finding that all opsonized microparticles had a net negative charge. Conversely, macrophages displayed a preference for internalization of serum opsonized oxidized (originally negative) microparticles, supporting the choice of positive microparticles for endothelial targeting. The internalization of opsonized microparticles by endothelial cells was further enhanced by the presence of inflammatory cytokines. These findings suggest that it may be possible to bioengineer silicon microparticles to favor opsonization with proteins that enhance uptake by endothelial cells, without a concurrent enhanced uptake by macrophages.

Ultrasonographic Surveillance with Selective CTA After Endovascular Repair of Abdominal Aortic Aneurysm

Journal of Endovascular Therapy : an Official Journal of the International Society of Endovascular Specialists. Feb, 2009  |  Pubmed ID: 19281282

To evaluate the agreement between color-coded duplex ultrasound (US) and computed tomographic angiography (CTA) in monitoring aneurysm diameter and detecting endoleaks after endovascular aneurysm repair (EVAR).

Multiparameter Computational Modeling of Tumor Invasion

Cancer Research. May, 2009  |  Pubmed ID: 19366801

Clinical outcome prognostication in oncology is a guiding principle in therapeutic choice. A wealth of qualitative empirical evidence links disease progression with tumor morphology, histopathology, invasion, and associated molecular phenomena. However, the quantitative contribution of each of the known parameters in this progression remains elusive. Mathematical modeling can provide the capability to quantify the connection between variables governing growth, prognosis, and treatment outcome. By quantifying the link between the tumor boundary morphology and the invasive phenotype, this work provides a quantitative tool for the study of tumor progression and diagnostic/prognostic applications. This establishes a framework for monitoring system perturbation towards development of therapeutic strategies and correlation to clinical outcome for prognosis.

Prediction of Drug Response in Breast Cancer Using Integrative Experimental/computational Modeling

Cancer Research. May, 2009  |  Pubmed ID: 19366802

Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome.

Design of Bio-mimetic Particles with Enhanced Vascular Interaction

Journal of Biomechanics. Aug, 2009  |  Pubmed ID: 19523635

The majority of particle-based delivery systems for the 'smart' administration of therapeutic and imaging agents have a spherical shape, are made by polymeric or lipid materials, have a size in the order of few hundreds of nanometers and a negligibly small relative density to aqueous solutions. In the microcirculation and deep airways of the lungs, where the creeping flow assumption holds, such small spheres move by following the flow stream lines and are not affected by external volume force fields. A delivery system should be designed to drift across the stream lines and interact repeatedly with the vessel walls, so that vascular interaction could be enhanced. The numerical approach presented in [Gavze, E., Shapiro, M., 1997. Particles in a shear flow near a solid wall: effect of nonsphericity on forces and velocities. International Journal of Multiphase Flow 23, 155-182.] is, here, proposed as a tool to analyze the dynamics of arbitrarily shaped particles in a creeping flow, and has been extended to include the contribution of external force fields. As an example, ellipsoidal particles with aspect ratio 0.5 are considered. In the absence of external volume forces, a net lateral drift (margination) of the particles has been observed for Stokes number larger than unity (St>1); whereas, for smaller St, the particles oscillate with no net lateral motion. Under these conditions, margination is governed solely by particle inertia (geometry and particle-to-fluid density ratio). In the presence of volume forces, even for fairly small St, margination is observed but in a direction dictated by the external force field. It is concluded that a fine balance between size, shape and density can lead to EVI particles (particles with enhanced vascular interaction) that are able to sense endothelial cells for biological and biophysical abnormalities, mimicking circulating platelets and leukocytes.

Straight Talk With... Mauro Ferrari. Interviewed by Jon Evans

Nature Medicine. Jul, 2009  |  Pubmed ID: 19584847

Quantitative Mechanics of Endothelial Phagocytosis of Silicon Microparticles

Cytometry. Part A : the Journal of the International Society for Analytical Cytology. Sep, 2009  |  Pubmed ID: 19610127

Endothelia, once thought of as a barrier to the delivery of therapeutics, is now a major target for tissue-specific drug delivery. Tissue- and disease-specific molecular presentations on endothelial cells provide targets for anchoring or internalizing delivery vectors. Porous silicon delivery vectors are phagocytosed by vascular endothelial cells. The rapidity and efficiency of silicon microparticle uptake lead us to delineate the kinetics of internalization. To discriminate between surface-attached and -internalized microparticles, we developed a double fluorescent/FRET flow cytometric approach. The approach relies on quenching of antibody-conjugated fluorescein isothiocyanate covalently attached to the microparticle surface by attachment of a secondary antibody labeled with an acceptor fluorophore, phycoerythrin. The resulting half-time for microparticle internalization was 15.7 min, with confirmation provided by live confocal imaging as well as transmission electron microscopy.

Laparoscopic Treatment of Splenic Artery Aneurysms

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Aug, 2009  |  Pubmed ID: 19631859

The purpose of this study was to report a series of 16 consecutive patients who underwent laparoscopic treatment of splenic artery aneurysms.

Conference Scene: Nanotechnology and Medicine: the Next Big Thing is Really Small

Nanomedicine (London, England). Aug, 2009  |  Pubmed ID: 19663590

Emerging trends from nanotechnology on a globalized scale have created the need for a platform to discuss advances and share developments in this fast growing field. A conference was held to attract a vast number of scientists, representatives from nanotechnology vendor companies, and a diverse array of investors, businessmen and industry participants. The scope of the meeting was to discuss and share developments, innovations and research in the growing, but still emerging science of nanotechnology. The thrust of nanotechnology towards the development of personalized medicine, along with the enforced partnership between the Alliance for NanoHealth (ANH) and the US FDA to solve the issues of safety and approval of nanotechnology-based products were principally recognized.

Shaping Nano-/micro-particles for Enhanced Vascular Interaction in Laminar Flows

Nanotechnology. Dec, 2009  |  Pubmed ID: 19904027

Non-spherical nano-/micro-particles can drift laterally (hydrodynamic margination) in a linear laminar flow under the concurrent effect of hydrodynamic and inertial forces. Such a feature can be exploited in the rational design of particle-based intravascular and pulmonary delivery systems and for designing new flow fractioning systems for high-throughput particle separation. A general approach is presented to predict the marginating behavior of non-spherical particles. The lateral drift velocity is shown to depend on the particle Stokes number St(a) and to grow with the size, density and rotational inertia of the particle. Elongated particles, in particular, low aspect ratio discoidal particles, exhibit the largest propensity to marginate in a linear laminar flow. In the blood microcirculation, at low shear rates (S<100 s(-1)), non-spherical particles oscillate around their trajectory and margination can only be achieved through the application of external force fields (gravitational, magnetic); whereas for larger S (100 s(-1)

Molecular Modeling of Glucose Diffusivity in Silica Nanochannels

Journal of Nanoscience and Nanotechnology. Nov, 2009  |  Pubmed ID: 19908533

The diffusivity of glucose was studied in confined environment of a 10 nm silica nanochannel to evaluate the influence of the interface on glucose transport at a nano-scale range. Molecular dynamics studies revealed that glucose forms a weakly adsorbed layer at the silica interface. The calculated diffusion coefficients were overestimated by up to 30% compared to the experimental ones, though they follow the same dependence on concentration. Close to the interface, radial diffusivity was observed to be lower than lateral, while diffusivities were affected by the interface up to 3 nm from it. This slowdown of glucose diffusivity is found to be related to the decrease in the probability of longer random walk jumps. It is also observed that the dynamics on the interface is characterized by adsorption-desorption processes. These results clearly suggest that glucose transport is affected by the interface in 10 nm nano-confinement.

Nanotechnology for Breast Cancer Therapy

Biomedical Microdevices. Feb, 2009  |  Pubmed ID: 18663578

Breast cancer is the field of medicine with the greatest presence of nanotechnological therapeutic agents in the clinic. A pegylated form of liposomally encapsulated doxorubicin is routinely used for treatment against metastatic cancer, and albumin nanoparticulate chaperones of paclitaxel were approved for locally recurrent and metastatic disease in 2005. These drugs have yielded substantial clinical benefit, and are steadily gathering greater beneficial impact. Clinical trials currently employing these drugs in combination with chemo and biological therapeutics exceed 150 worldwide. Despite these advancements, breast cancer morbidity and mortality is unacceptably high. Nanotechnology offers potential solutions to the historical challenge that has rendered breast cancer so difficult to contain and eradicate: the extreme biological diversity of the disease presentation in the patient population and in the evolutionary changes of any individual disease, the multiple pathways that drive disease progression, the onset of 'resistance' to established therapeutic cocktails, and the gravity of the side effects to treatment, which result from generally very poor distribution of the injected therapeutic agents in the body. A fundamental requirement for success in the development of new therapeutic strategies is that breast cancer specialists-in the clinic, the pharmaceutical and the basic biological laboratory-and nanotechnologists-engineers, physicists, chemists and mathematicians-optimize their ability to work in close collaboration. This further requires a mutual openness across cultural and language barriers, academic reward systems, and many other 'environmental' divides. This paper is respectfully submitted to the community to help foster the mutual interactions of the breast cancer world with micro- and nano-technology, and in particular to encourage the latter community to direct ever increasing attention to breast cancer, where an extraordinary beneficial impact may result. The paper initiates with an introductory overview of breast cancer, its current treatment modalities, and the current role of nanotechnology in the clinic. Our perspectives are then presented on what the greatest opportunities for nanotechnology are; this follows from an analysis of the role of biological barriers that adversely determine the biological distribution of intravascularly injected therapeutic agents. Different generations of nanotechnology tools for drug delivery are reviewed, and our current strategy for addressing the sequential bio-barriers is also presented, and is accompanied by an encouragement to the community to develop even more effective ones.

Mesoporous Silica Chips for Selective Enrichment and Stabilization of Low Molecular Weight Proteome

Proteomics. Feb, 2010  |  Pubmed ID: 20013801

The advanced properties of mesoporous silica have been demonstrated in applications, which include chemical sensing, filtration, catalysis, drug delivery and selective biomolecular uptake. These properties depend on the architectural, physical and chemical properties of the material, which in turn are determined by the processing parameters in evaporation-induced self-assembly. In this study, we introduce a combinatorial approach for the removal of the high molecular weight proteins and for the specific isolation and enrichment of low molecular weight species. This approach is based on mesoporous silica chips able to fractionate, selectively harvest and protect from enzymatic degradation, peptides and proteins present in complex human biological fluids. We present the characterization of the harvesting properties of a wide range of mesoporous chips using a library of peptides and proteins standard and their selectivity on the recovery of serum peptidome. Using MALDI-TOF-MS, we established the correlation between the harvesting specificity and the physicochemical properties of mesoporous silica surfaces. The introduction of this mesoporous material with fine controlled properties will provide a powerful platform for proteomics application offering a rapid and efficient methodology for low molecular weight biomarker discovery.

Tailoring of the Nanotexture of Mesoporous Silica Films and Their Functionalized Derivatives for Selectively Harvesting Low Molecular Weight Protein

ACS Nano. Jan, 2010  |  Pubmed ID: 20014864

We present a fast, efficient, and reliable system based on mesoporous silica chips to specifically fractionate and enrich the low molecular weight proteome. Mesoporous silica thin films with tunable features at the nanoscale were fabricated using the triblock copolymer template pathway. Using different templates and concentrations in the precursor solution, various pore size distributions, pore structures, and connectivity were obtained and applied for selective recovery of low mass proteins. In combination with mass spectrometry and statistic analysis, we demonstrated the correlation between the nanophase characteristics of the mesoporous silica thin films and the specificity and efficacy of low mass proteome harvesting. In addition, to overcome the limitations of the prefunctionalization method in polymer selection, plasma ashing was used for the first time for the treatment of the mesoporous silica surface prior to chemical modification. Surface charge modifications by different functional groups resulted in a selective capture of the low molecular weight proteins from serum sample. In conclusion, our study demonstrates that the ability to tune the physicochemical properties of mesoporous silica surfaces, for a selective enrichment of the low molecular weight proteome from complex biological fluids, has the potential to promote proteomic biomarker discovery.

Enabling Individualized Therapy Through Nanotechnology

Pharmacological Research : the Official Journal of the Italian Pharmacological Society. Aug, 2010  |  Pubmed ID: 20045055

Individualized medicine is the healthcare strategy that rebukes the idiomatic dogma of 'losing sight of the forest for the trees'. We are entering a new era of healthcare where it is no longer acceptable to develop and market a drug that is effective for only 80% of the patient population. The emergence of "-omic" technologies (e.g. genomics, transcriptomics, proteomics, metabolomics) and advances in systems biology are magnifying the deficiencies of standardized therapy, which often provide little treatment latitude for accommodating patient physiologic idiosyncrasies. A personalized approach to medicine is not a novel concept. Ever since the scientific community began unraveling the mysteries of the genome, the promise of discarding generic treatment regimens in favor of patient-specific therapies became more feasible and realistic. One of the major scientific impediments of this movement towards personalized medicine has been the need for technological enablement. Nanotechnology is projected to play a critical role in patient-specific therapy; however, this transition will depend heavily upon the evolutionary development of a systems biology approach to clinical medicine based upon "-omic" technology analysis and integration. This manuscript provides a forward looking assessment of the promise of nanomedicine as it pertains to individualized medicine and establishes a technology "snapshot" of the current state of nano-based products over a vast array of clinical indications and range of patient specificity. Other issues such as market driven hurdles and regulatory compliance reform are anticipated to "self-correct" in accordance to scientific advancement and healthcare demand. These peripheral, non-scientific concerns are not addressed at length in this manuscript; however they do exist, and their impact to the paradigm shifting healthcare transformation towards individualized medicine will be critical for its success.

Frontiers in Cancer Nanomedicine: Directing Mass Transport Through Biological Barriers

Trends in Biotechnology. Apr, 2010  |  Pubmed ID: 20079548

The physics of mass transport within body compartments and across biological barriers differentiates cancers from healthy tissues. Variants of nanoparticles can be manufactured in combinatorially large sets, varying by only one transport-affecting design parameter at a time. Nanoparticles can also be used as building blocks for systems that perform sequences of coordinated actions, in accordance with a prescribed logic. We refer to these as Logic-Embedded Vectors (LEVs). Nanoparticles and LEVs are ideal probes for the determination of mass transport laws in tumors, acting as imaging contrast enhancers, and can be employed for lesion-selective delivery of therapy. Their size, shape, density and surface chemistry dominate convective transport in the bloodstream, margination, cell adhesion, selective cellular uptake, as well as sub-cellular trafficking and localization. As argued here, the understanding of transport differentials in cancer, termed 'transport oncophysics', reveals a promising new frontier in oncology: the development of lesion-specific delivery particulates that exploit mass transport differentials to deploy treatment of greater efficacy and reduced side effects.

Tailored Porous Silicon Microparticles: Fabrication and Properties

Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry. Apr, 2010  |  Pubmed ID: 20162656

The use of mesoporous silicon particles for drug delivery has been widely explored thanks to their biodegradability and biocompatibility. The ability to tailor the physicochemical properties of porous silicon at the micro- and nanoscale confers versatility to this material. A method for the fabrication of highly reproducible, monodisperse, mesoporous silicon particles with controlled physical characteristics through electrochemical etching of patterned silicon trenches is presented. The particle size is tailored in the micrometer range and pore size in the nanometer range, the shape from tubular to discoidal to hemispherical, and the porosity from 46 to over 80%. In addition, the properties of the porous matrix are correlated with the loading of model nanoparticles (quantum dots) and their three-dimensional arrangement within the matrix is observed by transmission electron microscopy tomography. The methods developed in this study provide effective means to fabricate mesoporous silicon particles according to the principles of rational design for therapeutic vectors and to characterize the distribution of nanoparticles within the porous matrix.

Emerging Applications of Nanomedicine for the Diagnosis and Treatment of Cardiovascular Diseases

Trends in Pharmacological Sciences. May, 2010  |  Pubmed ID: 20172613

Nanomedicine is an emerging field that utilizes nanotechnology concepts for advanced therapy and diagnostics. This convergent discipline merges research areas such as chemistry, biology, physics, mathematics and engineering. It therefore bridges the gap between molecular and cellular interactions, and has the potential to revolutionize medicine. This review presents recent developments in nanomedicine research poised to have an important impact on the treatment of cardiovascular disease. This will occur through improvement of the diagnosis and therapy of cardiovascular disorders as atherosclerosis, restenosis and myocardial infarction. Specifically, we discuss the use of nanoparticles for molecular imaging and advanced therapeutics, specially designed drug eluting stents and in vivo/ex vivo early detection techniques.

Modulating Cellular Adhesion Through Nanotopography

Biomaterials. Jan, 2010  |  Pubmed ID: 19783034

Cellular adhesion is a fundamental process in the development of scaffolds for tissue engineering; in the design of biosensors and in preparing antibacterial substrates. A theoretical model is presented for predicting the strength of cellular adhesion to originally inert surfaces as a function of the substrate topography, accounting for both specific (ligand-receptor) and non-specific interfacial interactions. Three regimes have been identified depending on the surface energy (gamma) of the substrate: for small gamma, any increase in roughness is detrimental to adhesion; for large gamma, an optimal roughness exists that maximizes adhesion; and for intermediate gamma, surface roughness has a minor effect on adhesion. The results presented are in qualitative agreement with several experimental observations and can capture the long-term equilibrium configuration of the system. The model proposed supports the notion for rationally designing substrates where topography and physico-chemical properties are tailored to favour cellular proliferation whilst repelling bacterial adhesion.

Mixed Reality for Robotic Treatment of a Splenic Artery Aneurysm

Surgical Endoscopy. May, 2010  |  Pubmed ID: 19826869

Techniques of mixed reality can successfully be used in preoperative planning of laparoscopic and robotic procedures and to guide surgical dissection and enhance its accuracy.

A New Preoperative Predictor of Outcome in Ruptured Abdominal Aortic Aneurysms: the Time Before Shock (TBS)

Annals of Vascular Surgery. Apr, 2010  |  Pubmed ID: 19900784

In patients with ruptured abdominal aortic aneurysm (RAAA) and shock, the time lag between the onset of the symptoms due to RAAA and the presence of a full developed shock syndrome was evaluated to assess its prognostic meaning. This time lag was called time before shock (TBS).

Shaping the Micromechanical Behavior of Multi-phase Composites for Bone Tissue Engineering

Acta Biomaterialia. Sep, 2010  |  Pubmed ID: 20346422

Mechanical stiffness is a fundamental parameter in the rational design of composites for bone tissue engineering in that it affects both the mechanical stability and the osteo-regeneration process at the fracture site. A mathematical model is presented for predicting the effective Young's modulus (E) and shear modulus (G) of a multi-phase biocomposite as a function of the geometry, material properties and volume concentration of each individual phase. It is demonstrated that the shape of the reinforcing particles may dramatically affect the mechanical stiffness: E and G can be maximized by employing particles with large geometrical anisotropy, such as thin platelet-like or long fibrillar-like particles. For a porous poly(propylene fumarate) (60% porosity) scaffold reinforced with silicon particles (10% volume concentration) the Young's (shear) modulus could be increased by more than 10 times by just using thin platelet-like as opposed to classical spherical particles, achieving an effective modulus E approximately 8 GPa (G approximately 3.5 GPa). The mathematical model proposed provides results in good agreement with several experimental test cases and could help in identifying the proper formulation of bone scaffolds, reducing the development time and guiding the experimental testing.

Sustained Small Interfering RNA Delivery by Mesoporous Silicon Particles

Cancer Research. May, 2010  |  Pubmed ID: 20430760

RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms.

Cellular Association and Assembly of a Multistage Delivery System

Small (Weinheim an Der Bergstrasse, Germany). Jun, 2010  |  Pubmed ID: 20517877

The realization that blood-borne delivery systems must overcome a multiplicity of biological barriers has led to the fabrication of a multistage delivery system (MDS) designed to temporally release successive stages of particles or agents to conquer sequential barriers, with the goal of enhancing delivery of therapeutic and diagnostic agents to the target site. In its simplest form, the MDS comprises stage-one porous silicon microparticles that function as carriers of second-stage nanoparticles. Cellular uptake of nontargeted discoidal silicon microparticles by macrophages is confirmed by electron and atomic force microscopy (AFM). Using superparamagnetic iron oxide nanoparticles (SPIONs) as a model of secondary nanoparticles, successful loading of the porous matrix of silicon microparticles is achieved, and retention of the nanoparticles is enhanced by aminosilylation of the loaded microparticles with 3-aminopropyltriethoxysilane. The impact of silane concentration and reaction time on the nature of the silane polymer on porous silicon is investigated by AFM and X-ray photoelectron microscopy. Tissue samples from mice intravenously administered the MDS support co-localization of silicon microparticles and SPIONs across various tissues with enhanced SPION release in spleen, compared to liver and lungs, and enhanced retention of SPIONs following silane capping of the MDS. Phantom models of the SPION-loaded MDS display negative contrast in magnetic resonance images. In addition to forming a cap over the silicon pores, the silane polymer provides free amines for antibody conjugation to the microparticles, with both VEGFR-2- and PECAM-specific antibodies leading to enhanced endothelial association. This study demonstrates the assembly and cellular association of a multiparticle delivery system that is biomolecularly targeted and has potential for applications in biological imaging.

Drug Delivery: Cellular Association and Assembly of a Multistage Delivery System Small 12/2010

Small (Weinheim an Der Bergstrasse, Germany). Jun, 2010  |  Pubmed ID: 20535747

Vectoring SiRNA Therapeutics into the Clinic

Nature Reviews. Clinical Oncology. Sep, 2010  |  Pubmed ID: 20798696

An Integrated Approach for the Rational Design of Nanovectors for Biomedical Imaging and Therapy

Advances in Genetics. 2010  |  Pubmed ID: 20807601

The use of nanoparticles for the early detection, cure, and imaging of diseases has been proved already to have a colossal potential in different biomedical fields, such as oncology and cardiology. A broad spectrum of nanoparticles are currently under development, exhibiting differences in (i) size, ranging from few tens of nanometers to few microns; (ii) shape, from the classical spherical beads to discoidal, hemispherical, cylindrical, and conical; (iii) surface functionalization, with a wide range of electrostatic charges and biomolecule conjugations. Clearly, the library of nanoparticles generated by combining all possible sizes, shapes, and surface physicochemical properties is enormous. With such a complex scenario, an integrated approach is here proposed and described for the rational design of nanoparticle systems (nanovectors) for the intravascular delivery of therapeutic and imaging contrast agents. The proposed integrated approach combines multiscale/multiphysics mathematical models with in vitro assays and in vivo intravital microscopy (IVM) experiments and aims at identifying the optimal combination of size, shape, and surface properties that maximize the nanovectors localization within the diseased microvasculature.

Mesenchymal Stem Cells Promote Mammosphere Formation and Decrease E-cadherin in Normal and Malignant Breast Cells

PloS One. 2010  |  Pubmed ID: 20808935

Normal and malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew, referred to as stem cells, or tumor initiating cells (TIC). These cells can be enriched by growth as "mammospheres" in three-dimensional cultures.

Intracellular Trafficking of Silicon Particles and Logic-embedded Vectors

Nanoscale. Aug, 2010  |  Pubmed ID: 20820744

Mesoporous silicon particles show great promise for use in drug delivery and imaging applications as carriers for second-stage nanoparticles and higher order particles or therapeutics. Modulation of particle geometry, surface chemistry, and porosity allows silicon particles to be optimized for specific applications such as vascular targeting and avoidance of biological barriers commonly found between the site of drug injection and the final destination. In this study, the intracellular trafficking of unloaded carrier silicon particles and carrier particles loaded with secondary iron oxide nanoparticles was investigated. Following cellular uptake, membrane-encapsulated silicon particles migrated to the perinuclear region of the cell by a microtubule-driven mechanism. Surface charge, shape (spherical and hemispherical) and size (1.6 and 3.2 microm) of the particle did not alter the rate of migration. Maturation of the phagosome was associated with an increase in acidity and acquisition of markers of late endosomes and lysosomes. Cellular uptake of iron oxide nanoparticle-loaded silicon particles resulted in sorting of the particles and trafficking to unique destinations. The silicon carriers remained localized in phagosomes, while the second stage iron oxide nanoparticles were sorted into multi-vesicular bodies that dissociated from the phagosome into novel membrane-bound compartments. Release of iron from the cells may represent exocytosis of iron oxide nanoparticle-loaded vesicles. These results reinforce the concept of multi-functional nanocarriers, in which different particles are able to perform specific tasks, in order to deliver single- or multi-component payloads to specific sub-cellular compartments.

Enhanced Microcontact Printing of Proteins on Nanoporous Silica Surface

Nanotechnology. Oct, 2010  |  Pubmed ID: 20834118

We demonstrate porous silica surface modification, combined with microcontact printing, as an effective method for enhanced protein patterning and adsorption on arbitrary surfaces. Compared to conventional chemical treatments, this approach offers scalability and long-term device stability without requiring complex chemical activation. Two chemical surface treatments using functionalization with the commonly used 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde (GA) were compared with the nanoporous silica surface on the basis of protein adsorption. The deposited thickness and uniformity of porous silica films were evaluated for fluorescein isothiocyanate (FITC)-labeled rabbit immunoglobulin G (R-IgG) protein printed onto the substrates via patterned polydimethlysiloxane (PDMS) stamps. A more complete transfer of proteins was observed on porous silica substrates compared to chemically functionalized substrates. A comparison of different pore sizes (4-6 nm) and porous silica thicknesses (96-200 nm) indicates that porous silica with 4 nm diameter, 57% porosity and a thickness of 96 nm provided a suitable environment for complete transfer of R-IgG proteins. Both fluorescence microscopy and atomic force microscopy (AFM) were used for protein layer characterizations. A porous silica layer is biocompatible, providing a favorable transfer medium with minimal damage to the proteins. A patterned immunoassay microchip was developed to demonstrate the retained protein function after printing on nanoporous surfaces, which enables printable and robust immunoassay detection for point-of-care applications.

Combinatorial Selection of DNA Thioaptamers Targeted to the HA Binding Domain of Human CD44

Biochemistry. Oct, 2010  |  Pubmed ID: 20843027

CD44, the primary receptor for hyaluronic acid, plays an important role in tumor growth and metastasis. CD44-hyaluronic acid interactions can be exploited for targeted delivery of anticancer agents specifically to cancer cells. Although various splicing variants of CD44 are expressed on the plasma membrane of cancer cells, the hyaluronic acid binding domain (HABD) is highly conserved among the CD44 splicing variants. Using a novel two-step process, we have identified monothiophosphate-modified aptamers (thioaptamers) that specifically bind to the CD44's HABD with high affinities. Binding affinities of the selected thioaptamers for the HABD were in the range of 180-295 nM, an affinity significantly higher than that of hyaluronic acid (K(d) above the micromolar range). The selected thioaptamers bound to CD44 positive human ovarian cancer cell lines (SKOV3, IGROV, and A2780) but failed to bind the CD44 negative NIH3T3 cell line. Our results indicated that thio substitution at specific positions of the DNA phosphate backbone results in specific and high-affinity binding of thioaptamers to CD44. The selected thioaptamers will be of great interest for further development as a targeting or imaging agent for the delivery of therapeutic payloads for cancer tissues.

Identification of Thioaptamer Ligand Against E-selectin: Potential Application for Inflamed Vasculature Targeting

PloS One. 2010  |  Pubmed ID: 20927342

Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two-step selection strategy: a recombinant protein-based TA binding selection from a combinatorial library followed by a cell-based TA binding selection using E-selectin expressing human microvascular endothelial cells. ESTA-1 selectively bound to E-selectin with nanomolar binding affinity (K(D) = 47 nM) while exhibiting minimal cross reactivity to P- and L-selectin. Furthermore, ESTA-1 binding to E-selectin on the endothelial cells markedly antagonized the adhesion (over 75% inhibition) of sLe(x) positive HL-60 cells at nanomolar concentration. ESTA-1 also bound specifically to the inflamed tumor-associated vasculature of human carcinomas derived from breast, ovarian, and skin but not to normal organs, and this binding was highly associated with the E-selectin expression level. Similarly, intravenously injected ESTA-1 demonstrated distinct binding to the tumor vasculature in a breast cancer xenograft model. Together, our data substantiates the discovery of a thioaptamer (ESTA-1) that binds to E-selectin with high affinity and specificity, thereby highlighting the potential application of ESTA-1 for E-selectin targeted delivery.

Logic-embedded Vectors for Intracellular Partitioning, Endosomal Escape, and Exocytosis of Nanoparticles

Small (Weinheim an Der Bergstrasse, Germany). Dec, 2010  |  Pubmed ID: 20957619

A new generation of nanocarriers, logic-embedded vectors (LEVs), is endowed with the ability to localize components at multiple intracellular sites, thus creating an opportunity for synergistic control of redundant or dual-hit pathways. LEV encoding elements include size, shape, charge, and surface chemistry. In this study, LEVs consist of porous silicon nanocarriers, programmed for cellular uptake and trafficking along the endosomal pathway, and surface-tailored iron oxide nanoparticles, programmed for endosomal sorting and partitioning of particles into unique cellular locations. In the presence of persistent endosomal localization of silicon nanocarriers, amine-functionalized nanoparticles are sorted into multiple vesicular bodies that form novel membrane-bound compartments compatible with cellular secretion, while chitosan-coated nanoparticles escape from endosomes and enter the cytosol. Encapsulation within the porous silicon matrix protects these nanoparticle surface-tailored properties, and enhances endosomal escape of chitosan-coated nanoparticles. Thus, LEVs provide a mechanism for shielded transport of nanoparticles to the lesion, cellular manipulation at multiple levels, and a means for targeting both within and between cells.

Geometrical Confinement of Gadolinium-based Contrast Agents in Nanoporous Particles Enhances T1 Contrast

Nature Nanotechnology. Nov, 2010  |  Pubmed ID: 20972435

Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r(1) was observed: Magnevist, r(1) ≈ 14 mM(-1) s(-1)/Gd(3+) ion (∼ 8.15 × 10(+7) mM(-1) s(-1)/construct); gadofullerenes, r(1) ≈ 200 mM(-1) s(-1)/Gd(3+) ion (∼ 7 × 10(+9) mM(-1) s(-1)/construct); gadonanotubes, r(1) ≈ 150 mM(-1) s(-1)/Gd(3+) ion (∼ 2 × 10(+9) mM(-1) s(-1)/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (∼ 4 mM(-1) s(-1)/Gd(3+) ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd(3+) ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.

Biodegradable Porous Silicon Barcode Nanowires with Defined Geometry

Advanced Functional Materials. Jul, 2010  |  Pubmed ID: 21057669

Silicon nanowires are of proven importance in diverse fields such as energy production and storage, flexible electronics, and biomedicine due to the unique characteristics emerging from their one-dimensional semiconducting nature and their mechanical properties. Here we report the synthesis of biodegradable porous silicon barcode nanowires by metal assisted electroless etch of single crystal silicon with resistivity ranging from 0.0008 Ω-cm to 10 Ω-cm. We define the geometry of the barcode nanowiresby nanolithography and we characterize their multicolor reflectance and photoluminescence. We develop phase diagrams for the different nanostructures obtained as a function of metal catalyst, H(2)O(2) concentration, ethanol concentration and silicon resistivity, and propose a mechanism that explains these observations. We demonstrate that these nanowires are biodegradable, and their degradation time can be modulated by surface treatments.

Nanotexture Optimization by Oxygen Plasma of Mesoporous Silica Thin Film for Enrichment of Low Molecular Weight Peptides Captured from Human Serum

Science China. Chemistry. Nov, 2010  |  Pubmed ID: 21179395

This study investigated the optimization of mesoporous silica thin films by nanotexturing using oxygen plasma versus thermal oxidation. Calcination in oxygen plasma provides superior control over pore formation with regard to the pore surface and higher fidelity to the structure of the polymer template. The resulting porous film offers an ideal substrate for the selective partitioning of peptides from complex mixtures. The improved chemico-physical characteristics of porous thin films (pore size distribution, nanostructure, surface properties and pore connectivity) were systematically characterized with XRD, Ellipsometry, FTIR, TEM and N(2) adsorption/desorption. The enrichment of low molecular weight proteins captured from human serum on mesoporous silica thin films fabricated by both methodologies were investigated by comparison of their MALDI-TOF MS profiles. This novel on-chip fractionation technology offers advantages in recovering the low molecular weight peptides from human serum, which has been recognized as an informative resource for early diagnosis of cancer and other diseases.

Characterization of Controlled Bone Defects Using 2D and 3D Ultrasound Imaging Techniques

Physics in Medicine and Biology. Aug, 2010  |  Pubmed ID: 20679698

Ultrasound is emerging as an attractive alternative modality to standard x-ray and CT methods for bone assessment applications. As of today, however, there is a lack of systematic studies that investigate the performance of diagnostic ultrasound techniques in bone imaging applications. This study aims at understanding the performance limitations of new ultrasound techniques for imaging bones in controlled experiments in vitro. Experiments are performed on samples of mammalian and non-mammalian bones with controlled defects with size ranging from 400 microm to 5 mm. Ultrasound findings are statistically compared with those obtained from the same samples using standard x-ray imaging modalities and optical microscopy. The results of this study demonstrate that it is feasible to use diagnostic ultrasound imaging techniques to assess sub-millimeter bone defects in real time and with high accuracy and precision. These results also demonstrate that ultrasound imaging techniques perform comparably better than x-ray imaging and optical imaging methods, in the assessment of a wide range of controlled defects both in mammalian and non-mammalian bones. In the future, ultrasound imaging techniques might provide a cost-effective, real-time, safe and portable diagnostic tool for bone imaging applications.

Tailoring the Degradation Kinetics of Mesoporous Silicon Structures Through PEGylation

Journal of Biomedical Materials Research. Part A. Sep, 2010  |  Pubmed ID: 20694990

Injectable and implantable porosified silicon (pSi) carriers and devices for prolonged and controlled delivery of biotherapeutics offer great promise for treatment of various chronic ailments and acute conditions. Polyethylene glycols (PEGs) are important surface modifiers currently used in clinic mostly to avoid uptake of particulates by reticulo-endothelial system (RES). In this work we show for the first time that covalent attachment of PEGs to the pSi surface can be used as a means to tune degradation kinetics of silicon structures. Seven PEGs with varying molecular weights (245, 333, 509, 686, 1214, 3400, and 5000 Da) were employed and the degradation of PEGylated pSi hemispherical microparticles in simulated physiological conditions was monitored by means of ICP-AES, SEM, and fluorimetry. Biocompatibility of the systems with human macrophages in vitro was also evaluated. The results clearly indicate that controlled PEGylation of silicon microparticles can offer a sensitive tool to finely tune their degradation kinetics and that the systems do not induce release of proinflammatory cytokines IL-6 and IL-8 in THP1 human macrophages.

A Robust Nanofluidic Membrane with Tunable Zero-order Release for Implantable Dose Specific Drug Delivery

Lab on a Chip. Nov, 2010  |  Pubmed ID: 20697650

This manuscript demonstrates a mechanically robust implantable nanofluidic membrane capable of tunable long-term zero-order release of therapeutic agents in ranges relevant for clinical applications. The membrane, with nanochannels as small as 5 nm, allows for the independent control of both dosage and mechanical strength through the integration of high-density short nanochannels parallel to the membrane surface with perpendicular micro- and macrochannels for interfacing with the ambient solutions. These nanofluidic membranes are created using precision silicon fabrication techniques on silicon-on-insulator substrates enabling exquisite control over the monodispersed nanochannel dimensions and surface roughness. Zero-order release of analytes is achieved by exploiting molecule to surface interactions which dominate diffusive transport when fluids are confined to the nanoscale. In this study we investigate the nanofluidic membrane performance using custom diffusion and gas testing apparatuses to quantify molecular release rate and process uniformity as well as mechanical strength using a gas based burst test. The kinetics of the constrained zero-order release is probed with molecules presenting a range of sizes, charge states, and structural conformations. Finally, an optimal ratio of the molecular hydrodynamic diameter to the nanochannel dimension is determined to assure zero-order release for each tested molecule.

Erratum: Cellular Association and Assembly of a Multistage Delivery System

Small (Weinheim an Der Bergstrasse, Germany). Jul, 2010  |  Pubmed ID: 20623735

Cellular Association and Assembly of a Multistage Delivery System

Small (Weinheim an Der Bergstrasse, Germany). Jul, 2010  |  Pubmed ID: 20629053

Multistage Nanovectors: from Concept to Novel Imaging Contrast Agents and Therapeutics

Accounts of Chemical Research. Oct, 2011  |  Pubmed ID: 21902173

Over the last few decades a great variety of nanotechnology based platforms have been synthesized and fabricated to improve the delivery of active compounds to a disease site. Nanoparticles currently used in the clinic, and the majority of nanotherapeutics/nanodiagnostics under investigation, accommodate single- or multiple- functionalities on the same entity. Because many heterogeneous biological barriers can prevent therapeutic and imaging agents from reaching their intended targets in sufficient concentrations, there is an emerging requirement to develop a multimodular nanoassembly, in which different components with individual specific functions act in a synergistic manner. The multistage nanovectors (MSVs) were introduced in 2008 as the first system of this type. It comprises several nanocomponents or "stages", each of which is designed to negotiate one or more biological barriers. Stage 1 mesoporous silicon particles (S1MPs) were rationally designed and fabricated in a nonspherical geometry to enable superior blood margination and to increase cell surface adhesion. The main task of S1MPs is to efficiently transport nanoparticles that are loaded into their porous structure and to protect them during transport from the administration site to the disease lesion. Semiconductor fabrication techniques including photolithography and electrochemical etching allow for the exquisite control and precise reproducibility of S1MP physical characteristics such as geometry and porosity. Furthermore, S1MPs can be chemically modified with negatively/positively charged groups, PEG and other polymers, fluorescent probes, contrast agents, and biologically active targeting moieties including antibodies, peptides, aptamers, and phage. The payload nanoparticles, termed stage 2 nanoparticles (S2NPs), can be any currently available nanoparticles such as liposomes, micelles, inorganic/metallic nanoparticles, dendrimers, and carbon structures, within the approximate size range of 5-100 nm in diameter. Depending upon the physicochemical features of the S1MP (geometry, porosity, and surface modifications), a variety of S2NPs or nanoparticle "cocktails" can be loaded and efficiently delivered to the disease site. As demonstrated in the studies reviewed here, once the S2NPs are loaded into the S1MPs, a variety of novel properties emerge, which enable the design of new and improved imaging contrast agents and therapeutics. For example, the loading of the MRI Gd-based contrast agents onto hemispherical and discoidal S1MPs significantly increased the longitudal relaxivity (r1) to values of up to 50 times larger than those of clinically available gadolinium-based agents (~4 mM(-1) s(-1)/Gd(3+) ion). Furthermore, administration of a single dose of MSVs loaded with neutral nanoliposomes containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein enabled sustained EphA2 gene silencing for at least 21 days. As a result, the tumor burden was reduced in an orthotopic mouse model of ovarian cancer. We envision that the versatility of the MSV platform and its emerging properties will enable the creation of personalized solutions with broad clinical implications within and beyond the realm of cancer theranostics.

Gated and Near-surface Diffusion of Charged Fullerenes in Nanochannels

ACS Nano. Dec, 2011  |  Pubmed ID: 22032773

Nanoparticles and their derivatives have engendered significant recent interest. Despite considerable advances in nanofluidic physics, control over nanoparticle diffusive transport, requisite for a host of innovative applications, has yet to be demonstrated. In this study, we performed diffusion experiments for negatively and positively charged fullerene derivatives (dendritic fullerene-1, DF-1, and amino fullerene, AC60) in 5.7 and 13 nm silicon nanochannels in solutions with different ionic strengths. With DF-1, we demonstrated a gated diffusion whereby precise and reproducible control of the dynamics of the release profile was achieved by tuning the gradient of the ionic strength within the nanochannels. With AC60, we observed a near-surface diffusive transport that produced release rates that were independent of the size of the nanochannels within the range of our experiments. Finally, through theoretical analysis we were able to elucidate the relative importance of physical nanoconfinement, electrostatic interactions, and ionic strength heterogeneity with respect to these gated and near-surface diffusive transport phenomena. These results are significant for multiple applications, including the controlled administration of targeted nanovectors for therapeutics.

Molecular-targeted Nanotherapies in Cancer: Enabling Treatment Specificity

Molecular Oncology. Dec, 2011  |  Pubmed ID: 22071376

Chemotherapy represents a mainstay and powerful adjuvant therapy in the treatment of cancer. The field has evolved from drugs possessing all-encompassing cell-killing effects to those with highly targeted, specific mechanisms of action; a direct byproduct of enhanced understanding of tumorigenic processes. However, advances regarding development of agents that target key molecules and dysregulated pathways have had only modest impacts on patient survival. Several biological barriers preclude adequate delivery of drugs to tumors, and remain a formidable challenge to overcome in chemotherapy. Currently, the field of nanomedicine is enabling the delivery of chemotherapeutics, including repositioned drugs and siRNAs, by giving rise to carriers that provide for protection from degradation, prolonged circulation times, and increased tumor accumulation, all the while resulting in reduced patient morbidity. This review aims to highlight several innovative, nanoparticle-based platforms with the potential of providing clinical translation of several novel chemotherapeutic agents. We will also summarize work regarding the development of a multistage drug delivery strategy, a robust carrier platform designed to overcome several biological barriers while en route to tumors.

Bioengineering Nanotechnology: Towards the Clinic

Nanotechnology. Dec, 2011  |  Pubmed ID: 22101146

Self-assembled Zinc/copper Hydroxide Carbonates with Tunable Hierarchical Nanostructure

Journal of Nanoscience and Nanotechnology. Aug, 2011  |  Pubmed ID: 22103119

Here, we report a synthetic, polymer-mediated method for the self-assembly of zinc/copper hydroxide carbonate superstructures including 3D hierarchical sunflower-like, urchin-like, alga-like, and rotiform-like zinc hydroxide carbonate (ZHC) microstructures, and hierarchical copper hydroxide carbonate (CHC) microspheres with radiating nanoplates and nanorods. As a capping agent, poly(vinylpyrrolidone) (PVP) was found to play an important role in directing the growth and self-assembly of such unique structures. The crystal structure of the products and the resulting hierarchical superstructure morphology, as controlled by the molecular weight and concentration of PVP, were systematically investigated. A possible growth mechanism for the formation of hierarchical superstructures with different morphologies is also proposed.

Integration of Biomechanical Parameters in Tetrahedral Mass-spring Models for Virtual Surgery Simulation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2011  |  Pubmed ID: 22255350

Surgical simulation requires to have an operating scenario as similar as possible to the real conditions that the surgeon is going to face. Not only visual and geometric patient properties are needed to be reproduced, but also physical and biomechanical properties are theoretically required. In this paper a physically based patient specific simulator for solid organs is described, recalling the underlying theory and providing simulation results and comparisons. The main biomechanical parameters (Young's modulus and density) have been integrated in a Mass-Spring-Damper model (MSDm) based on a tetrahedral structured network. The proposed algorithms allow the automatic setting of node mass and spring stiffness, while the damping coefficient have been modeled using the Rayleigh approach. Moreover, the method automatically detects the organ external layer, allowing the usage of both the surface and internal Young's moduli: for the capsule (or stroma) and for the internal part (or parenchyma). Finally the model can be manually tuned to represent lesions with specific biomechanical properties. The method has beed tested with various material samples. The results have shown a good visual realism ensuring the performance required by an interactive simulation.

Proteomic Analysis of Serum Opsonins Impacting Biodistribution and Cellular Association of Porous Silicon Microparticles

Molecular Imaging. Feb, 2011  |  Pubmed ID: 21303614

Mass transport of drug delivery vehicles is guided by particle properties, such as size, shape, composition, and surface chemistry, as well as biomolecules and serum proteins that adsorb to the particle surface. In an attempt to identify serum proteins influencing cellular associations and biodistribution of intravascularly injected particles, we used two-dimensional gel electrophoresis and mass spectrometry to identify proteins eluted from the surface of cationic and anionic silicon microparticles. Cationic microparticles displayed a 25-fold greater abundance of Ig light variable chain, fibrinogen, and complement component 1 compared to their anionic counterparts. Anionic microparticles were found to accumulate in equal abundance in murine liver and spleen, whereas cationic microparticles showed preferential accumulation in the spleen. Immunohistochemistry supported macrophage uptake of both anionic and cationic microparticles in the liver, as well as evidence of association of cationic microparticles with hepatic endothelial cells. Furthermore, scanning electron micrographs supported cellular competition for cationic microparticles by endothelial cells and macrophages. Despite high macrophage content in the lungs and tumor, microparticle uptake by these cells was minimal, supporting differences in the repertoire of surface receptors expressed by tissue-specific macrophages. In summary, particle surface chemistry drives selective binding of serum components impacting cellular interactions and biodistribution.

Near-infrared Imaging Method for the in Vivo Assessment of the Biodistribution of Nanoporous Silicon Particles

Molecular Imaging. Feb, 2011  |  Pubmed ID: 21303615

In the development of new nanoparticle-based technologies for therapeutic and diagnostic purposes, understanding the fate of nanoparticles in the body is crucial. We recently developed a multistage vector delivery system comprising biodegradable and biocompatible nanoporous silicon particles (first-stage microparticles [S1MPs]) able to host, protect, and deliver second-stage therapeutic and diagnostic nanoparticles (S2NPs) on intravenous injection. This delivery system aims at sequentially overcoming the biologic barriers en route to the target delivery site by separating and assigning tasks to the coordinated logic-embedded vectors constituting it. In this work, by conjugating a near-infrared dye on the surface of the S1MP without compromising the porous structure and potential loading of S2NPs, we were able to monitor the in vivo distribution of S1MPs in healthy mice using an optical imaging system. It was observed that particles predominantly accumulated in the liver and spleen at the end of 24 hours. Further quantification of S1MPs in the major organs of the animals by elemental analysis of silicon using inductively coupled plasma-atomic electron spectroscopy verified the accuracy of in vivo near-infrared imaging as a tool for evaluation of nanovector biodistribution.

Patient Specific Surgical Simulator for the Evaluation of the Movability of Bimanual Robotic Arms

Studies in Health Technology and Informatics. 2011  |  Pubmed ID: 21335823

This work presents a simulator based on patient specific data for bimanual surgical robots. Given a bimanual robot with a particular geometry and kinematics, and a patient specific virtual anatomy, the aim of this simulator was to evaluate if a dexterous movability was obtainable to avoid collisions with the surrounding virtual anatomy in order to prevent potential damages to the tissues during the real surgical procedure. In addition, it could help surgeons to find the optimal positioning of the robot before entering the operative room. This application was tested using a haptic device to reproduce the interactions of the robot with deformable organs. The results showed good performances in terms of frame rate for the graphic, haptic, and dynamic processes.

Case Report of a Successful Treatment of Methicillin-resistant Staphylococcus Aureus (MRSA) Bacteremia and MRSA/vancomycin-resistant Enterococcus Faecium Cholecystitis by Daptomycin

Antimicrobial Agents and Chemotherapy. May, 2011  |  Pubmed ID: 21343441

A 72-year-old man, receiving 8 mg daptomycin/kg body weight/day for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, was diagnosed with MRSA/vancomycin-resistant Enterococcus faecium (VRE) cholecystitis (daptomycin MIC values, 1 and 2 mg/liter, respectively). After the fifth drug dose, the bile concentration of daptomycin was 66 mg/liter 5 min after drug administration, with the biliary concentration/MIC values higher than 30 for both bacterial strains. Therefore, daptomycin achieved therapeutic levels in bile, hence suggesting a role for the drug in the treatment of MRSA/VRE cholecystitis.

Device for Rapid and Agile Measurement of Diffusivity in Micro- and Nanochannels

Analytical Chemistry. Apr, 2011  |  Pubmed ID: 21434670

The lack of a viable theory for describing diffusivity when fluids are confined at the micro- and nanoscale [Ladero et al. Chem. Eng. Sci.2007, 62, 666-678; Deen AIChE J.1987, 33, 1409-1425] has necessitated accurate measurement of diffusivity (D) [Jin and Chen Chromatographia2000, 52, 17-21; Nie et al. Science1994, 266, 1018-1021; Durand et al. Anal. Chem.2009, 81, 5407-5412], crucial for a host of micro- and nanofluidic technologies [Grattoni et al. Curr. Pharm. Biotechnol.2010, 11, 343-365]. We demonstrate a rapid and agile method for the direct measurement of diffusivity in a system possessing 10(4) to 10(5) precisely fabricated channels with characteristic sizes (β) ranging from micro- to nanometers. Custom chambers allowed us to measure the diffusivity in a closed unperturbed system using UV/vis spectroscopy. D was measured for rhodamine B (RhoB) in aqueous solution in channels of 200 and 1 μm, as well as 13 and 5.7 nm. The observed logarithmic scaling of diffusivity with β, in close agreement with prior experiments, but far from theoretical prediction, surprisingly highlights that diffusivity is significantly altered even at the microscale. Accurate measurement of D by reducing the size of the source reservoir by 3 orders of magnitude (from 150 μL to 910 nL) proves that a substantial reduction in measurement time (from 7 days to 40 min) can be achieved. Our design thus is ready for rapid translation into a standard analytical tool--useful for multiple applications.

Nanomedicine in Cancer Therapy: Innovative Trends and Prospects

Cancer Science. Jul, 2011  |  Pubmed ID: 21447010

Cancer is a leading cause of morbidity and mortality worldwide, with recent advancements resulting in modest impacts on patient survival. Nanomedicine represents an innovative field with immense potential for improving cancer treatment, having ushered in several established drug delivery platforms. Nanoconstructs such as liposomes are widely used in clinics, while polymer micelles are in advanced phases of clinical trials in several countries. Currently, the field of nanomedicine is generating a new wave of nanoscale drug delivery strategies, embracing trends that involve the functionalization of these constructs with moieties that enhance site-specific delivery and tailored release. Herein, we discuss several advancements in established nanoparticle technologies such as liposomes, polymer micelles, and dendrimers regarding tumor targeting and controlled release strategies, which are being incorporated into their design with the hope of generating a more robust and efficacious nanotherapeutic modality. We also highlight a novel strategy known as multistage drug delivery; a rationally designed nanocarrier aimed at overcoming numerous biological barriers involved in drug delivery through the decoupling of various tasks that comprise the journey from the moment of systemic administration to arrival at the tumor site.

Size of the Nanovectors Determines the Transplacental Passage in Pregnancy: Study in Rats

American Journal of Obstetrics and Gynecology. Jun, 2011  |  Pubmed ID: 21481834

The objective of the study was to examine whether the size of silicon nanovectors (SNVs) inhibits their entrance into the fetal circulation.

Probing the Mechanical Properties of TNF-α Stimulated Endothelial Cell with Atomic Force Microscopy

International Journal of Nanomedicine. 2011  |  Pubmed ID: 21499414

TNF-α (tumor necrosis factor-α) is a potent pro-inflammatory cytokine that regulates the permeability of blood and lymphatic vessels. The plasma concentration of TNF-α is elevated (> 1 pg/mL) in several pathologies, including rheumatoid arthritis, atherosclerosis, cancer, pre-eclampsia; in obese individuals; and in trauma patients. To test whether circulating TNF-α could induce similar alterations in different districts along the vascular system, three endothelial cell lines, namely HUVEC, HPMEC, and HCAEC, were characterized in terms of 1) mechanical properties, employing atomic force microscopy; 2) cytoskeletal organization, through fluorescence microscopy; and 3) membrane overexpression of adhesion molecules, employing ELISA and immunostaining. Upon stimulation with TNF-α (10 ng/mL for 20 h), for all three endothelial cells, the mechanical stiffness increased by about 50% with a mean apparent elastic modulus of E ~5 ± 0.5 kPa (~3.3 ± 0.35 kPa for the control cells); the density of F-actin filaments increased in the apical and median planes; and the ICAM-1 receptors were overexpressed compared with controls. Collectively, these results demonstrate that sufficiently high levels of circulating TNF-α have similar effects on different endothelial districts, and provide additional information for unraveling the possible correlations between circulating pro-inflammatory cytokines and systemic vascular dysfunction.

Microfluidic Enrichment of Small Proteins from Complex Biological Mixture on Nanoporous Silica Chip

Biomicrofluidics. 2011  |  Pubmed ID: 21522500

The growing field of miniaturized diagnostics is hindered by a lack of pre-analysis treatments that are capable of processing small sample volumes for the detection of low concentration analytes in a high-throughput manner. This letter presents a novel, highly efficient method for the extraction of low-molecular weight (LMW) proteins from biological fluids, represented by a mixture of standard proteins, using integrated microfluidic systems. We bound a polydimethylsiloxane layer patterned with a microfluidic channel onto a well-defined nanoporous silica substrate. Using rapid, pressure-driven fractionation steps, this system utilizes the size-exclusion properties of the silica nanopores to remove high molecular weight proteins while simultaneously isolating and enriching LMW proteins present in the biological sample. The introduction of the microfluidic component offers important advantages such as high reproducibility, a simple user interface, controlled environment, the ability to process small sample volumes, and precise quantification. This solution streamlines high-throughput proteomics research on many fronts and may find broad acceptance and application in clinical diagnostics and point of care detection.

Agarose Surface Coating Influences Intracellular Accumulation and Enhances Payload Stability of a Nano-delivery System

Pharmaceutical Research. Jul, 2011  |  Pubmed ID: 21607779

Protein therapeutics often require repeated administrations of drug over a long period of time. Protein instability is a major obstacle to the development of systems for their controlled and sustained release. We describe a surface modification of nanoporous silicon particles (NSP) with an agarose hydrogel matrix that enhances their ability to load and release proteins, influencing intracellular delivery and preserving molecular stability.

Mesoporous Silica As a Membrane for Ultra-thin Implantable Direct Glucose Fuel Cells

Lab on a Chip. Jul, 2011  |  Pubmed ID: 21637881

The design, fabrication and characterization of an inorganic catalyst based direct glucose fuel cell using mesoporous silica coating as a functional membrane is reported. The desired use of mesoporous silica based direct glucose fuel cell is for a blood vessel implantable device. Blood vessel implantable direct glucose fuel cells have access to higher continuous glucose concentrations. However, reduction in the implant thickness is required for application in the venous system as part of a stent. We report development of an implantable device with a platinum thin-film (thickness: 25 nm) deposited on silicon substrate (500 μm) to serve as the anode, and graphene pressed on a stainless steel mesh (175 μm) to serve as the cathode. Control experiments involved the use of a surfactant-coated polypropylene membrane (50 μm) with activated carbon (198 μm) electrodes. We demonstrate that a mesoporous silica thin film (270 nm) is capable of replacing the conventional polymer based membranes with an improvement in the power generated over conventional direct glucose fuel cells.

Thioaptamer Conjugated Liposomes for Tumor Vasculature Targeting

Oncotarget. Apr, 2011  |  Pubmed ID: 21666286

Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo, the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer and liposome and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agent.

A Low-voltage Electrokinetic Nanochannel Drug Delivery System

Lab on a Chip. Aug, 2011  |  Pubmed ID: 21677944

Recent work has elucidated the potential of important new therapeutic paradigms, including metronomic delivery and chronotherapy, in which the precise timing and location of therapeutic administration has a significant impact on efficacy and toxicity. New drug delivery architectures are needed to not only release drug continuously at precise rates, but also synchronize their release with circadian cycles. We present an actively controlled nanofluidic membrane that exploits electrophoresis to control the magnitude, duration, and timing of drug release. The membrane, produced using high precision silicon fabrication techniques, has platinum electrodes integrated at the inlet and outlet that allow both amplification and reversal of analyte delivery with low applied voltage (at or below 2 VDC). Device operation was demonstrated with solutions of both fluorescein isothiocyanate conjugated bovine serum albumin and lysozyme using fluorescence spectroscopy, fluorescence microscopy, and a lysozyme specific bio-assay and has been characterized for long-term molecular release and release reversibility. Through a combination of theoretical and experimental analysis, the relative contributions of electrophoresis and electroosmosis have been investigated. The membrane's clinically relevant electrophoretic release rate at 2 VDC exceeds the passive release by nearly one order of magnitude, demonstrating the potential to realize the therapeutic paradigm goal.

E-selectin-targeted Porous Silicon Particle for Nanoparticle Delivery to the Bone Marrow

Advanced Materials (Deerfield Beach, Fla.). Sep, 2011  |  Pubmed ID: 21833996

Optimizing Particle Size for Targeting Diseased Microvasculature: from Experiments to Artificial Neural Networks

International Journal of Nanomedicine. 2011  |  Pubmed ID: 21845041

BACKGROUND: Nanoparticles with different sizes, shapes, and surface properties are being developed for the early diagnosis, imaging, and treatment of a range of diseases. Identifying the optimal configuration that maximizes nanoparticle accumulation at the diseased site is of vital importance. In this work, using a parallel plate flow chamber apparatus, it is demonstrated that an optimal particle diameter (d(opt)) exists for which the number (n(s)) of nanoparticles adhering to the vessel walls is maximized. Such a diameter depends on the wall shear rate (S). Artificial neural networks are proposed as a tool to predict n(s) as a function of S and particle diameter (d), from which to eventually derive d(opt). Artificial neural networks are trained using data from flow chamber experiments. Two networks are used, ie, ANN231 and ANN2321, exhibiting an accurate prediction for n(s) and its complex functional dependence on d and S. This demonstrates that artificial neural networks can be used effectively to minimize the number of experiments needed without compromising the accuracy of the study. A similar procedure could potentially be used equally effectively for in vivo analysis.

What Does Physics Have to Do with Cancer?

Nature Reviews. Cancer. Sep, 2011  |  Pubmed ID: 21850037

Large-scale cancer genomics, proteomics and RNA-sequencing efforts are currently mapping in fine detail the genetic and biochemical alterations that occur in cancer. However, it is becoming clear that it is difficult to integrate and interpret these data and to translate them into treatments. This difficulty is compounded by the recognition that cancer cells evolve, and that initiation, progression and metastasis are influenced by a wide variety of factors. To help tackle this challenge, the US National Cancer Institute Physical Sciences-Oncology Centers initiative is bringing together physicists, cancer biologists, chemists, mathematicians and engineers. How are we beginning to address cancer from the perspective of the physical sciences?

Direct Evidence for Catalase and Peroxidase Activities of Ferritin-platinum Nanoparticles

Biomaterials. Feb, 2011  |  Pubmed ID: 21112084

Using apoferritin (apoFt) as a nucleation substrate, we have successfully synthesized 1-2 nm platinum nanoparticles (Pt-Ft) which are highly stable. By directly measuring the products of Pt-Ft-catalyzed reactions, we showed, with no doubt, Pt-Ft possesses both catalase and peroxidase activities. With hydrogen peroxide as substrate, we observed oxygen gas bubbles were generated from hydrogen peroxide decomposed by Pt-Ft; the generation of oxygen gas strongly supports Pt-Ft reacts as catalase, other than peroxidase. While with organic dyes and hydrogen peroxide as substrates, distinctive color products were formed catalyzed by Pt-Ft, which indicates a peroxidase-like activity. Interestingly, these biomimetic properties showed differential response to pH and temperature for different reaction substrates. Pt-Ft showed a significant increase in catalase activity with increasing pH and temperature. The HRP-like activity of Pt-Ft was optimal at physiological temperature and slightly acidic conditions. Our current study demonstrates that Pt-Ft possesses both catalase and peroxidase activities for different substrates under different conditions.

Surface Engineering on Mesoporous Silica Chips for Enriching Low Molecular Weight Phosphorylated Proteins

Nanoscale. Feb, 2011  |  Pubmed ID: 21135976

Phosphorylated peptides and proteins play an important role in normal cellular activities, e.g., gene expression, mitosis, differentiation, proliferation, and apoptosis, as well as tumor initiation, progression and metastasis. However, technical hurdles hinder the use of common fractionation methods to capture phosphopeptides from complex biological fluids such as human sera. Herein, we present the development of a dual strategy material that offers enhanced capture of low molecular weight phosphoproteins: mesoporous silica thin films with precisely engineered pore sizes that sterically select for molecular size combined with chemically selective surface modifications (i.e. Ga3+, Ti4+ and Zr4+) that target phosphoroproteins. These materials provide high reproducibility (CV=18%) and increase the stability of the captured proteins by excluding degrading enzymes, such as trypsin. The chemical and physical properties of the composite mesoporous thin films were characterized by X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy and ellipsometry. Using mass spectroscopy and biostatistics analysis, the enrichment efficiency of different metal ions immobilized on mesoporous silica chips was investigated. The novel technology reported provides a platform capable of efficiently profiling the serum proteome for biomarker discovery, forensic sampling, and routine diagnostic applications.

Nanochannel Technology for Constant Delivery of Chemotherapeutics: Beyond Metronomic Administration

Pharmaceutical Research. Feb, 2011  |  Pubmed ID: 20593302

The purpose of this study is to demonstrate the long-term, controlled, zero-order release of low- and high-molecular weight chemotherapeutics through nanochannel membranes by exploiting the molecule-to-surface interactions presented by nanoconfinement.

Multi-stage Delivery Nano-particle Systems for Therapeutic Applications

Biochimica Et Biophysica Acta. Mar, 2011  |  Pubmed ID: 20493927

The daunting task for drug molecules to reach pathological lesions has fueled rapid advances in Nanomedicine. The progressive evolution of nanovectors has led to the development of multi-stage delivery systems aimed at overcoming the numerous obstacles encountered by nanovectors on their journey to the target site.

Nanodevices in Diagnostics

Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. Jan-Feb, 2011  |  Pubmed ID: 20229595

The real-time, personalized and highly sensitive early-stage diagnosis of disease remains an important challenge in modern medicine. With the ability to interact with matter at the nanoscale, the development of nanotechnology architectures and materials could potentially extend subcellular and molecular detection beyond the limits of conventional diagnostic modalities. At the very least, nanotechnology should be able to dramatically accelerate biomarker discovery, as well as facilitate disease monitoring, especially of maladies presenting a high degree of molecular and compositional heterogeneity. This article gives an overview of several of the most promising nanodevices and nanomaterials along with their applications in clinical practice. Significant work to adapt nanoscale materials and devices to clinical applications involving large interdisciplinary collaborations is already underway with the potential for nanotechnology to become an important enabling diagnostic technology.

Sporadic or Familial Head Neck Paragangliomas Enrolled in a Single Center: Clinical Presentation and Genotype/phenotype Correlations

Head & Neck. Jan, 2012  |  Pubmed ID: 22290790

BACKGROUND: The purpose of this study was to investigate clinical features and prevalence of germline mutations of patients with head/neck paragangliomas. METHODS: Genetic analysis on known susceptibility genes for paragangliomas (VHL, RET, SDHB, SDHC, SDHD, and SDHAF2) was performed in 17 consecutive patients with head/neck paraganglioma (age range, 14-82 years) and 17 relatives. RESULTS: Head/neck paragangliomas were usually symptomatic with "mass effect" (88.2%), without family history (82.3%), often multifocal (41.2%), never functioning, and malignant. Germline mutations were detected in 7 of 17 patients (41%; 6 SDHD and 1 SDHB). Patients with mutations were younger, with head/neck paragangliomas usually multifocal and with higher biologic aggressiveness than wild-type subjects. To date, 4 families have been studied and the prevalence of carriers was elevated (58.8%). These mutated relatives (age range, 17-71 years) were disease-free, except 4 patients in whom multiple head/neck paragangliomas were detected. CONCLUSION: Adequate morpho-functional screening and follow-up and, if possible, genetic testing is advisable in patients with head/neck paraganglioma. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.

Preparation, Characterization, and Cellular Associations of Silicon Logic-embedded Vectors

Methods in Enzymology. 2012  |  Pubmed ID: 22449918

Logic-embedded vectors (LEVs) have been introduced as a means to overcome sequential, biological barriers that prevent particle-based drug delivery systems from reaching their targets. In this chapter, we address the challenge of fabricating and optimizing LEVs to reach non-endosomal targets. We describe the general preparation, characterization, and cellular association of porous silicon-based LEVs. A specific example of LEV fabrication from start to finish, along with optimization and troubleshooting information, is presented to serve as a template for future designs.

Integrated Intravital Microscopy and Mathematical Modeling to Optimize Nanotherapeutics Delivery to Tumors

AIP Advances. Mar, 2012  |  Pubmed ID: 22489278

Inefficient vascularization hinders the optimal transport of cell nutrients, oxygen, and drugs to cancer cells in solid tumors. Gradients of these substances maintain a heterogeneous cell-scale microenvironment through which drugs and their carriers must travel, significantly limiting optimal drug exposure. In this study, we integrate intravital microscopy with a mathematical model of cancer to evaluate the behavior of nanoparticle-based drug delivery systems designed to circumvent biophysical barriers. We simulate the effect of doxorubicin delivered via porous 1000 x 400 nm plateloid silicon particles to a solid tumor characterized by a realistic vasculature, and vary the parameters to determine how much drug per particle and how many particles need to be released within the vasculature in order to achieve remission of the tumor. We envision that this work will contribute to the development of quantitative measures of nanoparticle design and drug loading in order to optimize cancer treatment via nanotherapeutics.

Patient-specific Surgical Simulator for the Pre-operative Planning of Single-incision Laparoscopic Surgery with Bimanual Robots

Computer Aided Surgery : Official Journal of the International Society for Computer Aided Surgery. 2012  |  Pubmed ID: 22489935

Introduction: The trend of surgical robotics is to follow the evolution of laparoscopy, which is now moving towards single-incision laparoscopic surgery. The main drawback of this approach is the limited maneuverability of the surgical tools. Promising solutions to improve the surgeon's dexterity are based on bimanual robots. However, since both robot arms are completely inserted into the patient's body, issues related to possible unwanted collisions with structures adjacent to the target organ may arise. Materials and Methods: This paper presents a simulator based on patient-specific data for the positioning and workspace evaluation of bimanual surgical robots in the pre-operative planning of single-incision laparoscopic surgery. Results: The simulator, designed for the pre-operative planning of robotic laparoscopic interventions, was tested by five expert surgeons who evaluated its main functionalities and provided an overall rating for the system. Discussion: The proposed system demonstrated good performance and usability, and was designed to integrate both present and future bimanual surgical robots.

Chlamydophila Pneumoniae Phospholipase D (CpPLD) Drives Th17 Inflammation in Human Atherosclerosis

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2012  |  Pubmed ID: 22232679

Phospholipases are produced from bacterial pathogens causing very different diseases. One of the most intriguing aspects of phospholipases is their potential to interfere with cellular signaling cascades and to modulate the host-immune response. Here, we investigated the role of the innate and acquired immune responses elicited by Chlamydophila pneumoniae phospholipase D (CpPLD) in the pathogenesis of atherosclerosis. We evaluated the cytokine and chemokine production induced by CpPLD in healthy donors' monocytes and in vivo activated T cells specific for CpPLD that infiltrate atherosclerotic lesions of patients with C. pneumoniae antibodies. We also examined the helper function of CpPLD-specific T cells for monocyte matrix metalloproteinase (MMP)-9 and tissue factor (TF) production as well as the CpPLD-induced chemokine expression by human venular endothelial cells (HUVECs). We report here that CpPLD is a TLR4 agonist able to induce the expression of IL-23, IL-6, IL-1β, TGF-β, and CCL-20 in monocytes, as well as CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1, and VCAM-1 in HUVECs. Plaque-derived T cells produce IL-17 in response to CpPLD. Moreover, CpPLD-specific CD4(+) T lymphocytes display helper function for monocyte MMP-9 and TF production. CpPLD promotes Th17 cell migration through the induction of chemokine secretion and adhesion molecule expression on endothelial cells. These findings indicate that CpPLD is able to drive the expression of IL-23, IL-6, IL-1β, TGF-β, and CCL-20 by monocytes and to elicit a Th17 immune response that plays a key role in the genesis of atherosclerosis.

Rapid Tumoritropic Accumulation of Systemically Injected Plateloid Particles and Their Biodistribution

Journal of Controlled Release : Official Journal of the Controlled Release Society. Feb, 2012  |  Pubmed ID: 22062689

Nanoparticles for cancer therapy and imaging are designed to accumulate in the diseased tissue by exploiting the Enhanced Permeability and Retention (EPR) effect. This limits their size to about 100nm. Here, using intravital microscopy and elemental analysis, we compare the in vivo localization of particles with different geometries and demonstrate that plateloid particles preferentially accumulate within the tumor vasculature at unprecedented levels, independent of the EPR effect. In melanoma-bearing mice, 1000×400nm plateloid particles adhered to the tumor vasculature at about 5% and 10% of the injected dose per gram organ (ID/g) for untargeted and RGD-targeted particles respectively, and exhibited the highest tumor-to-liver accumulation ratios (0.22 and 0.35). Smaller and larger plateloid particles, as well as cylindroid particles, were more extensively sequestered by the liver, spleen, and lungs. Plateloid particles appeared well-suited for taking advantage of hydrodynamic forces and interfacial interactions required for efficient tumoritropic accumulation, even without using specific targeting ligands.

Gadolinium Metallofullerenol Nanoparticles Inhibit Cancer Metastasis Through Matrix Metalloproteinase Inhibition: Imprisoning Instead of Poisoning Cancer Cells

Nanomedicine : Nanotechnology, Biology, and Medicine. Feb, 2012  |  Pubmed ID: 21930111

The purpose of this work is to study the antimetastasis activity of gadolinium metallofullerenol nanoparticles (f-NPs) in malignant and invasive human breast cancer models. We demonstrated that f-NPs inhibited the production of matrix metalloproteinase (MMP) enzymes and further interfered with the invasiveness of cancer cells in tissue culture condition. In the tissue invasion animal model, the invasive primary tumor treated with f-NPs showed significantly less metastasis to the ectopic site along with the decreased MMP expression. In the same animal model, we observed the formation of a fibrous cage that may serve as a physical barrier capable of cancer tissue encapsulation that cuts the communication between cancer- and tumor-associated macrophages, which produce MMP enzymes. In another animal model, the blood transfer model, f-NPs potently suppressed the establishment of tumor foci in lung. Based on these data, we conclude that f-NPs have antimetastasis effects and speculate that utilization of f-NPs may provide a new strategy for the treatment of tumor metastasis. FROM THE CLINICAL EDITOR: In this study utilizing metallofullerenol nanoparticles, the authors demonstrate antimetastasis effects and speculate that utilization of these nanoparticles may provide a new strategy in metastatic tumor therapy.

Value of Multidetector Computed Tomography Image Segmentation for Preoperative Planning in General Surgery

Surgical Endoscopy. Mar, 2012  |  Pubmed ID: 21947742

Using practical examples, this report aims to highlight the clinical value of patient-specific three-dimensional (3D) models, obtained segmenting multidetector computed tomography (MDCT) images, for preoperative planning in general surgery.

Multiscale Modeling of Circular and Elliptical Particles in Laminar Shear Flow

IEEE Transactions on Bio-medical Engineering. Jan, 2012  |  Pubmed ID: 21878403

Drug delivery systems for cancer prevention and pain management have been improved related to classical cancer chemotherapy. Nanotechnology with nanoparticles offers new ways in transport of drug molecules and contrast agents by the blood flow through the circulatory system. In this study, we use multiscale mesoscopic bridging procedure of the finite elements (FE) coupled with dissipative particle dynamics (DPD) and lattice Boltzmann (LB) method to model the motion of circular and elliptical particles in a 2-D laminar flow. Four examples are considered: 1) one sedimenting cylinder in a channel, 2) two sedimenting cylinders in a channel, 3) motion of four elliptical particles in a linear shear flow, and 4) motion of circular and elliptical particle in the arterial bifurcation geometry. A good agreement with solution from the literature available was found. These results show that the multiscale approach with coupled FE and DPD/LB methods can effectively be applied to model motion of micro/nanoparticles for a drug delivery system.