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anatomy | Definition, History, & Biology |

§ October 5th, 2019 § Filed under Nano Medicine Comments Off on anatomy | Definition, History, & Biology |

Anatomy, a field in the biological sciences concerned with the identification and description of the body structures of living things. Gross anatomy involves the study of major body structures by dissection and observation and in its narrowest sense is concerned only with the human body. Gross anatomy customarily refers to the study of those body structures large enough to be examined without the help of magnifying devices, while microscopic anatomy is concerned with the study of structural units small enough to be seen only with a light microscope. Dissection is basic to all anatomical research. The earliest record of its use was made by the Greeks, and Theophrastus called dissection anatomy, from ana temnein, meaning to cut up.

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morphology: Anatomy

The best known aspect of morphology, usually called anatomy, is the study of gross structure, or form, of organs and organisms. It should

Comparative anatomy, the other major subdivision of the field, compares similar body structures in different species of animals in order to understand the adaptive changes they have undergone in the course of evolution.

This ancient discipline reached its culmination between 1500 and 1850, by which time its subject matter was firmly established. None of the worlds oldest civilizations dissected a human body, which most people regarded with superstitious awe and associated with the spirit of the departed soul. Beliefs in life after death and a disquieting uncertainty concerning the possibility of bodily resurrection further inhibited systematic study. Nevertheless, knowledge of the body was acquired by treating wounds, aiding in childbirth, and setting broken limbs. The field remained speculative rather than descriptive, though, until the achievements of the Alexandrian medical school and its foremost figure, Herophilus (flourished 300 bce), who dissected human cadavers and thus gave anatomy a considerable factual basis for the first time. Herophilus made many important discoveries and was followed by his younger contemporary Erasistratus, who is sometimes regarded as the founder of physiology. In the 2nd century ce, Greek physician Galen assembled and arranged all the discoveries of the Greek anatomists, including with them his own concepts of physiology and his discoveries in experimental medicine. The many books Galen wrote became the unquestioned authority for anatomy and medicine in Europe because they were the only ancient Greek anatomical texts that survived the Dark Ages in the form of Arabic (and then Latin) translations.

Owing to church prohibitions against dissection, European medicine in the Middle Ages relied upon Galens mixture of fact and fancy rather than on direct observation for its anatomical knowledge, though some dissections were authorized for teaching purposes. In the early 16th century, the artist Leonardo da Vinci undertook his own dissections, and his beautiful and accurate anatomical drawings cleared the way for Flemish physician Andreas Vesalius to restore the science of anatomy with his monumental De humani corporis fabrica libri septem (1543; The Seven Books on the Structure of the Human Body), which was the first comprehensive and illustrated textbook of anatomy. As a professor at the University of Padua, Vesalius encouraged younger scientists to accept traditional anatomy only after verifying it themselves, and this more critical and questioning attitude broke Galens authority and placed anatomy on a firm foundation of observed fact and demonstration.

From Vesaliuss exact descriptions of the skeleton, muscles, blood vessels, nervous system, and digestive tract, his successors in Padua progressed to studies of the digestive glands and the urinary and reproductive systems. Hieronymus Fabricius, Gabriello Fallopius, and Bartolomeo Eustachio were among the most important Italian anatomists, and their detailed studies led to fundamental progress in the related field of physiology. William Harveys discovery of the circulation of the blood, for instance, was based partly on Fabriciuss detailed descriptions of the venous valves.

The new application of magnifying glasses and compound microscopes to biological studies in the second half of the 17th century was the most important factor in the subsequent development of anatomical research. Primitive early microscopes enabled Marcello Malpighi to discover the system of tiny capillaries connecting the arterial and venous networks, Robert Hooke to first observe the small compartments in plants that he called cells, and Antonie van Leeuwenhoek to observe muscle fibres and spermatozoa. Thenceforth attention gradually shifted from the identification and understanding of bodily structures visible to the naked eye to those of microscopic size.

The use of the microscope in discovering minute, previously unknown features was pursued on a more systematic basis in the 18th century, but progress tended to be slow until technical improvements in the compound microscope itself, beginning in the 1830s with the gradual development of achromatic lenses, greatly increased that instruments resolving power. These technical advances enabled Matthias Jakob Schleiden and Theodor Schwann to recognize in 183839 that the cell is the fundamental unit of organization in all living things. The need for thinner, more transparent tissue specimens for study under the light microscope stimulated the development of improved methods of dissection, notably machines called microtomes that can slice specimens into extremely thin sections. In order to better distinguish the detail in these sections, synthetic dyes were used to stain tissues with different colours. Thin sections and staining had become standard tools for microscopic anatomists by the late 19th century. The field of cytology, which is the study of cells, and that of histology, which is the study of tissue organization from the cellular level up, both arose in the 19th century with the data and techniques of microscopic anatomy as their basis.

In the 20th century anatomists tended to scrutinize tinier and tinier units of structure as new technologies enabled them to discern details far beyond the limits of resolution of light microscopes. These advances were made possible by the electron microscope, which stimulated an enormous amount of research on subcellular structures beginning in the 1950s and became the prime tool of anatomical research. About the same time, the use of X-ray diffraction for studying the structures of many types of molecules present in living things gave rise to the new subspecialty of molecular anatomy.

Scientific names for the parts and structures of the human body are usually in Latin; for example, the name musculus biceps brachii denotes the biceps muscle of the upper arm. Some such names were bequeathed to Europe by ancient Greek and Roman writers, and many more were coined by European anatomists from the 16th century on. Expanding medical knowledge meant the discovery of many bodily structures and tissues, but there was no uniformity of nomenclature, and thousands of new names were added as medical writers followed their own fancies, usually expressing them in a Latin form.

By the end of the 19th century the confusion caused by the enormous number of names had become intolerable. Medical dictionaries sometimes listed as many as 20 synonyms for one name, and more than 50,000 names were in use throughout Europe. In 1887 the German Anatomical Society undertook the task of standardizing the nomenclature, and, with the help of other national anatomical societies, a complete list of anatomical terms and names was approved in 1895 that reduced the 50,000 names to 5,528. This list, the Basle Nomina Anatomica, had to be subsequently expanded, and in 1955 the Sixth International Anatomical Congress at Paris approved a major revision of it known as the Paris Nomina Anatomica (or simply Nomina Anatomica). In 1998 this work was supplanted by the Terminologia Anatomica, which recognizes about 7,500 terms describing macroscopic structures of human anatomy and is considered to be the international standard on human anatomical nomenclature. The Terminologia Anatomica, produced by the International Federation of Associations of Anatomists and the Federative Committee on Anatomical Terminology (later known as the Federative International Programme on Anatomical Terminologies), was made available online in 2011.

morphology: Anatomy

The best known aspect of morphology, usually called anatomy, is the study of gross structure, or form, of organs and organisms. It should not be inferred however, that even the human body, which has been extensively studied, has been so completely explored that nothing

childhood disease and disorder: Anatomical differences

Not only is the childs body smaller than that of the adult, but it has different proportions; for example, the sitting height of the newborn infant represents about 70 percent of total body length. With rapid growth of the extremities, sitting height decreases

zoology: Anatomy or morphology

Descriptions of external form and internal organization are among the earliest records available regarding the systematic study of animals. Aristotle was an indefatigable collector and dissector of animals. He found differing degrees of structural complexity, which he described with regard to ways

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Esophagus Anatomy: Gross Anatomy, Microscopic Anatomy …

§ October 1st, 2019 § Filed under Nano Medicine Comments Off on Esophagus Anatomy: Gross Anatomy, Microscopic Anatomy …

The esophagus is a 25-cm long muscular tube that connects the pharynx to the stomach. [1] The length of the esophagus at birth varies between 8 and 10 cm and measures about 19 cm at age 15 years. [2]

The esophagus extends from the lower border of the cricoid cartilage (at the level of the sixth cervical vertebra) to the cardiac orifice of the stomach at the side of the body of the 11th thoracic vertebra. The upper limit in the newborn infant is found at the level of the fourth or fifth cervical vertebra, and it ends higher, at the level of the ninth thoracic vertebra. [2, 3]

In its vertical course, the esophagus has 2 gentle curves in the coronal plane. The first curve begins a little below the commencement of the esophagus and inclines to the left as far as the root of the neck and returns to the midline at the level of fifth thoracic vertebra. The second curve to the left is formed as the esophagus bends to cross the descending thoracic aorta, before it pierces the diaphragm. The esophagus also has anteroposterior curvatures that correspond to the curvatures of the cervical and thoracic part of the vertebral column. [1, 2]

The video below depicts the esophagus as viewed through an esophagoscope in a 3-year-old child.

The videos below depict other views of normal esophageal anatomy via endoscopy.

The video below depicts normal esophageal anatomy via esophagogastroduodenoscopy.

The esophagus has 3 constrictions in its vertical course, as follows:

The first constriction is at 15 cm from the upper incisor teeth, where the esophagus commences at the cricopharyngeal sphincter; this is the narrowest portion of the esophagus and approximately corresponds to the sixth cervical vertebra

The second constriction is at 23 cm from the upper incisor teeth, where it is crossed by the aortic arch and left main bronchus

The third constriction is at 40 cm from the upper incisor teeth, where it pierces the diaphragm; the lower esophageal sphincter (LES) is situated at this level [1, 2, 3]

These measurements are clinically important for endoscopy and endoscopic surgeries of the esophagus.

The esophagus has been subdivided into 3 portions, as follows:

The cervical portion extends from the cricopharyngeus to the suprasternal notch

The thoracic portion extends from the suprasternal notch to the diaphragm

The abdominal portion extends from the diaphragm to the cardiac portion of the stomach. [3]

The relationships of the cervical esophagus, thoracic esophagus, and abdominal esophagus are described below. [1, 2]

The cervical part of the esophagus

The trachea lies anterior to the esophagus and is connected to it by a loose connective tissue. Posteriorly, it is related to prevertebral muscles and prevertebral fascia covering the bodies of sixth, seventh, and eighth cervical vertebra. The thoracic duct lies on the left side at the level of the sixth cervical vertebra. The carotid sheath with its contents and lower poles of the lateral lobes of thyroid gland are in lateral relation to the esophagus on both the sides.

The thoracic part of the esophagus

The esophagus lies between the trachea and vertebral column in the superior mediastinum. On its way down, the esophagus passes behind the aortic arch, and, at the level of T4/T5 intervertebral discs, it enters the posterior mediastinum. The thoracic duct lies on the left side, and the left recurrent laryngeal nerve lies in the left tracheoesophageal groove. Laterally, on the left side, it is related to the aorta and left subclavian artery; on the right side, it is related to the azygos vein.

Anteriorly, the esophagus is related to the trachea, right pulmonary artery, left bronchus, pericardium with left atrium, and diaphragm. Posteriorly, the esophagus is related to the vertebral column, right posterior intercostal arteries, thoracic duct, thoracic part of the aorta, and diaphragm. In the posterior mediastinum, the esophagus is related to the descending thoracic aorta, left mediastinal pleura, azygos vein, and cardiac and pulmonary plexus.

The abdominal part of the esophagus

The esophagus passes through the right crus of the diaphragm. In its abdominal course, it is covered with the peritoneum of the greater sac anteriorly and on its left side, and it is covered with the lesser sac peritoneum on the right side. It comes to lie in the esophageal groove on the posterior surface of the left lobe of the liver and curves sharply to the left to join the stomach at the cardia. The right border continues evenly into the lesser curvature, whereas the left border is separated from the fundus of the stomach by the cardiac notch. [2]

See the list below:

The cervical portion is supplied by the inferior thyroid artery

The thoracic portion is supplied by bronchial and esophageal branches of the thoracic aorta

The abdominal portion is supplied by ascending branches of the left phrenic and left gastric arteries. [1]

Venous blood from the esophagus drains into a submucosal plexus. From this plexus, blood drains to the periesophageal venous plexus. Esophageal veins arise from this plexus and drain in a segmental way similar to the arterial supply, as follows:

From the cervical esophagus, veins drain into the inferior thyroid vein

From the thoracic esophagus, veins drain into the azygos veins, hemiazygos, intercostal, and bronchial veins

From the abdominal portion, esophagus veins drain into the left gastric vein; the left gastric vein is a tributary of the portal system. [1, 2]

The esophagus has an extensive, longitudinally continuous, submucosal lymphatic system. [2] The esophagus has 2 types of lymphatic vessels. A plexus of large vessels is present in the mucous membrane, and it is continuous above with the mucosal lymphatic vessels of pharynx and below with mucosal lymphatic vessels of gastric mucosa. The second plexus of finer vessels is situated in the muscular coat. Efferent vessels from the cervical part drain into the deep cervical nodes. Vessels from the thoracic part drain to the posterior mediastinal nodes and from the abdominal part drain to the left gastric nodes. Some vessels may pass directly to the thoracic duct. [1, 2]

Lymphatic drainage of the esophagus contains little barrier to spread, and esophageal lymphatics are densely interconnected. Hence, esophagus carcinoma can spread through the length of the esophagus via lymphatics and may have nodal involvement several centimeters away from the primary lesion. [3]

Recurrent laryngeal branches of the vagus nerve supply the striated muscle in the upper third of the esophagus, and cell bodies for these fibers are situated in the rostral part of the nucleus ambiguus. Motor supply to the nonstriated muscle is parasympathetic, and cell bodies for these fibers are situated in the dorsal nucleus of vagus. These fibers reach the esophagus through the vagus and its recurrent laryngeal branches. They synapse in the esophagus wall in the ganglia of submucosal plexus (Meissner) and myenteric plexus (Auerbach). The myenteric is situated between the outer longitudinal and inner circular muscle fibers. From these plexuses, short, postganglionic fibers emerge to innervate the mucous glands and smooth muscle fibers within the walls of the esophagus. [2]

Vasomotor sympathetic fibers that supply the esophagus arise from the upper 4-6 thoracic spinal cord segments. Fibers from the upper ganglia pass to the middle and inferior cervical ganglia and synapse on postganglionic neurons. The axons of these neurons innervate the vessels of the cervical and upper thoracic esophagus. Postsynaptic fibers from the lower ganglia pass to the esophageal plexus to innervate the distal esophagus. Afferent visceral pain fibers travel via the sympathetic fibers to the first 4 segments of the thoracic spinal cord. [1]

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About John Snow

§ October 1st, 2019 § Filed under Nano Medicine Comments Off on About John Snow

John Snow is an iconic figure in epidemiology and public health, best known for his work on cholera, for a famous map, and for organising the removal of a pump handle in Soho.

Less well known are his important contributions to anaesthesia and to epidemiological methods, and his engagement in public debates of the time. The breadth and depth of Snows activities provide a model for population researchers concerned not only with sound method but also with bringing their results to public benefit.

Indeed, though epidemiology is often described as the study of health-related aspects of populations, its methods are applicable to studies of virtually anything in populations, and disciplines which now acknowledge the methods and terminology of epidemiology range from education to crime science and economics.

Snow was born in York on 15 March 1813, one of eight children in a family of modest means. He apprenticed with a surgeon-apothecary in Newcastle from 1827 to 1833, and there witnessed the first epidemic of cholera in the UK.He then moved to London, qualified as physician in 1843 and set up general practice in Soho. Early in his career he became interested in the physiology of respiration in recognition of the major problem of asphyxia of the newborn.

These interests led him to be invited to witness one of the first applications of ether anaesthesia in the UK in December 1846. He immediately recognised the importance of ambient temperature and within one month published tables of the vapour pressure of ether.This initiated an important line of research on instruments for administering anaesthetics and led to his becoming the most prominent authority on anaesthesia in the UK. He administered chloroform to Queen Victoria at the birth of Prince Leopold in 1853.

The second great cholera epidemic arrived in London in 1848 and many attributed its cause to an atmospheric effluence or miasma. Snows firsthand experience of the disease in 1832, combined with studies of respiration, led him to question miasma theories and to publish the first edition of On the Mode of Communication of Cholera in 1849, in which he proposed that cholera was attributable to a self-replicating agent which was excreted in the cholera evacuations and inadvertently ingested, often, but not necessarily, through the medium of water.

When cholera returned in 1853, Snow recognised an ideal opportunity to test his hypothesis by comparing cholera mortality rates in populations of south London supplied by water drawn from sewage-contaminated versus uncontaminated regions of the Thames. He personally carried out a cohort study to make this comparison, recognising the need to confirm the water source of each case and to assure comparability of the populations concerned.

On 30 August 1854 while involved in these studies, a dramatic cholera epidemic began near his home in Soho leading to more than 550 deaths within two weeks. Analysis of the addresses of the cholera deaths and interviews of residents of the area led him to suspect that water from a pump on Broad Street was responsible and he prevailed upon the local council to remove the handle of the pump on 8 September 1854.

Though the epidemic was already in decline by that date, the rapidity of his action, the logic of the analysis, and the pragmatism of the response has made this a classic event in the history of public health, well known to students and practitioners the world over. The combination of these studies provided overwhelming evidence for an infectious agent, known now as Vibrio cholerae.

Snow described this work in the second edition of On the Mode of Communication of Cholera. He then expanded his public health interests by becoming involved in debates over legislation concerning nuisance industries in London, while maintaining his research and practice in anaesthesia until his death in 1858.

The 200th anniversary of Snows birth provides an occasion to celebrate his achievements, to consider their original context, to discuss their place in contemporary epidemiology, and consider their likely future, not only as the armamentarium of public health, but as a framework of method for science and society.

Image: John Snow. Credit: LSHTM Library & Archives.

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The First Use of the Microscope in Medicine

§ September 24th, 2019 § Filed under Nano Medicine Comments Off on The First Use of the Microscope in Medicine

The microscope is undoubtedly one of the greatest inventions that men have ever made. The use of lenses for spectacles (eyeglasses), distant vision (telescopes), and high magnification (microscopes) required early lens makers accurately to grind lenses with different focal lengths. During the 16th and 17th centuries, Holland and Italy were the principal countries for the construction and use of telescopes and microscopes.

The compound microscope (with two convex lenses) was invented in Holland around 1590 by two spectacle makers, Hans Jannsen and his son, Zacharias. During the early 1600s, Galileo (15641642) made several telescopes and microscopes that he called occhialino. Also in Italy, James Faber, a physician, coined the word microscope in 1625; and the first association of microscopists was formed.

In 1653, Petrus Borellus [1] wrote the first publication on the use of microscope in medicine. He described 100 observations and applications, including how to remove ingrowing eyelashes that are invisible to the naked eye. In 1646, Athanasius Kircher [2] (or Kirchner, as it is often spelled), a Jesuit priest, wrote that a number of things might be discovered in the blood of fever patients. In 1658, in his Scrutinium Pestis, Kirchner [3] described microscopic worms in plague victims which he suspected caused the disease that killed millions of people in Europe during the 17th century. Most likely, he was viewing pus cells, or perhaps red blood cells, since he could not possibly see the Bacillus pestis with his 32-power microscope. Another early microscopist was Joseph Campini of Bologna. His microscope was the first that was depicted in clinical use in medicine (Fig. 1) [4].

While there were many botanists and zoologists who used microscope in the 17th century, there were few physicians. The observations of Leeuwenhoek (16321723), a Dutch drapery maker, excelled all other microscopists, because of his skill in making high quality lenses. The red blood cell was described in 1667 by Swammerdam (16371680) [5] and in 1673 by Malpighi (16281694), but it was Leeuwenhoek in 1695 who first illustrated red blood cells in his Arcana [6]. In the 190 letters that he wrote to the Royal Society in London over a period of 50 years, Leeuwenhoek gave descriptions and illustrations of bacteria from the human mouth, protozoa, spermatozoa, striations of skeletal muscles and epithelial cells from a wart on the trunk of an elephant in the Amsterdam Zoo [79].

Malpighi (16281694) a microscopist, histologist and embryologist, was the first person to see the anastomosis between arterial and venous capillaries [10]. His descriptions of the Malpighian bodies of the kidney, the Malpighian corpuscles of the spleen, and the Malpighian layer of the epidermis are known to every student of medicine [11].

Despite the countless people, including royalty, who paid tribute to early microscopists, the medical world, practicing clinicians, and academic physicians generally ignored or ridiculed them. The microscope was not appreciated as a useful scientific instrument by leaders in morbid anatomy such as Morgagni (16821771), John Hunter (17281793), and Mettew Baillie (17611823). The first atlas of pathology [12], written by Baillie and published in 1799, contains not even one microscopic illustration among more than 100 engravings.

Clinical microscopy had a slow beginning; more than two centuries passed before the value of microscopes began to be appreciated by clinical and laboratory scientists. In 1800, Bichat (17711802), a young pathologist, published a book in which, for the first time, morbid anatomic and histopathologic changes of various organs of the body were discussed and illustrated [13]. Soon thereafter the microscope became an indispensable laboratory tool at medical schools all around the world.

This is the first illustration of the microscope in use for clinical examinations in medicine. The microscope designed by Joseph Campani of Bologna is standing on a table (in an enlarged form, left of the picture); and a hand-held microscope is shown in actual use to examine a wound on the leg of the recumbent patient. Note the woman who holds a candle and a mirror for optimal illumination. A second observer with a microscope (standing on the left) seems confused about whether he is using a microscope or a telescope. (Figure from page 372 of Acta Eruditorum, 1686, ref. [4]).

Borellus P. Historiarum et observationum medico-physicarum centuria. A Colomerium, Castris, 1653.

Kircher A. Ars magna lucis et umbrae, 1646.

Kircher A. Scrutinium Pestis, 1658.

Schelftrateus. Description of a new microscope made by Joseph Campani. Acta Eruditorum. Leipzig, 1686 p.372.

Swammerdam J. Tractus physicoanatomico medicus de respiratione usuque pulmonum. Abraham et Adrian, Lugduni Batavorum,1667.

Leeuwenhoek A van. Arcana natura detecta, Batav, Delphis, 1695.

Leeuwenhoek A van. Some microscopical observations, about animals in the scurf of the teeth,Phil Trans 1684;14:568574.

Leeuwenhoek A van. Microscopical observations concerning blood, milk, bone, the brain, spittle, and cuticula, etc. Phil Trans 1674,9:121128.

Leeuwenhoek A van. Ontledingen en ontdekkingen. Leiden, Delft, 1693 to 1718.

Malpighi M. De viscerum structura exercitatio anatomica. J Montij, Bononiae, 1666.

Malpighi M. Opera omnia. R Scott, Londini, 1686.

Baillie M. A series of engravings with explanations, which are intended to illustrate the morbid anatomy of some of the most important parts of the human body. W Bulmer & Co, London, 1799.

Bichat MFX. Trait des membranes en gnral et diverses membranes en particulier. Richard, Caille & Ravier, Paris, 1800.

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Microscopic colitis – Symptoms and causes – Mayo Clinic

§ September 14th, 2019 § Filed under Nano Medicine Comments Off on Microscopic colitis – Symptoms and causes – Mayo Clinic


Microscopic colitis is an inflammation of the large intestine (colon) that causes persistent watery diarrhea. The disorder gets its name from the fact that it's necessary to examine colon tissue under a microscope to identify it, since the tissue may appear normal with a colonoscopy or flexible sigmoidoscopy.

There are different subtypes of microscopic colitis:

Researchers believe collagenous (kuh-LAYJ-uh-nus) colitis and lymphocytic colitis may be different phases of the same condition. Symptoms, testing and treatment are the same for all subtypes.

Signs and symptoms of microscopic colitis include:

The symptoms of microscopic colitis can come and go frequently. Sometimes the symptoms resolve on their own.

If you have watery diarrhea that lasts more than a few days, contact your doctor so that your condition can be diagnosed and properly treated.

It's not clear what causes the inflammation of the colon found in microscopic colitis. Researchers believe that the causes may include:

Risk factors for microscopic colitis include:

Some research studies indicate that using certain medications may increase your risk of microscopic colitis. But not all studies agree.

Medications that may be linked to the condition include:

Most people are successfully treated for microscopic colitis. The condition does not increase your risk of colon cancer.

Microscopic colitis care at Mayo Clinic

June 26, 2019

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Microscopic colitis – Diagnosis and treatment – Mayo Clinic

§ September 14th, 2019 § Filed under Nano Medicine Comments Off on Microscopic colitis – Diagnosis and treatment – Mayo Clinic


A complete medical history and physical examination can help determine whether other conditions, such as celiac disease, may be contributing to your diarrhea.

Your doctor will also ask about any medications you are taking particularly aspirin, ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve), proton pump inhibitors, and selective serotonin reuptake inhibitors (SSRIs) which may increase your risk of microscopic colitis.

To help confirm a diagnosis of microscopic colitis, you may have one or more of the following tests and procedures:

Flexible sigmoidoscopy. This procedure is similar to a colonoscopy, but rather than viewing the entire colon, a flexible sigmoidoscopy allows your doctor to view the inside of the rectum and most of the sigmoid colon about the last 2 feet (61 centimeters) of the large intestine.

The doctor uses a slender, flexible, lighted tube (sigmoidoscope) to examine the intestinal lining. A tissue sample can be taken through the scope during the exam.

Because intestinal issues often appear normal in microscopic colitis, a definite diagnosis of microscopic colitis requires a colon tissue sample (biopsy) obtained during a colonoscopy or flexible sigmoidoscopy. In both subtypes of microscopic colitis, cells in colon tissue have a distinct appearance under the microscope, so the diagnosis is definite.

In addition to a colonoscopy or flexible sigmoidoscopy, you may have one or more of these tests to rule out other causes for your symptoms.

Microscopic colitis may get better on its own. But when symptoms persist or are severe, you may need treatment to relieve them. Doctors usually try a stepwise approach, starting with the simplest, most easily tolerated treatments.

Treatment usually begins with changes to your diet and medications that may help relieve persistent diarrhea. Your doctor may recommend that you:

If signs and symptoms persist, your doctor may recommend:

When the symptoms of microscopic colitis are severe, and medications aren't effective, your doctor may recommend surgery to remove all or part of your colon. Surgery is rarely needed to treat microscopic colitis.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Changes to your diet may help relieve diarrhea that you experience with microscopic colitis. Try to:

Here's some information to help you get ready for your appointment and know what to expect from your doctor.

Some basic questions to ask your doctor include:

Don't hesitate to ask questions anytime you don't understand something.

Be ready to answer questions your doctor is likely to ask you:

You may find some relief from persistent diarrhea by making changes to your diet:

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Challenges and strategies in anti-cancer nanomedicine …

§ June 2nd, 2019 § Filed under Nano Medicine Comments Off on Challenges and strategies in anti-cancer nanomedicine …

JavaScript is disabled on your browser. Please enable JavaScript to use all the features on this page.Abstract

Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.


EPR effect

Clinical translation

Pre-clinical models


Companion diagnostics

Patient pre-selection

Recommended articlesCiting articles (0)

2016 The Author(s). Published by Elsevier B.V.

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Nanomedicine – an overview | ScienceDirect Topics

§ May 21st, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine – an overview | ScienceDirect Topics

12.1 Why Nanomaterials?

Nanomedicine is a hot field. Up to 2004, only 72 scientific articles on nanomedicine had been published according to Medline, but during 20052015 that number soared to 10.502 (data retrieved July 30, 2015 from It can be argued, however, that nanoparticles (NPs) have an old history in medicine. Nanosilver used against bacterial infections is a well-known example, but nanosized agents have also been applied for many years to modulate immune responses. Colloidal gold used to treat rheumatoid arthritis1 and alum used as adjuvant for various vaccines2 have contained nanomaterials long before that term became familiar, or before the presence of nanosized components has been considered to be relevant. It is thus not quite true that there is no experience on effects of artificial nanomaterials on the human body. Many practical uses of NPs go back a long time, but medical applications are of special relevance, since here the agents are applied to health-compromised persons, they are applied intentionally, often locally, and usually in doses that would never be reached, for example, during unintentional work place exposure.

The use of NPs for modulating immunity seems to be an obvious perspective. Engineered NPs are nonself and they overlap in size with viruses (mostly 10200nm size range3), so they fall well within the target size range to which immunity is capable to respond, and since at least some types of NPs are toxic, they can be expected to result in danger signals as well (Fig. 12.1).

Figure 12.1. Nanoscale sizes compared to other relevant objects. Nanomaterials are in the size range of biological molecules and entities. The biological and the physical world interact on the same scale, which is the basis for many nanospecific effects that can be exploited for medical purposes.

In addition, some nanomaterials exhibit repetitive patterns originating from the process of synthesis, so even recognition by pattern recognition receptors may be envisioned. The present overview will highlight features of nanomedical agents without restricting itself to the ISO standard, which defines nanoparticles as objects that have in all three dimensions sizes between 1100nm (ISO/TS 27687:2008 Nanotechnologies Terminology and definitions for nano objects nanoparticle, nanofibre and nanoplate). Objects with sizes up to several hundred nm have been described and used as nanomedical agents, so in the present review, all materials that have been described as such will be considered as nanomedical agents. Strictly defined, nanopharmaceuticals should not only be in the nanosize range, but should also exploit the particular properties of the nanoscale for the therapeutic effect, so the nanoscale should add functionalities that cannot be obtained by using either the compound chemicals or bulk materials.4

Considering investigational and approved nanomedical products, the most prominent area of current use is in the treatment of cancers, where drug targeting is a major issue, but several approved drugs are also aiming at immunity.57 A general overview of interactions between nanomaterials and the immune system has been provided by several recent books.810 Here we will focus on medical applications that aim at modifying immune responses in a preventive or a therapeutic setting. In the context of nanosafety research, some types of NPs have been shown to stimulate the immune system, while others were reported to repress immunity. Confusingly, both claims have been made sometimes for very similar materials, reflecting the by now well recognized problem that many nanotoxicology studies have not provided enough data to rule out problems like contamination with endotoxin or with synthesis chemicals, insufficiently well described materials, particle aging effects, assay interference by particles, or batch-to-batch variation between nominally identical particle preparations.11 Quality issues in nanosafety testing have recently been extensively described by H. Krug.12

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Journal of Nanomedicine and Biotherapeutic Discovery- Open …

§ May 13th, 2019 § Filed under Nano Medicine Comments Off on Journal of Nanomedicine and Biotherapeutic Discovery- Open …

Nanomedicine is an application of nanotechnology which made its debut with greatly increased possibilities in the field of medicine. Nanomedicine desires to deliver research tools and clinically reformative devices in the near future.

Journal of Nanomedicine & Biotherapeutic Discovery is a scholarly open access journal publishing articles amalgamating broad range of fields of novel nano-medicine field with life sciences. Nanomedicine & Biotherapeutic Discovery is an international, peer-reviewed journal providing an opportunity to researchers and scientist to explore the advanced and latest research developments in the field of nanoscience & nanotechnology.

This is the best academic journal which focuses on the use nanotechnology in diagnostics and therapeutics; pharmacodynamics and pharmacokinetics of nanomedicine, drug delivery systems throughout the biomedical field, biotherapies used in diseases treatment including immune system-targeted therapies, hormonal therapies to the most advanced gene therapy and DNA repair enzyme inhibitor therapy. The journal also includes the nanoparticles, bioavailability, biodistribution of nanomedicines; delivery; imaging; diagnostics; improved therapeutics; innovative biomaterials; regenerative medicine; public health; toxicology; point of care monitoring; nutrition; nanomedical devices; prosthetics; biomimetics and bioinformatics.

The journal includes a wide range of fields in its discipline to create a platform for the authors to make their contribution towards the journal and the editorial office promises a peer review process for the submitted manuscripts for the quality of publishing. Biotherapeutics journals impact factors is mainly calculated based on the number of articles that undergo single blind peer review process by competent Editorial Board so as to ensure excellence, essence of the work and number of citations received for the same published articles.

The journal is using Editorial Manager System for quality peer review process. Editorial Manager is an online manuscript submission, review and tracking systems. Review processing is performed by the editorial board members of Journal of Nanomedicine & Biotherapeutic Discovery or outside experts; at least two independent reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission/review/revise/publish process.

Submit manuscript at or send as an e-mail attachment to the Editorial Office at[emailprotected]

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Nanomedicine Market 2019 Global Share, Trends …

§ April 29th, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine Market 2019 Global Share, Trends …

Apr 29, 2019 (Heraldkeeper via COMTEX) -- Nanomedicine Market 2019

This report focuses on the global Nanomedicinestatus, future forecast, growth opportunity, key market and key players. The study objectives are to present the Nanomedicine development in United States, Europe and China.

Nanomedicine is the medical application of nanotechnology.Nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines. As per the WHO factsheet, cancer is found to be one of the major causes of mortality and morbidity worldwide, with approximately 14 million new cases in 2012 and 8.2 million cancer-related deaths. Thus, demand for nanomedicine in order to curb such high incidence rate is expected to boost market progress during the forecast period. Potential pipeline of products based on the nanomolecules and associated technologies are anticipated to drive market with potential avenues of growth. Presence of around 40% of products in phase II of clinical development, is anticipated to result in a number of key commercialization over the coming decade influencing revenue generation over the forecast period. The customized treatment options available for eradication of genetic abnormalities also makes this technology a substantial option for precision medicine. Asia Pacific is expected to witness lucrative growth through to 2025 as a result of rise in number of research grants and increase in demand for prophylaxis of life-threatening diseases. Moreover, rise in the number of venture capital investors from developing economies of this region and increasing international research collaborations are anticipated to propel growth in nanotechnology-based healthcare industry.

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The key players covered in this studyCombimatrix Ablynx Abraxis Bioscience Celgene Mallinckrodt Arrowhead Research GE Healthcare Merck Pfizer Nanosphere Epeius Biotechnologies Cytimmune Sciences Nanospectra Biosciences

Market segment by Type, the product can be split intoQuantum dots Nanoparticles Nanoshells Nanotubes Nanodevices

Market segment by Application, split intoSegmentation encompasses oncology Infectious diseases Cardiology Orthopedics Others

Market segment by Regions/Countries, this report coversUnited States Europe China Japan Southeast Asia India Central & South America

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Table of Contents -Analysis of Key Points

1 Report Overview1.1 Study Scope 1.2 Key Market Segments 1.3 Players Covered 1.4 Market Analysis by Type 1.4.1 Global Nanomedicine Market Size Growth Rate by Type (2013-2025) 1.4.2 Quantum dots 1.4.3 Nanoparticles 1.4.4 Nanoshells 1.4.5 Nanotubes 1.4.6 Nanodevices 1.5 Market by Application 1.5.1 Global Nanomedicine Market Share by Application (2013-2025) 1.5.2 Segmentation encompasses oncology 1.5.3 Infectious diseases 1.5.4 Cardiology 1.5.5 Orthopedics 1.5.6 Others 1.6 Study Objectives 1.7 Years Considered

2 Global Growth Trends2.1 Nanomedicine Market Size 2.2 Nanomedicine Growth Trends by Regions 2.2.1 Nanomedicine Market Size by Regions (2013-2025) 2.2.2 Nanomedicine Market Share by Regions (2013-2018) 2.3 Industry Trends 2.3.1 Market Top Trends 2.3.2 Market Drivers 2.3.3 Market Opportunities

3 Market Share by Key Players3.1 Nanomedicine Market Size by Manufacturers 3.1.1 Global Nanomedicine Revenue by Manufacturers (2013-2018) 3.1.2 Global Nanomedicine Revenue Market Share by Manufacturers (2013-2018) 3.1.3 Global Nanomedicine Market Concentration Ratio (CR5 and HHI) 3.2 Nanomedicine Key Players Head office and Area Served 3.3 Key Players Nanomedicine Product/Solution/Service 3.4 Date of Enter into Nanomedicine Market 3.5 Mergers & Acquisitions, Expansion Plans


12 International Players Profiles12.1 Combimatrix12.1.1 Combimatrix Company Details 12.1.2 Company Description and Business Overview 12.1.3 Nanomedicine Introduction 12.1.4 Combimatrix Revenue in Nanomedicine Business (2013-2018) 12.1.5 Combimatrix Recent Development 12.2 Ablynx12.2.1 Ablynx Company Details 12.2.2 Company Description and Business Overview 12.2.3 Nanomedicine Introduction 12.2.4 Ablynx Revenue in Nanomedicine Business (2013-2018) 12.2.5 Ablynx Recent Development 12.3 Abraxis Bioscience12.3.1 Abraxis Bioscience Company Details 12.3.2 Company Description and Business Overview 12.3.3 Nanomedicine Introduction 12.3.4 Abraxis Bioscience Revenue in Nanomedicine Business (2013-2018) 12.3.5 Abraxis Bioscience Recent Development 12.4 Celgene12.4.1 Celgene Company Details 12.4.2 Company Description and Business Overview 12.4.3 Nanomedicine Introduction 12.4.4 Celgene Revenue in Nanomedicine Business (2013-2018) 12.4.5 Celgene Recent Development 12.5 Mallinckrodt12.5.1 Mallinckrodt Company Details 12.5.2 Company Description and Business Overview 12.5.3 Nanomedicine Introduction 12.5.4 Mallinckrodt Revenue in Nanomedicine Business (2013-2018) 12.5.5 Mallinckrodt Recent Development 12.6 Arrowhead Research12.6.1 Arrowhead Research Company Details 12.6.2 Company Description and Business Overview 12.6.3 Nanomedicine Introduction 12.6.4 Arrowhead Research Revenue in Nanomedicine Business (2013-2018) 12.6.5 Arrowhead Research Recent Development 12.7 GE Healthcare12.7.1 GE Healthcare Company Details 12.7.2 Company Description and Business Overview 12.7.3 Nanomedicine Introduction 12.7.4 GE Healthcare Revenue in Nanomedicine Business (2013-2018) 12.7.5 GE Healthcare Recent Development 12.8 Merck12.8.1 Merck Company Details 12.8.2 Company Description and Business Overview 12.8.3 Nanomedicine Introduction 12.8.4 Merck Revenue in Nanomedicine Business (2013-2018) 12.8.5 Merck Recent Development 12.9 Pfizer12.9.1 Pfizer Company Details 12.9.2 Company Description and Business Overview 12.9.3 Nanomedicine Introduction 12.9.4 Pfizer Revenue in Nanomedicine Business (2013-2018) 12.9.5 Pfizer Recent Development 12.10 Nanosphere12.10.1 Nanosphere Company Details 12.10.2 Company Description and Business Overview 12.10.3 Nanomedicine Introduction 12.10.4 Nanosphere Revenue in Nanomedicine Business (2013-2018) 12.10.5 Nanosphere Recent Development


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Nanomedicine Market Is Estimated To Be Valued At $350.8 …

§ April 28th, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine Market Is Estimated To Be Valued At $350.8 …

Apr 26, 2019 (AB Digital via COMTEX) -- According to a report,"Nanomedicine Market Analysis By Products, (Therapeutics, Regenerative Medicine, Diagnostics), By Application, (Clinical Oncology, Infectious diseases), By Nanomolecule (Gold, Silver, Iron Oxide, Alumina), & Segment Forecasts, 2018 - 2025" , published by Grand View Research, Inc.,   The global nanomedicine market is anticipated to reach USD 350.8 billion by 2025. Application of nanotechnology-based contrast reagents for diagnosis and monitoring of the effects of drugs on an unprecedented short timescale is also attributive drive growth in the coming years. Additionally, demand for biodegradable implants with longer lifetimes that enable tissue restoration is anticipated to influence demand. As per the WHO factsheet, cancer is found to be one of the major causes of mortality and morbidity worldwide, with approximately 14 million new cases in 2012 and 8.2 million cancer-related deaths.

Key Takeaways from the report:

U.S. nanomedicine market by products, 2013 - 2025 (USD Billion)

Browse More Reports in Pharmaceuticals Industry:

Pruritus Therapeutics Market: Growing worldwide prevalence of atopic dermatitis, allergic contact dermatitis and urticaria is expected to drive market growth during the forecast period. Introduction of new products based on scientific mechanistic understanding such as the identification of new T-cell subsets, particularly Th17, and Th22 and the patent expiration of PROTOPIC (tacrolimus) is expected to open up new avenues for manufacturers to capitalize on over the forecast period. 

Atrial fibrillation market: Rising occurrence of strokes, brain damage and atrial fibrillation owing to blood clots along with an increasing geriatric population is expected to drive industry growth.

Solutions such as nanoformulations with triggered release for tailor-made pharmacokinetics, nanoparticles for local control of tumor in combination with radiotherapy, and functionalized nanoparticles for targeted in-vivo activation of stem cell production are anticipated to drive R&D, consequently resulting in revenue generation in the coming years.

Nanomedicine market, by region, 2016 (%)

Biopharmaceutical and medical devices companies are actively engaged in development of novel products as demonstrated by the increasingly growing partnerships between leading enterprises and nanomedicine startups. For instance, in November 2015, Ablynx and Novo Nordisk signed a global collaboration and a licensing agreement for development and discovery of innovative drugs with multi-specific nanobodies. This strategic partnership is anticipated to rise the net annual sales of the products uplifting the market growth.

However, in contrary with the applications of nanotechnology, the entire process of lab to market approval is a tedious and expensive one with stringent regulatory evaluation involved thereby leading investors to remain hesitant for investments.

Grand View Research has segmented the nanomedicine market on the basis of product, application, nanomolecule type, and region:

Nanomedicine Product Outlook (Revenue, USD Billion; 2013 - 2025)

Nanomedicine Application Outlook (Revenue, USD Billion; 2013 - 2025)

Nanomedicine Nanomolecule Type Outlook (Revenue, USD Billion; 2013 - 2025)

Nanomedicine Regional Outlook (Revenue, USD Billion; 2013 - 2025)

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About Grand View Research

Grand View Research provides syndicated as well as customized research reports and consulting services on 46 industries across 25 major countries worldwide. This U.S.-based market research and consulting company is registered in California and headquartered in San Francisco. Comprising over 425 analysts and consultants, the company adds 1200+ market research reports to its extensive database each year. Supported by an interactive market intelligence platform, the team at Grand View Research guides Fortune 500 companies and prominent academic institutes in comprehending the global and regional business environment and carefully identifying future opportunities.

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Media Contact Company Name: Grand View Research, Inc. Contact Person: Sherry James, Corporate Sales Specialist - U.S.A. Email: Send Email Phone: 1-415-349-0058, Toll Free: 1-888-202-9519 Address:201, Spear Street, 1100 City: San Francisco State: California Country: United States Website:

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Regulating Nanomedicine at the Food and Drug Administration …

§ April 26th, 2019 § Filed under Nano Medicine Comments Off on Regulating Nanomedicine at the Food and Drug Administration …

Abstract The US Food and Drug Administration (FDA) oversees safety and efficacy of a broad spectrum of medical products (ie, drugs, biologics, and devices) under the auspices of federal legislation and agency regulations and policy. Complex and emerging nanoscale products challenge this regulatory framework and illuminate its shortcomings for combination products that integrate multiple mechanisms of therapeutic action. This article surveys current FDA regulatory structures and nanotechnology-specific guidance, discusses relevant nanomedicine products, and identifies regulatory challenges. Regulatory Demands of Nanotechnology

Nanotechnology is research and technology development on the nanoscale (traditionally 100 nanometers (nm) or less, or one billionth of a meter) at which particles have novel properties and functions because of their size.1 At this size, materials exhibit quantum effects, impacting fluorescence, conductivity, magnetic permeability, melting point, and reactivity.1 The ability to control atoms and molecules at the nanoscale has significantly advanced medical science and catalyzed the field of nanomedicine, defined by the National Institutes of Health as a highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone, muscle, or nerve.2 Nanomedicine also includes nanotechnology applications for diagnosis, monitoring, and control of biological systems.3

Cutting-edge nanomedicine applications often integrate chemical, mechanical, and biological properties to enable and enhance detection, diagnostic capabilities, and therapeutic modes of action. In the near future, it will be possible for a single nanomedicine product, once deployed in a patients body, to be programmed to target specific organs and tissues, create images, measure vital signs, diagnose in real time, and subsequently provide tailored therapeutics.

The US Food and Drug Administration (FDA), as a gatekeeper of health care products, plays a vital role in assessing nanomedicine products. However, its decades-old classifications to distinguish product domains for purposes of review and approval prove challenging for nanomedicine products due to their novel characteristics and cross-category features. In addition, nanoscale particles and materials have different risk profiles given their decreased size, increased biological activity, and unique properties. These risk profiles, which are largely unknown, create novel legal and ethical challenges for clinical trials, patient use, and public health.

The FDA is tasked with protecting public health and promoting innovations and striking a balance between the two when evaluating products generated by science and emerging technologies. The FDA regulates products under 2 primary statutes: the Food, Drug, and Cosmetic Act (FDCA), which addresses chemically synthesized drugs as well as devices; and the Public Health Service Act (PHSA), which addresses biologically derived therapeutic products.4 The FDA must characterize products under definitions provided by Congress in both the FDCA and the PHSA. Fundamentally, these definitions and supplemental FDA policies distinguish among 3 product areas based on whether the product has a chemical mode of action (drug), a mechanical mode of action (device), or a biological source. The Table provides statutory definitions for each of the 3 product domains. Nanotechnology products span all 3 regulated domains, and many products mechanisms of action span 2 or more of these domains.

The approval process for both new drugs and biological products is subject to 3 phases of clinical trials. Each phase includes laboratory and manufacturing controls; protections for human subjects; review and approval procedures; and requirements for labeling, adverse event disclosure, reporting and tracking, and postmarket surveillance, including ongoing assessment to ensure safety and efficacy using a risk-benefit approach tailored to a products intended use.4,9 Products developed to address an unmet health need or to treat a serious or life-threatening disease may qualify for abbreviated review and approval under breakthrough therapy status and other accelerated mechanisms.10 There are also abbreviated routes to market for drugs and biologics through the generic11 and biosimilar12 pathways based on comparisons to reference innovator products already approved by the FDA. These routes to market do not require full-scale clinical trials but only a showing of bioequivalence (for generics) and biosimilarity (for biosimilars).

Based on level of risk, devices enter the market in 1 of 2 ways: a premarket approval (PMA) process or a premarket notification (PMN) process. Like the new drug and biologic approval process, the PMA process for high-risk devices deemed potentially life saving and life supporting involves clinical trials tailored to a devices perceived risk classification and may involve specific safeguards to protect research subjects and demonstrate safety and efficacy.13 The PMN process, otherwise known as a clearance process for lower-risk devices, requires an applicant to demonstrate that a device is substantially equivalent to a device already on the market with the same or similar technological characteristics and intended use.14 Laboratory and manufacturing controls and requirements for labeling, tracking and adverse event reporting, and postmarket surveillance and ongoing assessment also apply to devices. The Government Accountability Office estimated that between 2003 and 2007, almost one-third of medical devices entered the market through the PMN clearance process, 67% were exempt from premarket review, and 1% were subject to the PMA process.14 Currently, the FDA requires first-in-kind devices, which hold promise to play a diagnostic or imaging role via a drug or biologic, to undergo market entry through the PMA process.15

The FDAs Office of Combination Products (OCP) assesses emerging technologies at the interface of the 3 product domains.16 A combination product is one containing a drug and a device; a drug and a biologic; a device and a biologic; or all 3 types of products. A combination product is categorized and reviewed according to its primary mode of action, which is the mode of action by which the product achieves its primary therapeutic effectwhether chemical, biological, or mechanical.17 Once the primary mode of action is determined, the FDA evaluates the product according to applicable statutory and regulatory requirements. For example, if the products primary mode of action is chemical, the FDA will apply drug requirements. The FDA can also adjust or combine regulatory requirements to address novel issues arising with combination products.

The combination product process has been subject to criticism for its shortcomings in classifying products that integrate chemical, biological, and mechanical elements; for a general lack of transparency; and for inconsistency in applying and making decisions about the requirements.18 Notably, the 21st Century Cures Act, enacted in December 2016, contains provisions for transparency and consistency in FDA procedures for classifying and evaluating combination products and for the conduct of collaborative product assessment.19 While not changing the FDCA in substance, the act served to nudge the agency on these issues. The FDA routinely classifies nanotechnology-derived products as combination products, assigning a primary regulatory route (ie, drug, device, or biologic) and supplementing with ad hoc requirements as necessary to assure safety and efficacy.

Nanoscale research reveals that, as particle size decreases, surface area increases along with the biological activity of particles.20 The unique physical properties of nanoparticles hold promise for surmounting some of the most difficult barriers to therapeutic and diagnostic efficacy. Nanoscale properties involving optical absorbance, fluorescence, and electrical and magnetic conductivity enable targeted localization, visualization, and treatment of cancerous tumors, for example.1 Nanoscale properties involving pharmacokinetics, biodistribution, and cell permeability assist in precision drug formulation and in getting the correct drug load to an exact location faster.1,21 Nanoparticles ability to interact directly with biological systems within the body increases the efficacy of myriad health applications.18

Review and approval of drugs, biologics, and devices in the nanorealm is ongoing, with many nanoproducts designated as combination products. For example, the FDA has approved nanoformulations of paclitaxel and doxorubicin as new cancer drugs, a nanoformulation of sirolimus (an immunosuppressant), and a nanoformulation of estradiol topical emulsion.22 The first approved nanodrug, the liposomal formulation of doxorubicin, consists of a nanoscale closed vesicle for drug delivery.23 These vesicles can also be composed of polymers, creating polymersomes that create a steric barrier and confer stealth properties to the drug carrier.23 Device nanoproducts that have entered the market through the PMN clearance process include a tissue reinforcement and hernia repair device (constructed with a nanoscale covalent-bonded titanium coating, imparting increased flexibility), a bone graft substitute (using betatricalcium phosphate nanoparticles that aggregate into 3-dimensional scaffolds with increased surface area for enhanced resorption), and a tissue-sealing and hemostasis system for laparoscopic and open surgery (using enhanced fluorescence properties of nanoparticles).24 A nanoformulation of the hepatitis A vaccine was also approved as a biologic.22

The FDA has published several nanotechnology-specific guidance documents instructing industry on agency policy.25,26 Topics include whether an FDA-regulated product involves an application of nanotechnology, drug and biological products that contain nanomaterials, and safety of nanomaterials in cosmetics and food products.26 Acknowledging that nanotechnology poses questions regarding the adequacy and application of our regulatory authorities, the FDAs Nanotechnology Task Force, assembled in August 2006 at the direction of the FDA commissioner, was asked to determine appropriate regulatory approaches and to identify and recommend mechanisms to address knowledge gaps.27 In July 2007, the task force concluded that nanoscale products did not warrant novel regulatory frameworks and thus were subject to traditional legal frameworks, including the combination product mechanism.27 Nanotechnology combination products were named by the task force as necessitating further explorationspecifically, whether employing the combination product approach to determine the regulatory pathway to market as a drug, medical device, or biological product was appropriate. The report states:

The very nature of nanoscale materialstheir dynamic quality as the size of nanoscale features change, for example, and their potential for diverse applicationscould permit development of highly integrated combinations of drugs, biological products, and/or devices, having multiple types of uses, such as combined diagnostic and therapeutic intended uses. As a consequence, the adequacy of the current paradigm for selecting regulatory pathways for combination products should be assessed to ensure predictable determinations of the most appropriate pathway for such highly integrated combination products.27

Subsequently, the FDA published 2 guidance documents on nanotechnology in the context of medical products. One outlines considerations for industry when determining whether a product involves an application of nanotechnology, which indicates the need for sponsors to communicate nanotechnology status to the FDA as part of the product review process.28 The other discusses a nanotechnology risk-based framework, specific requirements for conduct of nonclinical and clinical trials, manufacturing quality and controls, and special environmental considerations for drug and biologic products containing nanomaterials.29

The FDA continues to use a case-by-case approach for evaluating nanotechnology products, applying the combination product framework to determine the type of product and resulting regulatory requirements. There are persistent pleas from medical, scientific, and legal experts such as the National Academy of Medicine (formerly the Institute of Medicine) to fix inconsistent and inadequate drug, biologic, and device classifications as well as the combination product framework itself.14 Concomitant with the debate about whether existing regulatory structures and processes are adequate, broader questions have emerged regarding inherent risks of nanotechnology and products containing nanoparticles. Areas of concern include nanoparticle toxicity and human health impacts of exposure, especially effects of various exposure routes and routes of administration,30 unintended effects of nanoparticles ability to cross the blood-brain barrier, and long-term effects of nanoparticles.31

The FDA faces numerous challenges as nanomedicine progresses, and 3 core challenges stand out. The first is the adequacy of the regulatory framework itself; nanomedicine highlights the rigidity of product domains that dictate product approval requirements. At the nanoscale, decades-old definitions of chemical and mechanical action may not be suitable to characterize products with novel mechanisms of action and properties. For the purpose of evaluating such products, traditional definitional distinctions and accompanying legal requirements for review, approval, and postmarket surveillance and assessment may not be ideal. Current regulatory structures and processes may work for existing products, but the increasing complexity of nanotechnology and its convergence with other fields (eg, neurotechnologies and genetics) will likely strain their limits. Ongoing deliberations, stakeholder input, and agency policy must assess whether and to what extent current regulations are adaptable to newly emerging nanomedicine products or whether implementation of new frameworks is necessary to ensure safety and efficacy.

A second challenge has to do with the potential for novel risks, which raise questions about traditional safety and efficacy requirements appropriateness. Questions persist about whether nanoscale properties alter established risk-benefit measures and assessments of clinical trials and research protocols; whether and when abbreviated review of nanomedicine products is appropriate; and whether and when postmarket assessments should be tailored to address nano-specific toxicology and exposure concerns. As nanotechnology advances, particularly in the realm of human health, ample attention to scientific developments should also be paid to characterizing, assessing, and reporting adverse events. As part of the National Nanotechnology Initiative and other federal agency collaborations, large-scale research efforts are underway to characterize nanoscale materials and quantify their impact for purposes of developing toxicological assessment and testing tools.32 Information obtained from this research should be integrated into FDA review and approval processes as appropriate.

A third challenge has to do with whether labeling of nanomedicine products for consumers is sufficient to inform them that products contain nanotechnology or nanomaterials. This is not to say that explicit labeling should be a requirement; however, the FDA must contemplate whether increased patient and consumer education and consumer engagement is warranted and whether FDA policy on labeling requirements for nanoproducts responds well to public sentiment and the publics health literacy needs. For these efforts to succeedsimilar to consumer awareness campaigns and advocacy efforts in the realm of genetically modified food and biotechnologypositive perceptions and understanding of applications is essential.

National Institutes of Health. Nanomedicine: overview. Updated January 1, 2011. Accessed December 28, 2018.

Public Health Service Act 351, 42 USC 262 (2019).

21 USC 321(g)(1) (2019).

21 USC 321(p)(1) (2019).

42 USC 262(i) (2019).

21 USC 321(h) (2019).

Food, Drug, and Cosmetic Act 505, 21 USC 355 (2019).

Food, Drug, and Cosmetic Act 505(j), 21 USC 355(j) (2019).

42 USC 262 (2019).

Food, Drug, and Cosmetic Act 513, 515, 21 USC 360 (2019).

Institute of Medicine. Medical Devices and the Publics Health: The FDA 501(K) Clearance Process at 35 Years. Washington, DC: National Academies Press; 2011.

Paradise J. Regulatory frameworks for precision medicine at the FDA. SciTech Lawyer. 2018;15(1):12-17.

21 USC 353(g)(4)(A) (2006).

21 CFR 3.2(e) (2019).

Paradise J. Reassessing safety for nanotechnology combination products: what do biosimilars add to regulatory challenges for the FDA? St Louis Univ Law J. 2012;56:465-520.

21st Century Cures Act of 2016, Pub L No. 114-255, 130 Stat 1033.

Duncan R. Nanomedicines in action. Pharm J. 2004;273:485-488. Cited by: Wagner V, Dullaant A, Bock AK, Zweck A. The emerging nanomedicine landscape. Nat Biotechnol. 2006;24(10):1211-1217.

US Food and Drug Administration. FDAs approach to regulation of nanotechnology products. Updated March 23, 2018. Accessed October 1, 2018.

US Food and Drug Administration. Nanotechnology guidance documents. Updated March 23, 2018. Accessed October 1, 2018.

Nanotechnology Task Force, US Food and Drug Administration. Nanotechnology: a report of the US Food and Drug Administration Nanotechnology Task Force. Published July 25, 2007. Accessed October 1, 2018.

US Food and Drug Administration. Guidance for industry: considering whether an FDA-regulated product involves the application of nanotechnology. Published June 2014. Accessed October 1, 2018.

US Food and Drug Administration. Draft guidance for industry: drug products, including biological products that contain nanomaterials. Published December 2017. Accessed October 1, 2018.

Sargent JF Jr. The National Nanotechnology Initiative: overview, reauthorization, and appropriation issues. Congressional Research Service. Published December 16, 2014. Accessed February 13, 2019.

AMA J Ethics. 2019;21(4):E347-355.

The author(s) had no conflicts of interest to disclose.

The viewpoints expressed in this article are those of the author(s) and do not necessarily reflect the views and policies of the AMA.

Jordan Paradise, JD is Georgia Reithal Professor of Law at the Loyola University Chicago School of Law in Illinois, where she is also a faculty member in the Beazley Institute for Health Law and Policy. She previously served as a co-principal investigator on a National Science Foundation grant titled NIRT: Evaluating Oversight Models for Active Nanostructures and Nanosystems: Learning from Past Technologies in a Societal Context. Her scholarship explores legal and policy issues that arise with emerging medical products and technologies such as nanotechnology, synthetic biology, gene editing, and biosimilars.

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Nanomedicine –

§ April 14th, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine –

Our nanomedicine research will focus on cancer disease. The Gallogly College of Engineering will work in close collaboration with the Peggy and Charles Stephenson Cancer Center.

I. Can Photothermal Therapy be Used Effectively to Treat Tumors that Have Been Targeted with Single-Walled Carbon Nanotubes?

Partnership Project Photothermal and Immunostimulation of Melanoma in collaboration with OU-HSC Department of Pathology.

Project Goal: To determine the effectiveness in a mouse model of a new therapy for cutaneous metastatic melanoma by targeting single-walled carbon nanotubes (SWNTs) to the tumor vasculature, combined with photothermal therapy and immunostimulation.

Partnership Project Photothermal Therapy of Bladder Cancer Using Targeted Single Walled Carbon Nanotubes in collaboration with OU-HSC Department of Urology.

Project Goal: To determine the effectiveness in a mouse model of treating non-muscle invasive bladder cancer by photothermal therapy after binding of SWNTs to the tumors.

II. Can nanoparticles targeted to the tumor vasculature be used for effective imaging of vascularized tumors?

New Exploratory Project Gold Nanoparticles Targeted to the Breast Tumor Vasculature for Imaging.

Project Goal: To functionalize gold nanoparticles for targeting the tumor vasculature. To validate the binding to cells grown in vitro that mimic the tumor vasculature. To test the functionalized nanoparticles for imaging breast tumors grown in mice.

III. Can Tissue Scaffolds with Controllable Architectural Features from Micro to Nano be Used to Image and Treat Metastasizing Cancer Cells?

New Exploratory Project Imaging and Treating Metastasizing Cancer Cells In Vitro in collaboration with OU-HSC Department of Cell Biology.

Project Goal: To develop 3D in vitro generated tissue systems for studying the metastasis of cancer cells to bone tissue, both for the purposes of imaging and treatment.

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Nanomedicine Research | Houston Methodist

§ April 14th, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine Research | Houston Methodist

At Houston Methodist, our goal is to bring nanotechnologies to the clinic. By using interdisciplinary methods to combine nanoengineering, mathematical modeling and biomedical sciences, we develop nanotechnology-enabled therapeutic and diagnostic platforms to combat diseases including cancer, diabetes, cardiovascular and infectious diseases. Our main strategies are to make it possible for clinicians to detect disease early from blood proteomic signatures through the use of nanochips, to produce injectable nanovectors for targeted therapies and to design and create intelligent implants that allow controlled, time-released doses of substances. We have also created nanoscale scaffolding to aid in bone tissue engineering. Through our research, we are also attempting to understand the physics of mass transport within a cancer lesion and mass exchanges between cancer and surrounding host biology in order to create better nanomedicine treatments for cancer. We use several core facilities to advance our research goals; Molecular Diagnostics, Nanoengineering and Peptidomics-Nanoengineering to name just a few.


Unique Implants Release Medication at Molecular Level

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Nanoscopy for nanomedicine Institute for Bioengineering …

§ April 3rd, 2019 § Filed under Nano Medicine Comments Off on Nanoscopy for nanomedicine Institute for Bioengineering …

The main goal of our group is to use Super Resolution Microscopy (nanoscopy) to visualize and track in living cells and tissues self-assembled nanomaterials with therapeutic potential (nanomedicine).

TEM image of novel self-assembled nanofibers synthesized in the group.

The understanding of materials-cell interactions is the key towards the development of novel nanotechnology-based therapies for treatment of cancer and infectious diseases.Our group aims to use a multidisciplinary approach, at the interface of chemistry, physics and biology, to develop novel nanomaterials for the treatment of cancer and infectious diseases.

We aim at the development of novel nanocarriers for drug delivery based on self-assembly, i.e. able to build themselves. Molecular self-organization is ubiquitous in the biological world and represents for us a source of inspiration for the design of nanostructures with biomedical potential. In particular we focus on the development of self-assembled nanoparticles and nanofibers able to selectively target diseased cells and deliver locally therapeutic moieties such as drugs and genetic material (e.g. DNA, siRNA, mRNA).

A key point towards the development of novel nanotechnology-based therapies is the understanding of the behavior of nanomaterials in the complex biological environment. Here we use super resolution microscopy to track nanomaterials during their voyage in the biological environment and to visualize the interactions with blood components, immune system and target cells. We make use of a variety of super resolution techniques based on single molecule detection such a stochastic optical reconstruction microscopy (STORM), photoactivated localization microscopy (PALM), point accumulation for imaging in nanoscale topography (PAINT), and single particle tracking (SPT). These methods allow to achieve a resolution down to few nanometers and are therefore ideal to visualize nanosized synthetic objects in the biological environment. Super resolution microscopy provides a molecular picture of structure-activity relations and represent a guide towards the design of innovative materials for nanomedicine.

Eight IBECers were in the Netherlands on 13th and 14th September for the first ever IBEC-ICMS Symposium, NanoSens&Med.

Two IBEC groups have clubbed together to combine their expertise and reveal new knowledge that could advance the design of micro- and nanomotors for applications in health.

Three of IBECs women researchers have been successful in BISTs recent To the Mothers of Science call.

The Nanoscopy for Nanomedicine group has studied Single-Chain Polymeric Nanoparticles (SCPNs) mimicking enzymes as possible drug activators in biological environments, like the living cell.

An article by BIOCAT profiles the three winners in Catalonia of the last round of ERC Starting Grants, including IBECs Lorenzo Albertazzi.

A paper published in Small last month by Lorenzo Albertazzis group is featured in Advanced Science News, Wiley publishing companys in-house news website. This platform presents advances in various fields of research for a general audience.

The Nanoscopy for Nanomedicine junior group leader was successful in the European Research Councils 2017 call for Starting Grants, of which just 17 out of the total of 406 have been awarded to scientists working in Spain.

IBEC junior group leader Lorenzo Albertazzi is a contributor to the 2017 edition of ChemComm Emerging Investigators, which is published annually by the UKs Royal Society of Chemistry.

The AXA Research Fund, the international scientific philanthropy initiative of global insurer AXA, officially announced last week that it will devote 15.6m in 2016 to 44 new research projects with leading academic institutions in 16 countries.

New IBEC junior group leader Lorenzo Albertazzi and his former colleagues at the Eindhoven University of Technology, working together with industry partner Novartis, have made a leap in drug delivery vectors by developing a new type of carrier with some groundbreaking improvements.

Lorenzo Albertazzis research project funded by AXA, Novel approaches for Pandemic Virus Targeting Using Adaptive Polymers, is featured on the Granted Projects section of their website.

New IBEC junior group leader Lorenzo Albertazzi is profiled in El Mundos Personajes nicos section this week.

Dr Lorenzo Albertazzi, a nanoscientist whose research focuses on creating smart self-assembling materials for therapeutic applications, is joining IBEC this September.

(See full publication list in ORCID)

Liu, Yiliu, Pujals, Slvia, Stals, Patrick J. M., Paulhrl, Thomas, Presolski, Stanislav I., Meijer, E. W., Albertazzi, Lorenzo, Palmans, Anja R. A., (2018). Catalytically active single-chain polymeric nanoparticles: Exploring their functions in complex biological media Journal of the American Chemical Society 140, (9), 3423-3433

Dynamic single-chain polymeric nanoparticles (SCPNs) are intriguing, bioinspired architectures that result from the collapse or folding of an individual polymer chain into a nanometer-sized particle. Here we present a detailed biophysical study on the behavior of dynamic SCPNs in living cells and an evaluation of their catalytic functionality in such a complex medium. We first developed a number of delivery strategies that allowed the selective localization of SCPNs in different cellular compartments. Live/dead tests showed that the SCPNs were not toxic to cells while spectral imaging revealed that SCPNs provide a structural shielding and reduced the influence from the outer biological media. The ability of SCPNs to act as catalysts in biological media was first assessed by investigating their potential for reactive oxygen species generation. With porphyrins covalently attached to the SCPNs, singlet oxygen was generated upon irradiation with light, inducing spatially controlled cell death. In addition, Cu(I)- and Pd(II)-based SCPNs were prepared and these catalysts were screened in vitro and studied in cellular environments for the carbamate cleavage reaction of rhodamine-based substrates. This is a model reaction for the uncaging of bioactive compounds such as cytotoxic drugs for catalysis-based cancer therapy. We observed that the rate of the deprotection depends on both the organometallic catalysts and the nature of the protective group. The rate reduces from in vitro to the biological environment, indicating a strong influence of biomolecules on catalyst performance. The Cu(I)-based SCPNs in combination with the dimethylpropargyloxycarbonyl protective group showed the best performances both in vitro and in biological environment, making this group promising in biomedical applications.

Patio, Tania, Feiner-Gracia, Natalia, Arqu, Xavier, Miguel-Lpez, Albert, Jannasch, Anita, Stumpp, Tom, Schffer, Erik, Albertazzi, Lorenzo, Snchez, Samuel, (2018). Influence of enzyme quantity and distribution on the self-propulsion of non-Janus urease-powered micromotors Journal of the American Chemical Society 140, (25), 7896-7903

The use of enzyme catalysis to power micro- and nanomachines offers unique features such as biocompatibility, versatility, and fuel bioavailability. Yet, the key parameters underlying the motion behavior of enzyme-powered motors are not completely understood. Here, we investigate the role of enzyme distribution and quantity on the generation of active motion. Two different micromotor architectures based on either polystyrene (PS) or polystyrene coated with a rough silicon dioxide shell (PS@SiO2) were explored. A directional propulsion with higher speed was observed for PS@SiO2 motors when compared to their PS counterparts. We made use of stochastically optical reconstruction microscopy (STORM) to precisely detect single urease molecules conjugated to the micromotors surface with a high spatial resolution. An asymmetric distribution of enzymes around the micromotor surface was observed for both PS and PS@SiO2 architectures, indicating that the enzyme distribution was not the only parameter affecting the motion behavior. We quantified the number of enzymes present on the micromotor surface and observed a 10-fold increase in the number of urease molecules for PS@SiO2 motors compared to PS-based micromotors. To further investigate the number of enzymes required to generate a self-propulsion, PS@SiO2 particles were functionalized with varying amounts of urease molecules and the resulting speed and propulsive force were measured by optical tracking and optical tweezers, respectively. Surprisingly, both speed and force depended in a nonlinear fashion on the enzyme coverage. To break symmetry for active propulsion, we found that a certain threshold number of enzymes molecules per micromotor was necessary, indicating that activity may be due to a critical phenomenon. Taken together, these results provide new insights into the design features of micro/nanomotors to ensure an efficient development.

Delcanale, Pietro, Miret-Ontiveros, Bernat, Arista-Romero, Maria, Pujals, Silvia, Albertazzi, Lorenzo, (2018). Nanoscale mapping functional sites on nanoparticles by Points Accumulation for Imaging in Nanoscale Topography (PAINT) ACS Nano 12, (8), 7629-7637

The ability of nanoparticles to selectively recognize a molecular target constitutes the key toward nanomedicine applications such as drug delivery and diagnostics. The activity of such devices is mediated by the presence of multiple copies of functional molecules on the nanostructure surface. Therefore, understanding the number and the distribution of nanoparticle functional groups is of utmost importance for the rational design of effective materials. Analytical methods are available, but to obtain quantitative information at the level of single particles and single functional sites, i.e., going beyond the ensemble, remains highly challenging. Here we introduce the use of an optical nanoscopy technique, DNA points accumulation for imaging in nanoscale topography (DNA-PAINT), to address this issue. Combining subdiffraction spatial resolution with molecular selectivity and sensitivity, DNA-PAINT provides both geometrical and functional information at the level of a single nanostructure. We show how DNA-PAINT can be used to image and quantify relevant functional proteins such as antibodies and streptavidin on nanoparticles and microparticles with nanometric accuracy in 3D and multiple colors. The generality and the applicability of our method without the need for fluorescent labeling hold great promise for the robust quantitative nanocharacterization of functional nanomaterials.

Ardizzone, Antonio, Kurhuzenkau, Siarhei, Illa-Tuset, Slvia, Faraudo, Jordi, Bondar, Mykhailo, Hagan, David, Van Stryland, Eric W., Painelli, Anna, Sissa, Cristina, Feiner, Natalia, Albertazzi, Lorenzo, Veciana, Jaume, Ventosa, Nora, (2018). Nanostructuring lipophilic dyes in water using stable vesicles, quatsomes, as scaffolds and their use as probes for bioimaging Small , 14, (16), 1703851

Abstract A new kind of fluorescent organic nanoparticles (FONs) is obtained using quatsomes (QSs), a family of nanovesicles proposed as scaffolds for the nanostructuration of commercial lipophilic carbocyanines (1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI), 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indodicarbocyanine perchlorate (DiD), and 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indotricarbocyanine iodide (DiR)) in aqueous media. The obtained FONs, prepared by a CO2-based technology, show excellent colloidal- and photostability, outperforming other nanoformulations of the dyes, and improve the optical properties of the fluorophores in water. Molecular dynamics simulations provide an atomistic picture of the disposition of the dyes within the membrane. The potential of QSs for biological imaging is demonstrated by performing superresolution microscopy of the DiI-loaded vesicles in vitro and in cells. Therefore, fluorescent QSs constitute an appealing nanomaterial for bioimaging applications.

Krivitsky, Adva, Polyak, Dina, Scomparin, Anna, Eliyahu, Shay, Ofek, Paula, Tiram, Galia, Kalinski, Hagar, Avkin-Nachum, Sharon, Feiner Gracia, N., Albertazzi, Lorenzo, Satchi-Fainaro, Ronit, (2018). Amphiphilic poly()glutamate polymeric micelles for systemic administration of siRNA to tumors Nanomedicine: Nanotechnology, Biology, and Medicine , 14, (2), 303-315

RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target undruggable oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly()glutamate amine (APA) can serve as a cationic carrier to the negatively-charged oligonucleotides. APA polymers complexed with siRNA to form round-shaped, homogenous and reproducible nano-sized polyplexes bearing ~50 nm size and slightly negative charge. In addition, APA:siRNA polyplexes were shown to be potent gene regulators in vitro. In light of these preferred physico-chemical characteristics, their performance as systemically-administered siRNA nanocarriers was investigated. Intravenously-injected APA:siRNA polyplexes accumulated selectively in tumors and did not accumulate in the lungs, heart, liver or spleen. Nevertheless, the polyplexes failed to induce specific mRNA degradation, hence neither reduction in tumor volume nor prolonged mice survival was seen.

Casellas, Nicolas M., Pujals, Slvia, Bochicchio, Davide, Pavan, Giovanni M., Torres, Toms, Albertazzi, Lorenzo, Garca-Iglesias, Miguel, (2018). From isodesmic to highly cooperative: Reverting the supramolecular polymerization mechanism in water by fine monomer design Chemical Communications 54, (33), 4112-4115

Two structurally-similar discotic molecules able to self-assemble in water, forming supramolecular fibers, are reported. While both self-assembled polymers are indistinguishable from a morphological point-of-view, a dramatic change in their polymerization mechanism is observed (i.e., one self-assemble via an isodesmic mechanism, while the other shows one of the highest cooperativity values).

van Elsland, Daphne M., Pujals, Slvia, Bakkum, Thomas, Bos, Erik, Oikonomeas-Koppasis, Nikolaos, Berlin, Ilana, Neefjes, Jacques, Meijer, Annemarie H., Koster, Abraham J., Albertazzi, Lorenzo, van Kasteren, Sander I., (2018). Ultrastructural imaging of salmonella-host interactions using super-resolution correlative light-electron microscopy of bioorthogonal pathogens ChemBioChem , 19, (16), 1766-1770

The imaging of intracellular pathogens inside host cells is complicated by the low resolution and sensitivity of fluorescence microscopy and by the lack of ultrastructural information to visualize the pathogens. Herein, we present a new method to visualize these pathogens during infection that circumvents these problems: by using a metabolic hijacking approach to bioorthogonally label the intracellular pathogen Salmonella Typhimurium and by using these bioorthogonal groups to introduce fluorophores compatible with stochastic optical reconstruction microscopy (STORM) and placing this in a correlative light electron microscopy (CLEM) workflow, the pathogen can be imaged within its host cell context Typhimurium with a resolution of 20nm. This STORM-CLEM approach thus presents a new approach to understand these pathogens during infection.

Oria, Roger, Wiegand, Tina, Escribano, Jorge, Elosegui-Artola, Alberto, Uriarte, Juan Jose, Moreno-Pulido, Cristian, Platzman, Ilia, Delcanale, Pietro, Albertazzi, Lorenzo, Navajas, Daniel, Trepat, Xavier, Garca-Aznar, Jos Manuel, Cavalcanti-Adam, Elisabetta Ada, Roca-Cusachs, Pere, (2017). Force loading explains spatial sensing of ligands by cells Nature 552, 219-224

Cells can sense the density and distribution of extracellular matrix (ECM) molecules by means of individual integrin proteins and larger, integrin-containing adhesion complexes within the cell membrane. This spatial sensing drives cellular activity in a variety of normal and pathological contexts1,2. Previous studies of cells on rigid glass surfaces have shown that spatial sensing of ECM ligands takes place at the nanometre scale, with integrin clustering and subsequent formation of focal adhesions impaired when single integrinligand bonds are separated by more than a few tens of nanometres3,4,5,6. It has thus been suggested that a crosslinking adaptor protein of this size might connect integrins to the actin cytoskeleton, acting as a molecular ruler that senses ligand spacing directly3,7,8,9. Here, we develop gels whose rigidity and nanometre-scale distribution of ECM ligands can be controlled and altered. We find that increasing the spacing between ligands promotes the growth of focal adhesions on low-rigidity substrates, but leads to adhesion collapse on more-rigid substrates. Furthermore, disordering the ligand distribution drastically increases adhesion growth, but reduces the rigidity threshold for adhesion collapse. The growth and collapse of focal adhesions are mirrored by, respectively, the nuclear or cytosolic localization of the transcriptional regulator protein YAP. We explain these findings not through direct sensing of ligand spacing, but by using an expanded computational molecular-clutch model10,11, in which individual integrinECM bondsthe molecular clutchesrespond to force loading by recruiting extra integrins, up to a maximum value. This generates more clutches, redistributing the overall force among them, and reducing the force loading per clutch. At high rigidity and high ligand spacing, maximum recruitment is reached, preventing further force redistribution and leading to adhesion collapse. Measurements of cellular traction forces and actin flow speeds support our model. Our results provide a general framework for how cells sense spatial and physical information at the nanoscale, precisely tuning the range of conditions at which they form adhesions and activate transcriptional regulation.

Duro-Castano, Aroa, Nebot, Vicent J., Nio-Pariente, Amaya, Armin, Ana, Arroyo-Crespo, Juan J., Paul, Alison, Feiner-Gracia, Natalia, Albertazzi, Lorenzo, Vicent, Mara J., (2017). Capturing extraordinary soft-assembled charge-like polypeptides as a strategy for nanocarrier design Advanced Materials , 29, (39), 1702888

The rational design of nanomedicines is a challenging task given the complex architectures required for the construction of nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Herein, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in nonsalty aqueous solutions is identified, which matches the ubiquitous ordinaryextraordinary phenomenon previously described by physicists. For the first time, a bottom-up methodology for the stabilization of these nanosized soft-assembled star-shaped polyglutamates is also described, enabling the translation of theoretical research into nanomaterials with applicability within the drug-delivery field. Covalent capture of these labile assemblies provides access to unprecedented architectures to be used as nanocarriers. The enhanced in vitro and in vivo properties of these novel nanoconstructs as drug-delivery systems highlight the potential of this approach for tumor-localized as well as lymphotropic delivery.

Keywords: Charge-like, Drug delivery, Polymer therapeutics, Polypeptides, Self-assembly

Labernadie, A., Kato, T., Brugus, A., Serra-Picamal, X., Derzsi, S., Arwert, E., Weston, A., Gonzlez-Tarrag, V., Elosegui-Artola, A., Albertazzi, L., Alcaraz, J., Roca-Cusachs, P., Sahai, E., Trepat, X., (2017). A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion Nature Cell Biology , 19, (3), 224-237

Cancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show that CAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission is mediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at the cancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers -catenin recruitment and adhesion reinforcement dependent on -catenin/vinculin interaction. Impairment of E-cadherin/N-cadherin adhesion abrogates the ability of CAFs to guide collective cell migration and blocks cancer cell invasion. N-cadherin also mediates repolarization of the CAFs away from the cancer cells. In parallel, nectins and afadin are recruited to the cancer cell/CAF interface and CAF repolarization is afadin dependent. Heterotypic junctions between CAFs and cancer cells are observed in patient-derived material. Together, our findings show that a mechanically active heterophilic adhesion between CAFs and cancer cells enables cooperative tumour invasion.

Feiner-Gracia, Natalia, Buzhor, Marina, Fuentes, Edgar, Pujals, S., Amir, Roey J., Albertazzi, Lorenzo, (2017). Micellar stability in biological media dictates internalization in living cells Journal of the American Chemical Society 139, (46), 16677-16687

The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEGdendron hybrids and their self-assembled micelles in order to determine their structurestability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stabilityactivity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.

Feiner-Gracia, Natalia, Beck, Michaela, Pujals, Slvia, Tosi, Sbastien, Mandal, Tamoghna, Buske, Christian, Linden, Mika, Albertazzi, Lorenzo, (2017). Super-resolution microscopy unveils dynamic heterogeneities in nanoparticle protein corona Small , 13, (41), 1701631

The adsorption of serum proteins, leading to the formation of a biomolecular corona, is a key determinant of the biological identity of nanoparticles in vivo. Therefore, gaining knowledge on the formation, composition, and temporal evolution of the corona is of utmost importance for the development of nanoparticle-based therapies. Here, it is shown that the use of super-resolution optical microscopy enables the imaging of the protein corona on mesoporous silica nanoparticles with single protein sensitivity. Particle-by-particle quantification reveals a significant heterogeneity in protein absorption under native conditions. Moreover, the diversity of the corona evolves over time depending on the surface chemistry and degradability of the particles. This paper investigates the consequences of protein adsorption for specific cell targeting by antibody-functionalized nanoparticles providing a detailed understanding of corona-activity relations. The methodology is widely applicable to a variety of nanostructures and complements the existing ensemble approaches for protein corona study.

Keywords: Heterogeneity, Mesoporous silica nanoparticles, Protein corona, Super-resolution imaging, Targeting

Van Onzen, A. H. A. M., Albertazzi, L., Schenning, A. P. H. J., Milroy, L. G., Brunsveld, L., (2017). Hydrophobicity determines the fate of self-assembled fluorescent nanoparticles in cells Chemical Communications 53, (10), 1626-1629

The fate of small molecule nanoparticles (SMNPs) composed of self-assembling intrinsically fluorescent -conjugated oligomers was studied in cells as a function of side-chain hydrophobicity. While the hydrophobic SMNPs remained intact upon cellular uptake, the more hydrophilic SMNPs disassembled and dispersed throughout the cytosol.

Pujals, S., Tao, K., Terradellas, A., Gazit, E., Albertazzi, L., (2017). Studying structure and dynamics of self-Assembled peptide nanostructures using fluorescence and super resolution microscopy Chemical Communications 53, (53), 7294-7297

Understanding the formation and properties of self-Assembled peptide nanostructures is the basis for the design of new architectures for various applications. Here we show the potential of fluorescence and super resolution imaging to unveil the structural and dynamic features of peptide nanofibers with high spatiotemporal resolution.

Caballero, David, Blackburn, Sophie M., de Pablo, Mar, Samitier, Josep, Albertazzi, Lorenzo, (2017). Tumour-vessel-on-a-chip models for drug delivery Lab on a Chip , 17, 3760-3771

Nanocarriers for drug delivery have great potential to revolutionize cancer treatment, due to their enhanced selectivity and efficacy. Despite this great promise, researchers have had limited success in the clinical translation of this approach. One of the main causes of these difficulties is that standard in vitro models, typically used to understand nanocarriers' behaviour and screen their efficiency, do not provide the complexity typically encountered in living systems. In contrast, in vivo models, despite being highly physiological, display serious bottlenecks which threaten the relevancy of the obtained data. Microfluidics and nanofabrication can dramatically contribute to solving this issue, providing 3D high-throughput models with improved resemblance to in vivo systems. In particular, microfluidic models of tumour blood vessels can be used to better elucidate how new nanocarriers behave in the microcirculation of healthy and cancerous tissues. Several key steps of the drug delivery process such as extravasation, immune response and endothelial targeting happen under flow in capillaries and can be accurately modelled using microfluidics. In this review, we will present how tumour-vessel-on-a-chip systems can be used to investigate targeted drug delivery and which key factors need to be considered for the rational design of these materials. Future applications of this approach and its role in driving forward the next generation of targeted drug delivery methods will be discussed.

Bakker, Maarten H., Lee, Cameron C., Meijer, E. W., Dankers, Patricia Y. W., Albertazzi, Lorenzo, (2016). Multicomponent supramolecular polymers as a modular platform for intracellular delivery ACS Nano 10, (2), 1845-1852

Supramolecular polymers are an emerging family of nanosized structures with potential use in materials chemistry and medicine. Surprisingly, application of supramolecular polymers in the field of drug delivery has received only limited attention. Here, we explore the potential of PEGylated 1,3,5-benzenetricarboxamide (BTA) supramolecular polymers for intracellular delivery. Exploiting the unique modular approach of supramolecular chemistry, we can coassemble neutral and cationic BTAs and control the overall properties of the polymer by simple monomer mixing. Moreover, this platform offers a versatile approach toward functionalization. The core can be efficiently loaded with a hydrophobic guest molecule, while the exterior can be electrostatically complexed with siRNA. It is demonstrated that both compounds can be delivered in living cells, and that they can be combined to enable a dual delivery strategy. These results show the advantages of employing a modular system and pave the way for application of supramolecular polymers in intracellular delivery.

Beun, L. H., Albertazzi, L., Van Der Zwaag, D., De Vries, R., Cohen Stuart, M. A., (2016). Unidirectional living growth of self-assembled protein nanofibrils revealed by super-resolution microscopy ACS Nano 10, (5), 4973-4980

Protein-based nanofibrils are emerging as a promising class of materials that provide unique properties for applications such as biomedical and food engineering. Here, we use atomic force microscopy and stochastic optical reconstruction microscopy imaging to elucidate the growth dynamics, exchange kinetics, and polymerization mechanism for fibrils composed of a de novo designed recombinant triblock protein polymer. This macromolecule features a silk-inspired self-assembling central block composed of GAGAGAGH repeats, which are known to fold into a roll with turns at each histidine and, once folded, to stack, forming a long, ribbon-like structure. We find several properties that allow the growth of patterned protein nanofibrils: the self-assembly takes place on only one side of the growing fibrils by the essentially irreversible addition of protein polymer subunits, and these fibril ends remain reactive indefinitely in the absence of monomer ("living ends"). Exploiting these characteristics, we can grow stable diblock protein nanofibrils by the sequential addition of differently labeled proteins. We establish control over the block length ratio by simply varying monomer feed conditions. Our results demonstrate the use of engineered protein polymers in creating precisely patterned protein nanofibrils and open perspectives for the hierarchical self-assembly of functional biomaterials.

Keywords: Nanofibrils, Protein polymers, Self-assembly, STORM microscopy

Garzoni, M., Baker, M. B., Leenders, C. M. A., Voets, I. K., Albertazzi, L., Palmans, A. R. A., Meijer, E. W., Pavan, G. M., (2016). Effect of H-bonding on order amplification in the growth of a supramolecular polymer in water Journal of the American Chemical Society 138, (42), 13985-13995

While a great deal of knowledge on the roles of hydrogen bonding and hydrophobicity in proteins has resulted in the creation of rationally designed and functional peptidic structures, the roles of these forces on purely synthetic supramolecular architectures in water have proven difficult to ascertain. Focusing on a 1,3,5-benzenetricarboxamide (BTA)-based supramolecular polymer, we have designed a molecular modeling strategy to dissect the energetic contributions involved in the self-assembly (electrostatic, hydrophobic, etc.) upon growth of both ordered BTA stacks and random BTA aggregates. Utilizing this set of simulations, we have unraveled the cooperative mechanism for polymer growth, where a critical size must be reached in the aggregates before emergence and amplification of order into the experimentally observed fibers. Furthermore, we have found that the formation of ordered fibers is favored over disordered aggregates solely on the basis of electrostatic interactions. Detailed analysis of the simulation data suggests that H-bonding is a major source of this stabilization energy. Experimental and computational comparison with a newly synthesized 1,3,5-benzenetricarboxyester (BTE) derivative, lacking the ability to form the H-bonding network, demonstrated that this BTE variant is also capable of fiber formation, albeit at a reduced persistence length. This work provides unambiguous evidence for the key 1D driving force of hydrogen bonding in enhancing the persistency of monomer stacking and amplifying the level of order into the growing supramolecular polymer in water. Our computational approach provides an important relationship directly linking the structure of the monomer to the structure and properties of the supramolecular polymer.

Aloi, Antonio, Vargas Jentzsch, Andreas, Vilanova, Neus, Albertazzi, Lorenzo, Meijer, E. W., Voets, Ilja K., (2016). Imaging nanostructures by single-molecule localization microscopy in organic solvents Journal of the American Chemical Society 138, (9), 2953-2956

The introduction of super-resolution fluorescence microscopy (SRM) opened an unprecedented vista into nanoscopic length scales, unveiling a new degree of complexity in biological systems in aqueous environments. Regrettably, supramolecular chemistry and material science benefited far less from these recent developments. Here we expand the scope of SRM to photoactivated localization microscopy (PALM) imaging of synthetic nanostructures that are highly dynamic in organic solvents. Furthermore, we characterize the photophysical properties of commonly used photoactivatable dyes in a wide range of solvents, which is made possible by the addition of a tiny amount of an alcohol. As proof-of-principle, we use PALM to image silica beads with radii close to Abbes diffraction limit. Individual nanoparticles are readily identified and reliably sized in multicolor mixtures of large and small beads. We further use SRM to visualize nm-thin yet m-long dynamic, supramolecular polymers, which are among the most challenging molecular systems to image.

da Silva, Ricardo M. P., van der Zwaag, Daan, Albertazzi, Lorenzo, Lee, Sungsoo S., Meijer, E. W., Stupp, Samuel I., (2016). Super-resolution microscopy reveals structural diversity in molecular exchange among peptide amphiphile nanofibres Nature Communications 7, 11561

The dynamic behaviour of supramolecular systems is an important dimension of their potential functions. Here, we report on the use of stochastic optical reconstruction microscopy to study the molecular exchange of peptide amphiphile nanofibres, supramolecular systems known to have important biomedical functions. Solutions of nanofibres labelled with different dyes (Cy3 and Cy5) were mixed, and the distribution of dyes inserting into initially single-colour nanofibres was quantified using correlative image analysis. Our observations are consistent with an exchange mechanism involving monomers or small clusters of molecules inserting randomly into a fibre. Different exchange rates are observed within the same fibre, suggesting that local cohesive structures exist on the basis of [beta]-sheet discontinuous domains. The results reported here show that peptide amphiphile supramolecular systems can be dynamic and that their intermolecular interactions affect exchange patterns. This information can be used to generate useful aggregate morphologies for improved biomedical function.

DeKoker, Stefaan, Cui, Jiwei, Vanparijs, Nane, Albertazzi, Lorenzo, Grooten, Johan, Caruso, Frank, DeGeest, Bruno G., (2016). Engineering polymer hydrogel nanoparticles for lymph node-targeted delivery Angewandte Chemie - International Edition , 55, (4), 1334-1339

The induction of antigen-specific adaptive immunity exclusively occurs in lymphoid organs. As a consequence, the efficacy by which vaccines reach these tissues strongly affects the efficacy of the vaccine. Here, we report the design of polymer hydrogel nanoparticles that efficiently target multiple immune cell subsets in the draining lymph nodes. Nanoparticles are fabricated by infiltrating mesoporous silica particles (ca. 200nm) with poly(methacrylic acid) followed by disulfide-based crosslinking and template removal. PEGylation of these nanoparticles does not affect their cellular association invitro, but dramatically improves their lymphatic drainage invivo. The functional relevance of these observations is further illustrated by the increased priming of antigen-specific Tcells. Our findings highlight the potential of engineered hydrogel nanoparticles for the lymphatic delivery of antigens and immune-modulating compounds.

Keywords: Dendritic cells, Disulfides, Hydrogels, Nanoparticles, Vaccines

Li, Hui, Fierens, Kaat, Zhang, Zhiyue, Vanparijs, Nane, Schuijs, Martijn J., Van Steendam, Katleen, Feiner Gracia, Natlia, De Rycke, Riet, De Beer, Thomas, De Beuckelaer, Ans, De Koker, Stefaan, Deforce, Dieter, Albertazzi, Lorenzo, Grooten, Johan, Lambrecht, Bart N., De Geest, Bruno G., (2016). Spontaneous protein adsorption on graphene oxide nanosheets allowing efficient intracellular vaccine protein delivery ACS Applied Materials & Interfaces , 8, (2), 1147-1155

Nanomaterials hold potential of altering the interaction between therapeutic molecules and target cells or tissues. High aspect ratio nanomaterials in particular have been reported to possess unprecedented properties and are intensively investigated for their interaction with biological systems. Graphene oxide (GOx) is a water-soluble graphene derivative that combines high aspect ratio dimension with functional groups that can be exploited for bioconjugation. Here, we demonstrate that GOx nanosheets can spontaneously adsorb proteins by a combination of interactions. This property is then explored for intracellular protein vaccine delivery, in view of the potential of GOx nanosheets to destabilize lipid membranes such as those of intracellular vesicles. Using a series of in vitro experiments, we show that GOx nanosheet adsorbed proteins are efficiently internalized by dendritic cells (DCs: the most potent class of antigen presenting cells of the immune system) and promote antigen cross-presentation to CD8 T cells. The latter is a hallmark in the induction of potent cellular antigen-specific immune responses against intracellular pathogens and cancer.Nanomaterials hold potential of altering the interaction between therapeutic molecules and target cells or tissues. High aspect ratio nanomaterials in particular have been reported to possess unprecedented properties and are intensively investigated for their interaction with biological systems. Graphene oxide (GOx) is a water-soluble graphene derivative that combines high aspect ratio dimension with functional groups that can be exploited for bioconjugation. Here, we demonstrate that GOx nanosheets can spontaneously adsorb proteins by a combination of interactions. This property is then explored for intracellular protein vaccine delivery, in view of the potential of GOx nanosheets to destabilize lipid membranes such as those of intracellular vesicles. Using a series of in vitro experiments, we show that GOx nanosheet adsorbed proteins are efficiently internalized by dendritic cells (DCs: the most potent class of antigen presenting cells of the immune system) and promote antigen cross-presentation to CD8 T cells. The latter is a hallmark in the induction of potent cellular antigen-specific immune responses against intracellular pathogens and cancer.

van der Zwaag, Daan, Vanparijs, Nane, Wijnands, Sjors, De Rycke, Riet, De Geest, Bruno G., Albertazzi, Lorenzo, (2016). Super resolution imaging of nanoparticles cellular uptake and trafficking ACS Applied Materials & Interfaces , 8, (10), 6391-6399

Understanding the interaction between synthetic nanostructures and living cells is of crucial importance for the development of nanotechnology-based intracellular delivery systems. Fluorescence microscopy is one of the most widespread tools owing to its ability to image multiple colors in native conditions. However, due to the limited resolution, it is unsuitable to address individual diffraction-limited objects. Here we introduce a combination of super-resolution microscopy and single-molecule data analysis to unveil the behavior of nanoparticles during their entry into mammalian cells. Two-color Stochastic Optical Reconstruction Microscopy (STORM) addresses the size and positioning of nanoparticles inside cells and probes their interaction with the cellular machineries at nanoscale resolution. Moreover, we develop image analysis tools to extract quantitative information about internalized particles from STORM images. To demonstrate the potential of our methodology, we extract previously inaccessible information by the direct visualization of the nanoparticle uptake mechanism and the intracellular tracking of nanoparticulate model antigens by dendritic cells. Finally, a direct comparison between STORM, confocal microscopy, and electron microscopy is presented, showing that STORM can provide novel and complementary information on nanoparticle cellular uptake.Understanding the interaction between synthetic nanostructures and living cells is of crucial importance for the development of nanotechnology-based intracellular delivery systems. Fluorescence microscopy is one of the most widespread tools owing to its ability to image multiple colors in native conditions. However, due to the limited resolution, it is unsuitable to address individual diffraction-limited objects. Here we introduce a combination of super-resolution microscopy and single-molecule data analysis to unveil the behavior of nanoparticles during their entry into mammalian cells. Two-color Stochastic Optical Reconstruction Microscopy (STORM) addresses the size and positioning of nanoparticles inside cells and probes their interaction with the cellular machineries at nanoscale resolution. Moreover, we develop image analysis tools to extract quantitative information about internalized particles from STORM images. To demonstrate the potential of our methodology, we extract previously inaccessible information by the direct visualization of the nanoparticle uptake mechanism and the intracellular tracking of nanoparticulate model antigens by dendritic cells. Finally, a direct comparison between STORM, confocal microscopy, and electron microscopy is presented, showing that STORM can provide novel and complementary information on nanoparticle cellular uptake.

Beuwer, Michael A., Knopper, M. F., Albertazzi, Lorenzo, van der Zwaag, Daan, Ellenbroek, Wouter G., Meijer, E. W., Prins, Menno W. J., Zijlstra, Peter, (2016). Mechanical properties of single supramolecular polymers from correlative AFM and fluorescence microscopy Polymer Chemistry , 7, (47), 7260-7268

We characterize the structure and mechanical properties of 1,3,5-benzenetricarboxamide (BTA) supramolecular polymers using correlative AFM and fluorescence imaging. AFM allows for nanoscale structural investigation but we found that statistical analysis is difficult because these structures are easily disrupted by the AFM tip. We therefore correlate AFM and fluorescence microscopy to couple nanoscale morphological information to far-field optical images. A fraction of the immobilized polymers are in a clustered or entangled state, which we identify based on diffraction limited fluorescence images. We find that clustered and entangled polymers exhibit a significantly longer persistence length that is broader distributed than single unentangled polymers. By comparison with numerical simulations we find significant heterogeneity in the persistence length of single unentangled polymers, which we attribute to polymer-substrate interactions and the presence of structural diversity within the polymer.

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Nanobiotix a nanomedicine company

§ March 26th, 2019 § Filed under Nano Medicine Comments Off on Nanobiotix a nanomedicine company



Watch our

R&D Day


Dr. David Raben, MD University of Colorado, Denver, CO, USADr. Tanguy Seiwert, MD University of Chicago Medicine, Chicago, IL, USADr. Colette Shen, MD, PhD University of North Carolina, Chapel Hill, NC, USADr. Jared Weiss, MD University of North Carolina, Chapel Hill, NC, USADr. James Welsh, MD MD Anderson Cancer Center, Houston, TX, USA

JUNE 21, 2018

Nanobiotix announces

positive phase II/III topline data

in soft tissue sarcoma with NBTXR3





















MEET US AT:AACR 2019, Atlanta


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Nanomedicine | Ardena

§ March 13th, 2019 § Filed under Nano Medicine Comments Off on Nanomedicine | Ardena

This fast-evolving field uses nanoscale or nanostructured materials to impart unique pharmacokinetic and therapeutic effects such as enhanced dissolution rate and oral bioavailability, targeted delivery, enhanced efficacy and reduced toxicity.

The control of materials in the nanometer size range requires scientifically demanding chemistry, analysis and manufacturing techniques. Our nanomedicine expertise encompasses formulation, process and analytical development, GMP manufacturing and dossier development.

We are experts in the following formulations:

Once we identify a suitable formulation, our scientists develop phase-appropriate production processes in accordance with cGMP and mitigate technology transfer issues by using the same teams for development and manufacturing.

Techniques include:

In our cGMP-compliant manufacturing facilities, we can produce volumes of a couple of millilitres to multiple litres, using batch-type and continuous-flow processes. We also work with highly-potent drug substances and can deliver nanosuspensions and nanoparticle solutions as sterile finished drug products in vials or syringes.

To support product development and to perform quality control of GMP-produced drug products, we utilise state-of-the-art analytical techniques such as:

Having advanced a wide range of nanomedicine formulations into the clinic, we are used to developing new manufacturing techniques and analytical procedures under fierce regulatory scrutiny. Our understanding of the regulatory landscape gives your nanomedicine project the greatest chance of approval.

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Nanomaterials – Wikipedia

§ February 8th, 2019 § Filed under Nano Medicine Comments Off on Nanomaterials – Wikipedia

Nanomaterials describe, in principle, materials of which a single unit is sized (in at least one dimension) between 1 to 1000 nanometres (109 meter) but usually is 1 to 100nm (the usual definition of nanoscale[1]).

Nanomaterials research takes a materials science-based approach to nanotechnology, leveraging advances in materials metrology and synthesis which have been developed in support of microfabrication research. Materials with structure at the nanoscale often have unique optical, electronic, or mechanical properties.[2]

Nanomaterials are slowly becoming commercialized[3] and beginning to emerge as commodities.[4]

There are significant differences among agencies on the definition of a nanomaterial.[5]

In ISO/TS 80004, nanomaterial is defined as a "material with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale", with nanoscale defined as the "length range approximately from 1 nm to 100 nm". This includes both nano-objects, which are discrete pieces of material, and nanostructured materials, which have internal or surface structure on the nanoscale; a nanomaterial may be a member of both these categories.[6]

On 18 October 2011, the European Commission adopted the following definition of a nanomaterial: "A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1nm 100nm. In specific cases and where warranted by concerns for the environment, health, safety or competitiveness the number size distribution threshold of 50% may be replaced by a threshold between 1% to 50%."[7]

Engineered nanomaterials have been deliberately engineered and manufactured by humans to have certain required properties.[8]

Legacy nanomaterials are those that were in commercial production prior to the development of nanotechnology as incremental advancements over other colloidal or particulate materials.[9][10][11] They include carbon black and titanium dioxide nanoparticles.[12]

Nanomaterials may be incidentally produced as a byproduct of mechanical or industrial processes. Sources of incidental nanoparticles include vehicle engine exhausts, welding fumes, combustion processes from domestic solid fuel heating and cooking. For instance, the class of nanomaterials called fullerenes are generated by burning gas, biomass, and candle.[13] It can also be a byproduct of wear and corrosion products.[14] Incidental atmospheric nanoparticles are often referred to as ultrafine particles, which are unintentionally produced during an intentional operation, and could contribute to air pollution.[15][16]

Biological systems often feature natural, functional nanomaterials. The structure of foraminifera (mainly chalk) and viruses (protein, capsid), the wax crystals covering a lotus or nasturtium leaf, spider and spider-mite silk,[17] the blue hue of tarantulas,[18] the "spatulae" on the bottom of gecko feet, some butterfly wing scales, natural colloids (milk, blood), horny materials (skin, claws, beaks, feathers, horns, hair), paper, cotton, nacre, corals, and even our own bone matrix are all natural organic nanomaterials.

Natural inorganic nanomaterials occur through crystal growth in the diverse chemical conditions of the Earth's crust. For example, clays display complex nanostructures due to anisotropy of their underlying crystal structure, and volcanic activity can give rise to opals, which are an instance of a naturally occurring photonic crystals due to their nanoscale structure. Fires represent particularly complex reactions and can produce pigments, cement, fumed silica etc.

Natural sources of nanoparticles include combustion products forest fires, volcanic ash, ocean spray, and the radioactive decay of radon gas. Natural nanomaterials can also be formed through weathering processes of metal- or anion-containing rocks, as well as at acid mine drainage sites.[15]

"Lotus effect", hydrophobic effect with self-cleaning ability

Close-up of the underside of a gecko's foot as it walks on a glass wall (spatula: 200 10-15nm)

SEM micrograph of a butterfly wing scale (5000)

Brazilian Crystal Opal. The play of color is caused by the interference and diffraction of light between silica spheres (150 - 300nm in diameter).

Blue hue of a species of tarantula (450nm 20nm)

Nano-objects are often categorized as to how many of their dimensions fall in the nanoscale. A nanoparticle is defined a nano-object with all three external dimensions in the nanoscale, whose longest and the shortest axes do not differ significantly. A nanofiber has two external dimensions in the nanoscale, with nanotubes being hollow nanofibers and nanorods being solid nanofibers. A nanoplate has one external dimension in the nanoscale, and if the two larger dimensions are significantly different it is called a nanoribbon. For nanofibers and nanoplates, the other dimensions may or may not be in the nanoscale, but must be significantly larger. A significant different in all cases is noted to be typically at least a factor of 3.[19]

Nanostructured materials are often categorized by what phases of matter they contain. A nanocomposite is a solid containing at least one physically or chemically distinct region, or collection of regions, having at least one dimension in the nanoscale.. A nanofoam has a liquid or solid matrix, filled with a gaseous phase, where either phase has dimensions on the nanoscale. A nanoporous material is a solid material containing nanopores, cavities with dimensions on the nanoscale. A nanocrystalline material has a significant fraction of crystal grains in the nanoscale.[20]

In other sources, nanoporous materials and nanofoam are sometimes considered nanostructures but not nanomaterials because only the voids and not the materials themselves are nanoscale.[21] Although the ISO definition only considers round nano-objects to be nanoparticles, other sources use the term nanoparticle for all shapes.[22]

Nanoparticles have all three dimensions on the nanoscale. Nanoparticles can also be embedded in a bulk solid to form a nanocomposite.[21]

The fullerenes are a class of allotropes of carbon which conceptually are graphene sheets rolled into tubes or spheres. These include the carbon nanotubes (or silicon nanotubes) which are of interest both because of their mechanical strength and also because of their electrical properties.[23]

The first fullerene molecule to be discovered, and the family's namesake, buckminsterfullerene (C60), was prepared in 1985 by Richard Smalley, Robert Curl, James Heath, Sean O'Brien, and Harold Kroto at Rice University. The name was a homage to Buckminster Fuller, whose geodesic domes it resembles. Fullerenes have since been found to occur in nature.[24] More recently, fullerenes have been detected in outer space.[25]

For the past decade, the chemical and physical properties of fullerenes have been a hot topic in the field of research and development, and are likely to continue to be for a long time. In April 2003, fullerenes were under study for potential medicinal use: binding specific antibiotics to the structure of resistant bacteria and even target certain types of cancer cells such as melanoma. The October 2005 issue of Chemistry and Biology contains an article describing the use of fullerenes as light-activated antimicrobial agents. In the field of nanotechnology, heat resistance and superconductivity are among theproperties attracting intense research.

A common method used to produce fullerenes is to send a large current between two nearby graphite electrodes in an inert atmosphere. The resulting carbon plasma arc between the electrodes cools into sooty residue from which many fullerenes can be isolated.

There are many calculations that have been done using ab-initio Quantum Methods applied to fullerenes. By DFT and TDDFT methods one can obtain IR, Raman and UV spectra. Results of such calculations can be compared with experimental results.

Inorganic nanomaterials, (e.g. quantum dots, nanowires and nanorods) because of their interesting optical and electrical properties, could be used in optoelectronics.[26] Furthermore, the optical and electronic properties of nanomaterials which depend on their size and shape can be tuned via synthetic techniques. There are the possibilities to use those materials in organic material based optoelectronic devices such as Organic solar cells, OLEDs etc. The operating principles of such devices are governed by photoinduced processes like electron transfer and energy transfer. The performance of the devices depends on the efficiency of the photoinduced process responsible for their functioning. Therefore, better understanding of those photoinduced processes in organic/inorganic nanomaterial composite systems is necessary in order to use them in optoelectronic devices.

Nanoparticles or nanocrystals made of metals, semiconductors, or oxides are of particular interest for their mechanical, electrical, magnetic, optical, chemical and other properties.[27][28] Nanoparticles have been used as quantum dots and as chemical catalysts such as nanomaterial-based catalysts. Recently, a range of nanoparticles are extensively investigated for biomedical applications including tissue engineering, drug delivery, biosensor.[29][30]

Nanoparticles are of great scientific interest as they are effectively a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nano-scale this is often not the case. Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials.

Nanoparticles exhibit a number of special properties relative to bulk material. For example, the bending of bulk copper (wire, ribbon, etc.) occurs with movement of copper atoms/clusters at about the 50nm scale. Copper nanoparticles smaller than 50nm are considered super hard materials that do not exhibit the same malleability and ductility as bulk copper. The change in properties is not always desirable. Ferroelectric materials smaller than 10nm can switch their polarization direction using room temperature thermal energy, thus making them useless for memory storage. Suspensions of nanoparticles are possible because the interaction of the particle surface with the solvent is strong enough to overcome differences in density, which usually result in a material either sinking or floating in a liquid. Nanoparticles often have unexpected visual properties because they are small enough to confine their electrons and produce quantum effects. For example, gold nanoparticles appear deep red to black in solution.

The often very high surface area to volume ratio of nanoparticles provides a tremendous driving force for diffusion, especially at elevated temperatures. Sintering is possible at lower temperatures and over shorter durations than for larger particles. This theoretically does not affect the density of the final product, though flow difficulties and the tendency of nanoparticles to agglomerate do complicate matters. The surface effects of nanoparticles also reduces the incipient melting temperature.

The smallest possible crystalline wires with cross-section as small as a single atom can be engineered in cylindrical confinement.[31][32][33] Carbon nanotubes, a natural semi-1D nanostructure, can be used as a template for synthesis. Confinement provides mechanical stabilization and prevents linear atomic chains from disintegration; other structures of 1D nanowires are predicted to be mechanically stable even upon isolation from the templates.[34][35]

2D materials are crystalline materials consisting of a two-dimensional single layer of atoms. The most important representative graphene was discovered in 2004.Thin films with nanoscale thicknesses are considered nanostructures, but are sometimes not considered nanomaterials because they do not exist separately from the substrate.[21]

Some bulk materials contain features on the nanoscale, including nanocomposites, nanocrystalline materials, nanostructured films, and nanotextured surfaces.[21]

Box-shaped graphene (BSG) nanostructure is an example of 3D nanomaterial.[36] BSG nanostructure has appeared after mechanical cleavage of pyrolytic graphite. This nanostructure is a multilayer system of parallel hollow nanochannels located along the surface and having quadrangular cross-section. The thickness of the channel walls is approximately equal to 1nm. The typical width of channel facets makes about 25nm.

Nano materials are used in a variety of, manufacturing processes, products and healthcare including paints, filters, insulation and lubricant additives. In healthcare Nanozymes are nanomaterials with enzyme-like characteristics.[37] They are an emerging type of artificial enzyme, which have been used for wide applications in such as biosensing, bioimaging, tumor diagnosis,[38] antibiofouling and more. In paints nanomaterials are used to improve UV protection and improve ease of cleaning.[39] High quality filters may be produced using nanostructures, these filters are capable of removing particulate as small as a virus as seen in a water filter created by Seldon Technologies. In the air purification field, nano technology was used to combat the spread of MERS in Saudi Arabian hospitals in 2012.[40] Nanomaterials are being used in modern and human-safe insulation technologies, in the past they were found in Asbestos-based insulation.[41] As a lubricant additive, nano materials have the ability to reduce friction in moving parts. Worn and corroded parts can also be repaired with self-assembling anisotropic nanoparticles called TriboTEX.[40]Nanomaterials can also be used in three-way-catalyst (TWC) applications. TWC converters have the advantage of controlling the emission of nitrogen oxides (NOx), which are precursors to acid rain and smog[42]. In core-shell structure, nanomaterials form shell as the catalyst support to protect the noble metals such as palladium and rhodium[43]. The primary function is that the supports can be used for carrying catalysts active components, making them highly dispersed, reducing the use of noble metals, enhancing catalysts activity, and improving the mechanical strength.

The goal of any synthetic method for nanomaterials is to yield a material that exhibits properties that are a result of their characteristic length scale being in the nanometer range (1 100nm). Accordingly, the synthetic method should exhibit control of size in this range so that one property or another can be attained. Often the methods are divided into two main types, "bottom up" and "top down."

Bottom up methods involve the assembly of atoms or molecules into nanostructured arrays. In these methods the raw material sources can be in the form of gases, liquids or solids. The latter require some sort of disassembly prior to their incorporation onto a nanostructure. Bottom up methods generally fall into two categories: chaotic and controlled.

Chaotic processes involve elevating the constituent atoms or molecules to a chaotic state and then suddenly changing the conditions so as to make that state unstable. Through the clever manipulation of any number of parameters, products form largely as a result of the insuring kinetics. The collapse from the chaotic state can be difficult or impossible to control and so ensemble statistics often govern the resulting size distribution and average size. Accordingly, nanoparticle formation is controlled through manipulation of the end state of the products. Examples of chaotic processes are laser ablation, exploding wire, arc, flame pyrolysis, combustion, and precipitation synthesis techniques.

Controlled processes involve the controlled delivery of the constituent atoms or molecules to the site(s) of nanoparticle formation such that the nanoparticle can grow to a prescribed sizes in a controlled manner. Generally the state of the constituent atoms or molecules are never far from that needed for nanoparticle formation. Accordingly, nanoparticle formation is controlled through the control of the state of the reactants. Examples of controlled processes are self-limiting growth solution, self-limited chemical vapor deposition, shaped pulse femtosecond laser techniques, and molecular beam epitaxy.

Novel effects can occur in materials when structures are formed with sizes comparable to any one of many possible length scales, such as the de Broglie wavelength of electrons, or the optical wavelengths of high energy photons. In these cases quantum mechanical effects can dominate material properties. One example is quantum confinement where the electronic properties of solids are altered with great reductions in particle size. The optical properties of nanoparticles, e.g. fluorescence, also become a function of the particle diameter. This effect does not come into play by going from macrosocopic to micrometer dimensions, but becomes pronounced when the nanometer scale is reached.

In addition to optical and electronic properties, the novel mechanical properties of many nanomaterials is the subject of nanomechanics research. When added to a bulk material, nanoparticles can strongly influence the mechanical properties of the material, such as the stiffness or elasticity. For example, traditional polymers can be reinforced by nanoparticles (such as carbon nanotubes) resulting in novel materials which can be used as lightweight replacements for metals. Such composite materials may enable a weight reduction accompanied by an increase in stability and improved functionality.[44]

Finally, nanostructured materials with small particle size such as zeolites, and asbestos, are used as catalysts in a wide range of critical industrial chemical reactions. The further development of such catalysts can form the basis of more efficient, environmentally friendly chemical processes.

The first observations and size measurements of nano-particles were made during the first decade of the 20th century. Zsigmondy made detailed studies of gold sols and other nanomaterials with sizes down to 10nm and less. He published a book in 1914.[45] He used an ultramicroscope that employs a dark field method for seeing particles with sizes much less than light wavelength.

There are traditional techniques developed during the 20th century in interface and colloid science for characterizing nanomaterials. These are widely used for first generation passive nanomaterials specified in the next section.

These methods include several different techniques for characterizing particle size distribution. This characterization is imperative because many materials that are expected to be nano-sized are actually aggregated in solutions. Some of methods are based on light scattering. Others apply ultrasound, such as ultrasound attenuation spectroscopy for testing concentrated nano-dispersions and microemulsions.[46]

There is also a group of traditional techniques for characterizing surface charge or zeta potential of nano-particles in solutions. This information is required for proper system stabilzation, preventing its aggregation or flocculation. These methods include microelectrophoresis, electrophoretic light scattering and electroacoustics. The last one, for instance colloid vibration current method is suitable for characterizing concentrated systems.

The chemical processing and synthesis of high performance technological components for the private, industrial and military sectors requires the use of high purity ceramics, polymers, glass-ceramics and material composites. In condensed bodies formed from fine powders, the irregular sizes and shapes of nanoparticles in a typical powder often lead to non-uniform packing morphologies that result in packing density variations in the powder compact.

Uncontrolled agglomeration of powders due to attractive van der Waals forces can also give rise to in microstructural inhomogeneities. Differential stresses that develop as a result of non-uniform drying shrinkage are directly related to the rate at which the solvent can be removed, and thus highly dependent upon the distribution of porosity. Such stresses have been associated with a plastic-to-brittle transition in consolidated bodies, and can yield to crack propagation in the unfired body if not relieved.[47][48][49]

In addition, any fluctuations in packing density in the compact as it is prepared for the kiln are often amplified during the sintering process, yielding inhomogeneous densification. Some pores and other structural defects associated with density variations have been shown to play a detrimental role in the sintering process by growing and thus limiting end-point densities. Differential stresses arising from inhomogeneous densification have also been shown to result in the propagation of internal cracks, thus becoming the strength-controlling flaws.[50][51]

It would therefore appear desirable to process a material in such a way that it is physically uniform with regard to the distribution of components and porosity, rather than using particle size distributions which will maximize the green density. The containment of a uniformly dispersed assembly of strongly interacting particles in suspension requires total control over particle-particle interactions. It should be noted here that a number of dispersants such as ammonium citrate (aqueous) and imidazoline or oleyl alcohol (nonaqueous) are promising solutions as possible additives for enhanced dispersion and deagglomeration. Monodisperse nanoparticles and colloids provide this potential.[52]

Monodisperse powders of colloidal silica, for example, may therefore be stabilized sufficiently to ensure a high degree of order in the colloidal crystal or polycrystalline colloidal solid which results from aggregation. The degree of order appears to be limited by the time and space allowed for longer-range correlations to be established. Such defective polycrystalline colloidal structures would appear to be the basic elements of sub-micrometer colloidal materials science, and, therefore, provide the first step in developing a more rigorous understanding of the mechanisms involved in microstructural evolution in high performance materials and components.[53][54]

The quantitative analysis of nanomaterials showed that nanoparticles, nanotubes, nanocrystalline materials, nanocomposites, and graphene have been mentioned in 400000, 181000, 144000, 140000, and 119000 ISI-indexed articles, respectively, by Sep 2018. As far as patents are concerned, nanoparticles, nanotubes, nanocomposites, graphene, and nanowires have been played a role in 45600, 32100, 12700, 12500, and 11800 patents, respectively. Monitoring approximately 7000 commercial nano-based products available on global markets revealed that the properties of around 2330 products have been enabled or enhanced aided by nanoparticles. Liposomes, nanofibers, nanocolloids, and aerogels were also of the most common nanomaterials in consumer products.[55]

The European Union Observatory for Nanomaterials (EUON) has produced a database (NanoData) that provides information on specific patents, products, and research publications on nanomaterials.

The World Health Organization (WHO) published a guideline on protecting workers from potential risk of manufactured nanomaterials at the end of 2017.[56] WHO used a precautionary approach as one of its guiding principles. This means that exposure has to be reduced, despite uncertainty about the adverse health effects, when there are reasonable indications to do so. This is highlighted by recent scientific studies that demonstrate a capability of nanoparticles to cross cell barriers and interact with cellular structures.[57][58] In addition, the hierarchy of controls was an important guiding principle. This means that when there is a choice between control measures, those measures that are closer to the root of the problem should always be preferred over measures that put a greater burden on workers, such as the use of personal protective equipment (PPE). WHO commissioned systematic reviews for all important issues to assess the current state of the science and to inform the recommendations according to the process set out in the WHO Handbook for guideline development. The recommendations were rated as "strong" or "conditional" depending on the quality of the scientific evidence, values and preferences, and costs related to the recommendation.

The WHO guidelines contain the following recommendations for safe handling of MNMs:[citation needed]

A. Assess health hazards of MNMs

B. Assess exposure to MNMs

C. Control exposure to MNMs

For health surveillance WHO could not make a recommendation for targeted MNM-specific health surveillance programmes over existing health surveillance programmes that are already in use owing to the lack of evidence. WHO considers training of workers and worker involvement in health and safety issues to be best practice but could not recommend one form of training of workers over another, or one form of worker involvement over another, owing to the lack of studies available. It is expected that there will be considerable progress in validated measurement methods and risk assessment and WHO expects to update these guidelines in five years time, in 2022.

Because nanotechnology is a recent development, the health and safety effects of exposures to nanomaterials, and what levels of exposure may be acceptable, are subjects of ongoing research.[8] Of the possible hazards, inhalation exposure appears to present the most concern. Animal studies indicate that carbon nanotubes and carbon nanofibers can cause pulmonary effects including inflammation, granulomas, and pulmonary fibrosis, which were of similar or greater potency when compared with other known fibrogenic materials such as silica, asbestos, and ultrafine carbon black. Although the extent to which animal data may predict clinically significant lung effects in workers is not known, the toxicity seen in the short-term animal studies indicate a need for protective action for workers exposed to these nanomaterials, although no reports of actual adverse health effects in workers using or producing these nanomaterials were known as of 2013.[59] Additional concerns include skin contact and ingestion exposure,[59][60][61] and dust explosion hazards.[62][63]

Elimination and substitution are the most desirable approaches to hazard control. While the nanomaterials themselves often cannot be eliminated or substituted with conventional materials,[8] it may be possible to choose properties of the nanoparticle such as size, shape, functionalization, surface charge, solubility, agglomeration, and aggregation state to improve their toxicological properties while retaining the desired functionality.[64] Handling procedures can also be improved, for example, using a nanomaterial slurry or suspension in a liquid solvent instead of a dry powder will reduce dust exposure.[8] Engineering controls are physical changes to the workplace that isolate workers from hazards, mainly ventilation systems such as fume hoods, gloveboxes, biosafety cabinets, and vented balance enclosures.[65] Administrative controls are changes to workers' behavior to mitigate a hazard, including training on best practices for safe handling, storage, and disposal of nanomaterials, proper awareness of hazards through labeling and warning signage, and encouraging a general safety culture. Personal protective equipment must be worn on the worker's body and is the least desirable option for controlling hazards.[8] Personal protective equipment normally used for typical chemicals are also appropriate for nanomaterials, including long pants, long-sleeve shirts, and closed-toed shoes, and the use of safety gloves, goggles, and impervious laboratory coats.[65] In some circumstances respirators may be used.[64]

Exposure assessment is a set of methods used to monitor contaminant release and exposures to workers. These methods include personal sampling, where samplers are located in the personal breathing zone of the worker, often attached to a shirt collar to be as close to the nose and mouth as possible; and area/background sampling, where they are placed at static locations. The assessment should use both particle counters, which monitor the real-time quantity of nanomaterials and other background particles; and filter-based samples, which can be used to identify the nanomaterial, usually using electron microscopy and elemental analysis.[64][66] As of 2016, quantitative occupational exposure limits have not been determined for most nanomaterials. The U.S. National Institute for Occupational Safety and Health has determined non-regulatory recommended exposure limits for carbon nanotubes, carbon nanofibers,[59] and ultrafine titanium dioxide.[67] Agencies and organizations from other countries, including the British Standards Institute[68] and the Institute for Occupational Safety and Health in Germany,[69] have established OELs for some nanomaterials, and some companies have supplied OELs for their products.[8]

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The Promise of Nanomedicine – Laboratory Equipment

§ December 20th, 2018 § Filed under Nano Medicine Comments Off on The Promise of Nanomedicine – Laboratory Equipment

More than a decade ago, nanotechnology became an integral part of the overall scientific research world. Governments started funding programs specifically aimed at nanotechnology, research universities opened their facilities and coursework to the new discipline, and journals focusing on nano research became commonplace.And now, many researchers believe, its nanomedicines turn to do the same. Nanomedicinewhich has emerged as nanotechnologys most important sub-disciplineis the application of nanotechnology to the prevention and treatment of disease in the human body. It is already having an impact clinically among some of the deadliest diseases in the world.

Nanomedicine is far from the stuff of science fiction. The possibilities for nanomedicine to help us diagnose, treat and image diseases are endless. Imagine a smart nanomedicine that is able to bind to tumor cells and enhance imaging and diagnosis, at the same time as being able to deliver a gene therapy or chemotherapy agent. With the technologies available to us and our multidisciplinary teams, this will be possible in my lifetime, said Phoebe Phillips, head of the pancreatic cancer translational research group at the University of New South Wales in Sydney.

Phillips and her team have created a nanoparticle that dramatically increases its effectiveness as an anti-cancer drug for patients with pancreatic cancers, which is one of the fastest killing cancers from time of initial detection, often leaving patients with no suitable treatment options and only weeks to live.

While nanomedicine canand likely willplay a role in diagnostics, regenerative medicine, prosthetics and more, the effect the sub-discipline is currently having on the treatment of autoimmune diseases and cancers is significant.

Nanomedicine for HIVThirty years ago, a diagnosis of HIV/AIDS was essentially a guarantee of a painful, protracted death. It wasnt until 1996 that researchers discovered antiretroviral drugs, and the potent combination therapy that leads to successful management of HIV/AIDS in most cases. However, not much has changed since that discovery. Those suffering from the autoimmune disease still require daily oral dosing of three to four pills, and chronic oral dosing has significant complications that can arise from the high pill burden experienced by patients, leading to non-adherence to therapies for a variety of reasons.

Ive been working in HIV for over 20 years, Andrew Owen, professor of molecular and clinical pharmacology at the University of Liverpool (UK) told Laboratory Equipment. I was trying to understand the variability in drug exposure that occurs between different individuals and the genetic basis for that. We were finding a lot of interesting things, but they werent clinically implementable. They gave us a good understanding of why drug exposure was variable, but it didnt actually help the patients in any way.

In an attempt to solve the problem rather than just characterize it, Owen turned to nanomedicine in 2009, eventually becoming part of the first team to conduct human trials of orally dosed nanomedicines for HIV. Since then, Owen and his interdisciplinary team at the Liverpool Nanomedicine Partnership have secured more than 20 million of research funding for a multitude of nanomedicine-based approaches to HIV, such low-dose oral delivery, long-acting injectable medications and targeted delivery of antiretrovirals.

Some of Owens most important research to date tackles two of the pharmaceutical industrys biggest challenges: oral delivery of potent drugs and supply and demand.

One of the major problems that has plagued drug discovery and drug development over the last 30 years has been compatibility with oral drug delivery, Owen explained. The pharmaceutical industry has wrestled with that because they can develop very potent molecules across diseases, but actually delivering those molecules orally is very challenging. As you try to design into the molecule oral bioavailabilty, you usually get further away from the potency you want.

The Liverpool team solved this problem with the creation of Solid Drug Nanoparticles. The technology consists of combining a normal drug, in its solid form, with particles on that drug that are measurable within the nanometer scale. There are other things packed into the formulation as well, such as FDA-approved stabilizers that are proven to help disperse the drug. Owen says it is all about increasing the surface area covered by the drug.

If you imagine you take a granulated form of the drug, youre going to get big chunks of drugs in the intestinal tract when dissolution happens. But if you have nanometer-sized particles within the GI tract, then you are going to get a complete coating of the inside of the intestine after you take the drug, Owen explained. What that does is it massively increases the surface area covered by the drug, which saturates all sorts of drug influx processes within the GI tract.

Since 80 percent of a humans immune system is concentrated in the gut, the Solid Drug Nanoparticles are the perfect mechanism. The immune cells in the gut instinctually move toward the particles, creating a pathway for the drugs to cross the intestines, move through the lymphatic system, and finally into the systematic circulation.

In February, Owen presented the results of two trials at the Conference on Retroviruses and Opportunistic Infections (CROI) that confirmed his Solid Drug Nanoparticles can be effective at a 50 percent dose reduction. Specifically, Owen and his team applied the nanomedicine-based approach to the formulation of two drugs: efvirenz (EFV) and lopinavir (LPV). EFV is the current WHO-recommended regimen, with 70 percent of adult HIV patients in low- and middle-income countries taking the medication. At 50 percent of the dose, the patients in the trial were able to maintain plasma concentrations of the conventional dose.

Globally, the supply of drugs needed to treat every patient with HIV is outstripping manufacturing capabilitymeaning we, as a human species, cannot physically make enough HIV medication to treat everyone with the disease. A 50 percent reduction in dose means twice as many patients served with the existing drug supply.Owen and his team are working with multiple global partners to move the technology forward. For the drugs already formulated, the Medicines Patent Pool and Clinical Health Access are helping to scale up and take them to market. Meanwhile, USAIDs Project OPTIMIZE is applying the nanoparticle technology to the newest HIV drugs for use in low- and middle-income countries.

For their latest collaboration with Johns Hopkins University, the Liverpool team was just awarded $3 million to examine the use of implantable technologies that can deliver drugs for weeks, or even months.

The current oral drug regimens for HIV comprises three drugs in combinationone is the major driver for efficacy, and the other two are nucleoside reverse transcriptase inhibitors that prevent resistance to the main drug. However, current injectable formulations are only available with the main drugnone include the nucleoside reverse transcriptase inhibitors.

So, our project aims to develop the first long-acting injectable nucleoside reverse transcriptase inhibitors so that we can use them to have a fully long-acting regimen that matches the current clinical paradigm for therapy, Owen said.

The Liverpool/Hopkins team has also thought about applying their long-acting injectable technology to other chronic diseases, such as malaria and tuberculosis, as well as some cardiovascular applications.

Nanomedicine for diabetesWhen the nanoparticles he was working with as an imaging tool didnt produce the desired results, Pere Santamaria grew frustratedbut he didnt give up. Instead, the doctor and professor at the University of Calgary (Canada) changed his assumptions and pursued his experimentuntil the data came pouring in that confirmed it wasnt a failed experiment at all. Rather, it was a discovery.

The discovery of Navacims was a bit serendipitous, Santamaria told Laboratory Equipment. Thankfully I am a little OCD and I didnt let the failed experiment go.Navacims are an entirely new class of nanomedicine drugs that harness the ability to stop disease without impairing normal immunity. Santamaria has been studying Navacims for the past 17 years, ever since unintentionally developing them. He even started a spin-off company, Parvus Therapeutics, Inc., to help bring the drugs to market.

In autoimmune diseases, white blood cells, which are normally responsible for warding off foreign invaders and disease, turn on the body, attacking the good cells and causing their destruction. Each specific autoimmune disease results from an attack against thousands of individual protein fragments in the targeted organ, such as the insulin-producing pancreatic cells in the case of type 1 diabetes.

But Santamarias studies show that nanoparticles decorated with protein targets acting as bait for disease-causing white blood cells can actually be used to reprogram the cells to rightfully suppress the disease they once intended to cause.

Once the immune system recognizes the presence of a Navacim, a white blood cell is reprogrammed by epigenetic changes into a lymphocyte that no longer wants to cause tissue damage, but rather work to suppress disease. According to Santamaria, the reprogramming step is immediately followed by an expansion of that population of lymphocytesone now-good white blood cell dividing into a million.

Basically they turn the tables on the immune system, and then there is a very sophisticated series of downstream cellular events that arise from that reprogramming event that involves the recruitment of other lymphocytes and other cell types that completely suppress the inflammation in the organ that is being infected, Santamaria explained. This happens extremely efficiently and comprehensively. This is an approach that can efficiently, selectively and specifically blend a complex response without impairing basic immunity.

In addition, the design of Navacims is modular, meaning the nanomedicine can be applied to severalif not allautoimmune diseases, including multiple sclerosis and rheumatoid arthritis. Navacims can be altered to target different diseases by simply changing a small portion of the bait molecules on the nanoparticles. Santamarias studies have shown this to work in about seven autoimmune diseases thus far.

In April, Santamarias company Parvus entered into a license and collaboration agreement with Novartis for Navacims. Under the terms of the agreement, Novartis receives exclusive worldwide rights to use Parvus Navacim technology to develop and commercialize products for the treatment of type 1 diabetes, and will be responsible for clinical-stage development and commercialization. Parvus will still be responsible for conducting ongoing preclinical work in the diabetes area, with some research funding from Novartis.

Weve had such a long time to prove ourselves, that this is not a flash in the pan, that this is something serious and robust, Santamaria said. We know so much about the mechanisms of our actions, and so much granularity. I think there are no other drugs that have reached the clinic with this level of understanding. That was painful in the beginning for us, but in the end its going to be good.

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Liposomal formulation of polyacrylate-peptide conjugate as a new vaccine candidate against cervical cancer, Khongkow M, LiuTY, Bartlett S, Hussein WM, Nevagi R, Jia ZF, Monteiro MJ, Wells J, Ruktanonchai UR, Skwarczynski M, Toth I, Prec. Nanomed. 2018 Oct;1(3):186-196.

In this study, the authors describe the improvement of vaccine delivery via using a polymer-based delivery system. Authors demonstrate that the combination of polymer-based and liposome delivery systems may be effective without the use of additional adjuvant and with just a single-dose immunization.

Nanoparticle-Encapsulated Doxorubicin Demonstrates Superior Tumor Cell Kill in Triple Negative Breast Cancer Subtypes Intrinsically Resistant to Doxorubicin, Krausz AE, Adler BL, Makdisi J, Schairer D, Rosen J, Landriscina A, Navati M, Alfieri A, Friedman JM, Nosanchuk JD, Rodriguez-Gabin A, Ye KQ, McDaid HM, Friedman AJ, , Prec. Nanomed. 2018 Oct;1(3):172-185.

The treatment of triple-negative breast cancer is often difficult due to frequent resistance to doxorubicin. Using different nano-formulations based on sol-gel technology to encapsulate doxorubicin, the authors here showed enhanced dose-response metrics and tumor cell kill of these cancer cells due to an increased drug accumulation in the local tumor environment.Specific Molecular Recognition as a Strategy to Delineate Tumor Margin Using Topically Applied Fluorescence Embedded Nanoparticles, Barton S, Li B, Siuta M, Janve VA, Song J, Holt CM, Tomono T, Ukawa M, Kumagai H, Tobita E, Wilson K, Sakuma S, Pham W. Prec. Nanomed. 2018 Oct;1(3):197-210.

The ability to delineate the tumor accurately during operation is important to ensure all tumor cells are resected. Here, the authors describe the development of a multimodal imaging probe using nanospheres to target epithelial cells of pancreatic cancer. The specificity to target only tumor cells was clearly shown in both in-vitro and in-vivo experiments.

Plasma samples from mouse strains and humans demonstrate different susceptibilities to complement activation, Neun BW, Sznsi G, Szebeni J, Dobrovolskaia M., Prec. Nanomed. 2018 Oct;1(3):197-210.

The authors describe the importance of mouse strain selection for in vitro complement activation analysis addressing also the existence of inter- and intraspecies variability.

Cellular Trafficking of Sn-2 Phosphatidylcholine Prodrugs Studied withFluorescence Lifetime Imaging and Super-resolution Microscopy; Maji D, Lu J, Sarder P, Schmieder AH, Cui G, Yang X, Pan D, Lew MD, Achilefu S, Lanza GM. Prec. Nanomed. 2018 July;1(2):127-145.

Skin Biosensing and Bioanalysis: What the Future Holds; Ng KW, Moghimi SM. Prec. Nanomed. 2018 July;1(2):124-127.

A Coming Era of Precision Diagnostics Based on Nano-assisted Mass Spectrometry; Li RX, Gurav DD, Wan JJ, Qian K. Prec. Nanomed. 2018 July;1(2):162-172.

Rational Design of a siRNA Delivery System: ALOX5 and Cancer Stem Cells as Therapeutic Targets, Rafael D, Andrade F, Montero S, Gener P, Seras-Franzoso J, Martnez F, Gonzlez P, Florindo H, Arango D, Says J, Abasolo I, Videira M, Schwartz Jr. S. Prec. Nanomed. 2018 July;1(2):86-105. Lysozyme transport to the brain by Liposomes; Nordling-David MM, Rachmin E, Etty Grad E, Golomb G, Prec. Nanomed. 2018 July;1(2):146-161.Retinal Multipotent Stem-Cell Derived MiEye Spheroid 3D Culture Model for Preclinical Screening of Non-viral Gene Delivery Systems,; Chen DW, Foldvari M. Prec. Nanomed. 2018 July;1(2):106-123.

The Story of Precision Nanomedicine the Journal; Lajos P Balogh, Prec. Nanomed. 2018, Apr; 1(1):1-4. Balancing Interests of Science, Scientists, and the Publishing Business; Lajos P Balogh, Prec. Nanomed. 2018, Apr; 1(1):5-14. Improving Innovation in Nano-Healthcare Funding, Mike Eaton, Prec. Nanomed. 2018 Apr; 1(1):15-17.

Immunocompatibility of Rad-PC-Rad liposomes in vitro, based on human complement activation and cytokine release; Matviykiv S, Buscema M, Gerganova G, Mszros T, Kozma GT, Mettal U, Neuhaus F, Ishikawa T, SzebeniJ, Zumbuehl A, Mller B. Prec. Nanomed. 2018 Apr;1(1):43-62.

Discrepancies in the in vitro and in vivo role of scavenger receptors in clearance of nanoparticles by Kupffer cells; Wang G, Groman E, Simberg D. Prec. Nanomed. 2018 Apr;1(1):76-85.

Origins to Outcomes: A Role for Extracellular Vesicles in Precision Medicine; Savage, J, Maguire, CM, Prina-Mello A. Prec. Nanomed. 2018, Apr; 1(1):18-42.A porcine model of complement activation-related pseudoallergy to nanopharmaceuticals: Pros and cons of translation to a preclinical safety test; Szebeni J, Bedcs P, Dzsi L, Urbanics R. Prec. Nanomed. 2018 Apr;1(1):63-75.

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