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Made-in-space organs could soon be reality – ETHealthworld.com

§ March 12th, 2020 § Filed under Nano Medicine Comments Off on Made-in-space organs could soon be reality – ETHealthworld.com

Astronauts are growing the beginnings of new organs on board the International Space Station.

The experiment is an attempt to grow human tissue by sending adult human stem cells into space, and allowing them to grow in space.

Eventually, it is hoped, the stem cells will develop into bone, cartilage and other organs. If that is successful, the discoveries could be used to try and grow organs for transplant, the scientists involved say.

The experiment uses weightlessness as a tool, according to Cara Thiel, one of the two researchers from the University of Zurich. The lack of gravity on board the ISS will be used to encourage the stem cells to grow into tissue in three dimensions, rather than the single-layer structures that form on Earth.

It is being conducted by the astronauts on board the ISS using a mobile mini-laboratory that was sent on a SpaceX rocket last week. The experiment will last for a month, during which scientists will watch to see how the stem cells grow.

If it is successful, they hope to switch from a small laboratory to bigger production. From there, they could use the process to generate tissue for transplants by taking cells from patients, or generating organ-like material, either ensuring that it works for a specific patients or reducing the number of animals used in experiments.

On Earth, tissue grows in monolayer cultures: generating flat, 2D tissue. But investigations both in space and Earth suggest that in microgravity, cells exhibit spatially unrestricted growth and assemble into complex 3D aggregates, said Oliver Ullrich, who is also leading the research.

Previous research has involved simulated ad real experiments, mostly using tumour cells, and placing real human stem cells into microgravity simulators. But for the next stage of the research there is no alternative to the ISS, he says, as 3D tissue formation of this kind requires several days or even weeks in microgravity.

After the month-long experiment, the scientists will get the samples back and expect to see successful formation of organoids smaller, more simple versions of organs inside the test tubes.

Scientists are still not sure why the conditions of the ISS lead to the assembly of complex 3D tissue structures. Scientists are still continuing to research how the gravitational force and the molecular machinery in the cell interact to create new and different kinds of tissue on Earth and in space.

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Global Antiviral Therapeutics Industry Assessment, 2028 – Yahoo Finance

§ March 12th, 2020 § Filed under Nano Medicine Comments Off on Global Antiviral Therapeutics Industry Assessment, 2028 – Yahoo Finance

Dublin, March 12, 2020 (GLOBE NEWSWIRE) -- The "Antiviral Therapeutics - Technologies, Markets & Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.

This report reviews the current state-of-art of antiviral approaches including vaccines, pharmaceuticals and innovative technologies for delivery of therapeutics.

Markets for antivirals are considered according to viruses and diseases caused by them and also according to management approaches: antiviral drugs, vaccines, MAbs and innovative approaches that include immunological and use of other technologies such as gene therapy, antisense, RNAi and nanobiotechnology. Antiviral markets are estimated starting with 2018 with projections up to the year 2028.

Profiles of 194 companies that are involved in developing various technologies and products are profiled and with 175 collaborations. These include major pharmaceutical companies (12), Biopharmaceutical companies with antiviral products (86), Antiviral drug companies (26) as well as viral vaccine companies (71). The report is supplemented with 54 tables, 15 figures and 550 references from the literature.

The introduction starts with a practical classification of viral diseases according to their commercial importance. Various antiviral approaches are described including pharmaceuticals and molecular biological therapies such as gene therapy and RNA interference (RNAi) as well as vaccines for virus infections. Expert opinion is given about the current problems and needs in antiviral therapy. SWOT (strengths, weaknesses, opportunities and threats) analysis of antiviral approaches is presented against the background of concept of an ideal antiviral agent.

A novel feature of this report is the use of nanotechnology in virology and its potential for antiviral therapeutics. Interaction of nanoparticles with viruses are described. NanoViricides are polymeric micelles, which act as nanomedicines to destroy viruses. Various methods for local as well as systemic delivery of antiviral agents and vaccines are described. Nanobiotechnology plays an important role in improving delivery of antivirals. Advantages and limitations of delivery of gene-based, antisense and RNAi antiviral therapeutics are discussed.

Anti-influenza measures applicable to human as well as avian forms are described including the recent epidemic of swine flu. Resistance can develop against neuraminidase inhibitors although it is less than that with adamantanes. Considering these problems, there is need for a more effective agent. Investigations into alternative anti-influenza target will probably expand in the coming years. These include the development of mechanisms to inhibit fusion between the virus envelope and the cell membrane.

After a discussion of current therapies of AIDS/HIV and their limitations, new strategies in development of antiviral agents are described. Drug resistance and toxicities are emerging as major treatment challenges. Based on a review of technologies and drugs in development, it can be stated that there are good prospects are of finding a cure for HIV/AIDS in the next decade.

Hepatitis viruses are described with focus on hepatitis C virus (HCV) and hepatitis B virus (HBV). Despite the presence of numerous drug candidates in the anti-HCV pipeline, and the commitment of major R&D resources by many pharmaceutical companies, it might still take several years for any new anti-HCV drugs to reach the market. Although many companies are focusing their efforts on developing viral inhibitors, cellular targets in the host are beginning to emerge as attractive possibilities because they might enable the development of broad-spectrum antiviral drugs with less chance for developing viral resistance.

Various commercially important viruses include herpes simplex (HSV) and human papilloma virus (HPV). There a number of treatments but HSV is not destroyed completely and remains dormant and activates from time to time to cause various clinical manifestations.

There is discussion about the role of HPV in cervical cancer and vaccines available now seem to be adequate in preventing HSV-induced cervical cancer. There is no effective vaccine for respiratory syncytial virus (RSV) although monoclonal antibody (MAb) treatment is useful for prophylaxis and reducing the clinical manifestations. There is a need for an agent to eliminate this virus.

Various viruses that either occur in epidemics or in tropics and some naturally emerging infectious diseases are described, e.g. viral hemorrhagic fevers such as dengue and West Nile virus infection. These are a constant threat and impossible to anticipate. Some of these lack antiviral agents or vaccines for prevention. Although these include some of the most serious viral disorders, the development of antiviral agents for these is not commercially attractive. Current research and approaches to these virus infections are discussed.

Story continues

Key Topics Covered

Executive Summary1. Introduction to Virology2. Antiviral Approaches3. Vaccines for Virus Infections4. Role of Nanotechnology in Developing Antiviral Agents5. Delivery of Antivirals6. Competitive Assessment of Antiviral Approaches7. Influenza Viruses8. AIDS/HIV9. Hepatitis Viruses10. Miscellaneous Commercially Important Virus Infections11. Viruses with High Impact but Low Commercial Significance12. Markets for Antivirals13. Companies14. References

For more information about this report visit https://www.researchandmarkets.com/r/4zwgxv

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

CONTACT: ResearchAndMarkets.comLaura Wood, Senior Press Managerpress@researchandmarkets.comFor E.S.T Office Hours Call 1-917-300-0470For U.S./CAN Toll Free Call 1-800-526-8630For GMT Office Hours Call +353-1-416-8900

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RELIEF THERAPEUTICS Holding SA (SIX: RLF) announces the proposal of Prof. Jonathan Javitt, M.D., M.P.H., at the upcoming general assembly as Vice…

§ March 11th, 2020 § Filed under Nano Medicine Comments Off on RELIEF THERAPEUTICS Holding SA (SIX: RLF) announces the proposal of Prof. Jonathan Javitt, M.D., M.P.H., at the upcoming general assembly as Vice…

GENEVA--(BUSINESS WIRE)--RELIEF THERAPEUTICS Holding SA (SIX-RLF, "Relief" or the "Company") announces today that Prof. Jonathan C. Javitt, MD, MPH will be proposed for election as Vice-Chairman of its Board of Directors at the Annual General Meeting to be held on June 19, 2020. Prof. Javitt has already joined Relief Therapeutics team as a consultant and his appointment to the Board will allow for the seamless coordination of Reliefs development of RLF-100 (Aviptadil) for the treatment of Acute Respiratory Distress Syndrome (ARDS) in patients infected by the COVID-19 Coronavirus. ARDS is the primary cause of death in those patients who succumb to COVID-19 infection.

RLF-100, acquired by Relief from Mondo Biotech, AG, has an Investigational New Drug (IND) from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to advance in clinical testing and has been awarded orphan drug designation by both agencies for treatment of ARDS, Acute Lung Injury, and Sarcoidosis. Aviptadil is a novel formulation of Vasoactive Intestinal Polypeptide (VIP), a naturally occurring peptide hormone that is known to be concentrated in the lungs after systemic injection. A combination formulation with phentolamine for intracavernous injection has been approved in Europe for treatment of erectile dysfunction, with a 20-year proven record of safety.

Numerous animal studies demonstrate the potential of Aviptadil to reduce lung inflammation in a variety of models and edema. Phase 1b/2 studies in humans, involving a total of 76 patients, have shown that Aviptadil has the potential to reduce bronchospasm under certain circumstances, reduce pulmonary arterial hypertension and treat other features of pulmonary inflammation, including a significant decrease in the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-). Among them, a Phase 2 pilot trial using RLF-100 in 8 patients with ARDS showed very good safety and encouraging signals suggesting potential efficacy.

After carefully reviewing the preclinical and clinical data, we believe that RLF-100 has the potential to be a safe and effective treatment for Acute Respiratory Distress Syndrome in patients infected by COVID-19, who otherwise have less than 50% chance of survival, even with ventilation and other acute care respiratory therapy.

Prof. Javitt has a career-long involvement with the development of lifesaving interventions for public health threats. He served as an advisor in healthcare to four Presidential Administrations (Reagan, Bush 41, Clinton, and Bush 43). He joined the administration of President George W. Bush on the afternoon of September 11, 2001 and was subsequently appointed as a Special Employee of the Office of the Undersecretary of Defense. He was also appointed to serve as Senior Fellow of the National Security Health Policy Center of the Potomac Institute for Policy Studies. President Bush subsequently commissioned Javitt to lead the Presidents Information Technology Advisory Committee healthcare initiative, which resulted in the establishment of the Office of the National Coordinator for Health IT. In 2016, Javitt was granted the Alumnus of Merit Designation by the Harvard Chan School of Public Health for his work.

Humanity is threatened by a deadly virus that has demonstrated a propensity to kill up to 3.5% of those infected and 15% of those age 80 and over. Conventional forms for respiratory support have so far failed to preserve life in the majority of those who develop Acute Respiratory Distress that is seen in a minority of those infected. Commented Raghuram (Ram) Selvaraju, PhD, MBA, Chairman of Relief. We are cautiously optimistic that the effects of RLF-100 in containing lung inflammation seen in Sarcoidosis and Acute Lung Injury may carry over to the acute lung inflammation seen in COVID-19 patients.

Although the vast majority of those infected by COVID-19 survive the disease, those who develop Acute Respiratory Distress Syndrome suffer a mortality rate that is estimated at 30% to 50% with best possible care, said Javitt. It is unclear that sufficient acute care hospital beds exist to support the number of people who might be affected should public health measures fail to contain the epidemic. As such, coronavirus-infected patients who develop ARDS are at particularly high risk. After carefully reviewing the preclinical and clinical data that were submitted to FDA in connection with its review of RLF-100s IND and Orphan Drug Designation, we believe that RLF-100 has potential to be a safe and effective treatment for ARDS in general and, in particular for COVID-19-induced ARDS. Owing to the rapidly expanding size of the epidemic and the extraordinary unmet medical need, we intend to initiate clinical trials on an urgent schedule in order to bring a potentially life-saving therapeutic to market as soon as possible.

Although the current epidemic prompts the need to urgently explore and propose rapid solutions aimed at establishing new lines of efficient and safe treatment against COVID-19 and its comorbidities, the timelines to develop an Experimental Medicinal Product into a medicine for prescription to the general population remain long and cumbersome. The demonstration that Aviptadil fulfils the regulatory criteria to become a commercial drug will necessarily follow the authorities driven clinical development path even if special adaptation thereof may be envisioned. Relief is confident that it will rapidly compile all necessary information to apply for and receive authorization to test in human the efficacy of Aviptadil in alleviating COVID-19-induced ARDS.

About RELIEF THERAPEUTICS Holding SARelief is a company developing drugs via participation in active entities that have obtained intellectual properties through their own research activities or via in-licensing. Development activities of Relief group of companies focus primarily on clinical-stage projects based on molecules of natural origin (peptides and proteins) with a history of clinical testing and use in human patients or a strong scientific rational. Currently, Relief is concentrating its efforts on developing new treatment solutions for indications related to diabetic complications and respiratory diseases.

About RLF-100RLF-100 (Aviptadil) is a patented formulation of Vasoactive Intestinal Polypeptide (VIP). VIP was originally developed in combination with phentolamine and is currently marketed in Europe for the treatment of erectile dysfunction. VIP is known to be highly concentrated in the lung and to inhibit a variety of inflammatory cytokines. Aviptadil was awarded Orphan Drug Designation in 2001 by the US FDA for treatment of Acute Respiratory Distress Syndrome and in 2005 for treatment of Pulmonary Arterial Hypertension. Aviptadil was awarded Orphan Drug Designation by the European Medicines Agency in 2006 for the treatment of Acute Lung Injury and in 2007 for the treatment of Sarcoidosis. Both the US FDA and the EMEA have granted Investigational New Drug licenses for human phase 2 trials of Aviptadil. A clinical study evaluating the efficacy of Aviptadil in patients with pulmonary sarcoidosis is currently being conducted by the university of Freiburg, Germany.

About Acute Respiratory Distress SyndromeAcute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin coloration. Among those who survive, a decreased quality of life is relatively common. Causes may include viral infection, sepsis, pancreatitis, trauma, pneumonia, and aspiration. The underlying mechanism involves diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. The primary treatment involves mechanical ventilation together with treatments directed at the underlying cause. Ventilation strategies include using low volumes and low pressures. If oxygenation remains insufficient, lung recruitment maneuvers and neuromuscular blockers may be used. The syndrome is associated with a death rate between 35 and 50%. Globally, ARDS affects more than 3 million people a year.

RELIEF THERAPEUTICS Holding SA is listed on the SIX Swiss Exchange under the symbol RLF. For further information, please visit the Relief website at http://www.relieftherapeutics.com or contact at contact@relieftherapeutics.com

Disclaimer: This communication expressly or implicitly contains certain forward-looking statements concerning RELIEF THERAPEUTICS Holding SA and its business. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of RELIEF THERAPEUTICS Holding SA to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. RELIEF THERAPEUTICS Holding SA is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise.

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RELIEF THERAPEUTICS Holding SA (SIX: RLF) announces the proposal of Prof. Jonathan Javitt, M.D., M.P.H., at the upcoming general assembly as Vice...

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Should Black America be worried about Coronavirus? – TheGrio

§ March 11th, 2020 § Filed under Nano Medicine Comments Off on Should Black America be worried about Coronavirus? – TheGrio

As the new coronavirus aka COVID-19 makes its way around the planet and the United States with global infections over 100,000 and current death toll upwards 3800, health officials and politicians statewide and worldwide are declaring emergency.

Even though the common flu kills globally up to over 600,000 people annually, the super contagious coronavirus with a relatively longer latency period is somehow outshining that fact, tapping into a global fear that comes with being a new pandemic.

Both in China and Italy, millions are being quarantined, stocks markets are dipping, oil prices are falling, SouthXSouthwest canceled. Cruise ships are being held at bay. And even Senator Ted Cruz is voluntarily quarantining himself after a one-minute contact with someone who tested positive to the virus. With this global backdrop, one must wonder if we are ready for all of this.

READ MORE: Waffle House employee tests positive for Coronavirus

Juliette Keyyem, former department of Homeland security official, in her essay, The U.S. Isnt Ready for the Whats About to Happen for The Atlantic, the sub-headline reads:

Even with robust government response to the novel coronavirus, many people will be in peril. And the United States in anything but prepared.

And on the other hand, a piece in the TheConversion.com offers Ten Reasons you ought not to panic.

Whether all of this proves to be a very sad historical catastrophe or a massive overreaction, this is nevertheless a serious moment and begs the question: are Black people ready and what can we do to maximize preparedness in a world where Black life and health collectively struggles against poverty, muted healthcare access, disproportionate pre-existing issues, and history of medical racism.

Black folks have a particular history with contagion and medical racism, since the days of slavey and colonialism when the white man exposed us to all sorts of new diseases. George Washington wore dentures made from the teeth of African people, and enslaved Black women were used as human guinea pigs in gynecological experiments.

Whats more, the Tuskegee experiment is a reminder of how Black men were once part of a government study, and the victims of a racist conspiracy that left them untreated and ill with Syphilis for years. That history continues to fuel suspicions of the medical profession within the Black community.

Over a century ago, long before the current coronavirus outbreak, there was another pandemic with present-day implications. The 1918 flu epidemic killed 675,000 Americans, and between 50 and 100 million people globally, more than the total number of casualties in World War I.

READ MORE: New York State prisoners to make hand sanitizers to combat coronavirus

One of those who succumbed to the flu that year in the most curious of ironies was the grandfather of Donald Trump. One of the reasons why the flu was so deadly and spread so widely is that in America and Europe, the news media and political leaders hid the truth.

Through censorship and pressure on public health officials to lie, the public was not informed of the dangers. Woodrow Wilson, the racist president of his day who contracted the flu himself, made no public statements about the pandemic, and even enacted a law making it a crime punishable by 20 years in prison to publish information that could hurt the war effort.

Meanwhile, 1918 was the height of segregation and racial violence, when Black people were politically disenfranchised and denied health services, as white supremacy maintained theories about their biological inferiority and compromised their health, safety, education and socioeconomic status. In response to these circumstances, the black community mobilized, created institutions and hospitals and took care of their own sick people.

Theres lots of reasons for distrust around medicine for black people, and the distrust of medicine is not monolithic. There are reasons why certain kinds of people are afraid of medicine, said Dr. Steven Thrasher, assistant professor atthe Northwestern University Medill School of Journalism, Media, Integrated Marketing and Communications told theGrio.

Some are legitimate, some are not. But we have a long history of being tested on against our will, and also at the same time of being disproportionately harmed by diseases and outbreaks, and so I think its important to take this stuff seriously.

Im not aware yet of racial breakdowns of how this is playing out nationally, but certainly in terms of my own research which is primarily about HIV and police violence and gun violence, these things always disproportionately impact us. So Im particularly worried, he added.

READ MORE: LeBron refuses to play if Coronavirus keeps fans barred from arenas

Today, faced with a president who lies to your face about the gravity of the coronavirus crisis, the Black community must be vigilant. There is no telling what Trump will do to exploit the pandemic to further his white supremacist policies, lest you forget the 70,000 migrant children already locked up in ICE detention centers, including Black children from Africa, the Caribbean and Latin America.

Understanding the context of American medical racism should inspire an awareness and diligent plan of action especially when confronting a potentially deadly infectious disease such as COVID-19.

First we must all do our part in minimizing the spread of this virus. According to the World Health Organization, the advice is: we should wash our hands frequently, maintain social distance, avoid touching your face, practice good respiratory hygiene, and if you have fever, cough and hard breathing seek medical attention.

Secondly, separate facts from fiction. Just because Black folks are not the face of the coronavirus, does not mean we have special protection. The low numbers here and in Africa might be more about Black folks conservative practice of traveling outside their country and general segregated domestic travel patterns in the U.S.

In fact, BBC reportsthat Africa has more than 30 cases including countries such as Egypt, Nigeria and South Africa.

The COVID-19 gravely affects seniors and people with pre-existing conditions, such as compromised immune system, hypertension, cardiovascular diseases and diabetes. As Bloomberg news reported, top Coronavirus doctors in Wuhan, China, say high Blood pressure is major death risk. Since hypertension affects African Americans in higher numbers we must pay attention.

Contracting and falling ill to the coronavirus cannot be the way you find out you have diabetes or heart disease. This is why having access to regular medical care to know your pre-existing conditions is a smart way to protect oneself and ones community from the harm and spread of infectious diseases like the coronavirus.

So areas in our community where medical care is especially lacking, like in prisons and the homeless population, we should be intelligently worried. Dr. Thrasher also points out that, homelessness is a huge driver of incarceration, and those are two ways where the coronavirus could affect Black people very badly.

When we think of world changing disasters, we think of big things, like hurricanes, tornadoes, earthquakes or maybe even some gigantic meteorite headed our way. But history has shown us repeatedly that it is the little things, the microscopic elements that we need to really worry about.

Whether it is the black plague, influenza, polio, HIV, infectious diseases are beyond scary, testing humans capacity and social politics for survival. And while natural disasters and pandemics may create some level of surface unity around a common enemy, it also promotes systemic privileges, and exposes the most vulnerable among us, when the stakes are at their highest.

Chances are great that COVID-19 will be contained and that a vaccine will be found and the biggest casualty here will be our fleeting fear of extinction. Chances are also great that this new coronavirus will expose the best and worst of what lurks in the cytoplasm of our humanity.

And whether the source of the pandemic is lab created or natural, medical racism and mistrust are real things, and so we must be prepared, nevertheless for now and for the future. The best way to do that going forward is to advocate for the best preventative care and healthcare system access, before the cough, before the chest pain, before the hospital visit and before the grave.

Opinion articles reflect the thoughts and opinions of the authors and do not necessarily reflect the opinions of theGrio and its staff.

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Closed borders and black weddings: what the 1918 flu teaches us about coronavirus – The Guardian

§ March 11th, 2020 § Filed under Nano Medicine Comments Off on Closed borders and black weddings: what the 1918 flu teaches us about coronavirus – The Guardian

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Will warming spring temperatures slow the coronavirus outbreak? – Antigua Observer

§ March 11th, 2020 § Filed under Nano Medicine Comments Off on Will warming spring temperatures slow the coronavirus outbreak? – Antigua Observer

(Nationalgeographic.com) Whether the coronavirus thats quickly spreading around the world will follow the flu season and subside with springs arrival is unsatisfyingly uncertain, and many scientists say its too soon to know how the dangerous virus will behave in warmer weather.

Dozens of viruses exist in the coronavirus family, but only seven afflict humans. Four are known to cause mild colds in people, while others are more novel, deadly, and thought to be transmitted from animals like bats and camels. Health officials have labeled this new virus SARS-CoV-2 and its disease COVID-19.

The prospect that summer could stave off a pandemic is enticing. Last month, President Donald Trump tweeted about Chinas efforts to contain the virus, saying they would be successful, especially as the weather starts to warm.

Viruses that cause influenza or milder coronavirus colds do tend to subside in warmer months because these types of viruses have what scientists refer to as seasonality, so the presidents comments have some scientific backing. But its highly uncertain that SARS-CoV-2 will behave the same way. Those currently studying the disease say their research is too early to predict how the virus will respond to changing weather. (See how coronavirus compares to flu, Ebola and other outbreaks.)

I hope it will show seasonality, but its hard to know, says Stuart Weston, a postdoctoral fellow at the University of Maryland School of Medicine, where the virus is being actively studied.

As of March 6, more than98,000 coronavirus cases had been confirmedin 88 countries, with experts saying the disease is likely to keep spreading.

At the most basic level, you can think of flu and coronaviruses as a collection of proteins and lipids. They pass from person to person via physical contact, but they can also exist on hard surfaces or in the cough of a sick persons respiratory droplets.

Once outside a human body, external forces will cause the virus to deteriorate. The alcohol in hand sanitizer, for example, breaks down these proteins and lipids, making the virus less stable and less likely to successfully cause an infection. (Once your bodys infected, this is what coronavirus does.)

Research about why some viruses are seasonal has been largely centered around those that cause the flu, a disease long associated with winter months. Flu season generally lasts from October to April or March. Scientists have a number of theories for why that is.

Some suggest its closer quartersto escape the cold weather, people cluster indoors, where human-to-human transmission becomes more likely. To understand why northern latitudes see an uptick in flu cases during winter, researchers have looked at how the virus spreads in different temperature and humidity levels.

And relatively recent research suggests that dry, cold air may also help viruses stay intact in the air or travel farther as they become airborne.

One of the first studies to test how environmental conditions affect viral transmission waspublished in 2007, and it looked at how influenza spread through guinea pigs infected in a lab. High temperatures and in particular high humidity slowed the influenza spread, and at very high humidity levels, the virus stopped spreading completely. Warmer air holds more moisture, which prevents airborne viruses from traveling as far as they would in dry air. In humid conditions, the small liquid droplets in a cough or sneeze gather more moisture as theyre expelled. Eventually too heavy to stay airborne, they drop to the ground.

Studies outside the labshow similar results, though some tropical regions have more cases of flu during rainy season, when people also cluster indoors.

Scientists hypothesize that low humidity, which often occurs in winter, might impair the function of the mucus in your nose, which your body uses to trap and expel foreign bodies like viruses or bacteria. Cold, dry air can make that normally gooey mucus drier and less efficient at trapping a virus.

Ian Lipkin, director of the Columbia Universitys Center for Infection and Immunity, has been studying the novel coronavirus. He says sunlight, which is less abundant in winter, can also help break down viruses that have been transmitted to surfaces.

UV light breaks down nucleic acid. It almost sterilizes [surfaces]. If youre outside, its generally cleaner than inside simply because of that UV light, he says.

UV light is so effective at killing bacteria and viruses its often used in hospitals to sterilize equipment.

Though the coronavirus and the flu are both respiratory infections, not enough is known about SARS-CoV-2 to predict if it will have the same seasonal patterns.

To better understand this outbreak, scientists are looking at comparable outbreaks like SARS and MERS. SARS, which started its spread in late 2002, shares almost 90 percent of its DNA with the current virus. The SARS outbreak started in November and lasted until July, which only hints at seasonality, says Weston, and containment may have resulted from early intervention. In other words, did it disappear with warmer weather, or did treatment and prevention efforts simply work?

MERS began in September 2012 in Saudi Arabia, where temperatures are generally high. Unlike SARS, it was never fully contained, and new cases are occasionally reported. The novel coronavirus has also begun to circulate locally in the Middle East, namely in Iran and the United Arab Emirates.

We dont see too much evidence of seasonality in MERS, says Weston.

But whether SARS and MERS were truly seasonal or if this virus will imitate SARS is unclear. Weston says their lab is focused on developing treatments and vaccines for the virus, which he cautions wont likely be available for a least a year, if not several.

Harvard epidemiologist Marc Lipsitch doesnt think any weather changes will put a big dent in how the virus spreads. COVID-19 has now been documented around the world. If the virus is anything like a typical flu virus, it may worsen in Southern Hemisphere regions as the seasons change.

David Heymann from the London School of Hygiene and Tropical Medicine says not enough is known about this new virus to predict how it will change with different weather conditions.

The risk of making predictions without an evidence base is that they could, if they prove to be wrong, be taken as verity and give a false security, Heymann says via email.

The emphasis today should continue to be on containment to elimination where possible, he cautions.

According to the Centers for Disease Control (CDC), people are most contagious when theyre showing symptoms. However, some experts suspect official counts may underestimate the number of infected people, sayingnot everyone infected will develop a severe illness.

Were only seeing the most severe cases, says Weston. There may be some infection going on that isnt being detected.

Many experts are saying SARS-CoV-2will likely become endemic, joining the other existing four coronaviruses that cause mild colds, or becoming a seasonal health hazard like the flu.

To prevent contracting an illness from any virus, the World Health Organization recommends frequently washing your hands, avoiding close contact with those showing symptoms like coughing or sneezing, and seeking treatment if sick.

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Scientists developed the worlds most sophisticated lab model of the human body – Tech Explorist

§ March 11th, 2020 § Filed under Nano Medicine Comments Off on Scientists developed the worlds most sophisticated lab model of the human body – Tech Explorist

Current practices in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity. These occurrences are mostly the result of erroneous data generated by in vivo and in vitro preclinical models that do not accurately recapitulate human physiology.

To speed up new drugs to market and reduce animal testing, scientists from the Wake Forest Institute for Regenerative Medicine (WFIRM) have come up with a mindblowing solution. They have developed the worlds most sophisticated laboratory model of the human body, a system of miniaturized organs that can be used to detect harmful and adverse effects of drugs before they are prescribed to patients.

Scientists developed this system from many human cell types that are combined into human tissues representing a majority of the organs in the human body, such as the heart, liver, and lungs. Each of these miniature organs is tiny 3D tissue-like structures about one-millionth the size of an adult human organ.

Anthony Atala, MD, of the Wake Forest Institute for Regenerative Medicine and the studys senior author said,The most important capability of the human organ tissue system is the ability to determine whether or not a drug is toxic to humans very early in development and its potential use in personalized medicine. Weeding out problematic drugs early in the development or therapy process can save billions of dollars and potentially save lives.

During the experiment, this new model shows the potential of quantifying toxicity measure toxicity in many drugs approved for human use. Although toxicity from the recalled drugs was not found initially using standard 2D cell culture systems and animal testing models, and adverse effects were not detected throughout three levels of human clinical trials, this new system can readily detect toxicity, replicating the damage seen in humans.

To create the model, scientists isolated tiny samples of human tissue cells and engineered them into miniature versions of the human organ. These tissue cells can contain blood vessel cells, immune system cells, and even fibroblasts.

Each of these organs, also known as organ tissue equivalents, performs the same functions that they do in the human body. For example, the heart beats about 60 times each minute, the lung breaths the air from the surrounding environment, and the liver breaks down toxic compounds into harmless waste products.

Co-author Aleks Skardal, Ph.D., formerly of WFIRM and now at Ohio State University, said,We knew very early on that we needed to include all of the major cell types that were present in the original organ. To model the bodys different responses to toxic compounds, we needed to include all of the cell types that produce these responses.

Another exciting thing about the model that each system contains media, a substance containing nutrients and oxygen that is circulated among all the organ types, delivering oxygen, and removing waste. The small blood system n these devices use a technology called microfluidics to recirculate test compounds through the organ system and remove the drug breakdown products that each organ is producing.

Co-author Thomas Shupe, Ph.D., of WFIRM, said,Creating little human organs for drug testing was a logical extension of the work we have accomplished in building human-scale organs. Many of the same technologies we have developed at the human-scale level, like including a very natural environment for the cells to live in, also produced excellent results when brought down to the microscopic level.

Additional co-authors include Julio Aleman, Steven Forsythe, Shiny Rajan, Sean Murphy, Mahesh Devarasetty, Nima Pourhabibi Zarandi, Goodwell Nzou, Robert Wicks, Hooman Sadri-Ardekani, Colin Bishop, Shay Soker, and Adam Hall.

Authors Skardal, Shupe, Soker, Murphy, Bishop, and Atala are inventors on patent rights related to this work owned by Wake Forest University Health Sciences. The patents, whose value may be affected by publication, have the potential to generate royalty income in which the inventors would share.

The study is published in the journal Biofabrication.

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Scientists Create Human ‘Body-On-A-Chip’ Featuring Tiny Replica Organs In The Lab – IFLScience

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Scientists Create Human ‘Body-On-A-Chip’ Featuring Tiny Replica Organs In The Lab – IFLScience

Researchers have created what they say is the world's most sophisticated lab model of the human body: a system of mini-organs made fromreal human cells and stem cells.

While it may sound like attempts to make a miniature Frankensteins monster in a petri dish, the researchers are actually hoping to create an entire lab model of miniaturized human organs that could become invaluable for drug testing and biomedical research.

Reporting in the journal Biofabrication, scientists from Wake Forest Institute for Regenerative Medicine (WFIRM) in North Carolina created a human organ tissue system that features a miniature heart-like organ that beats about 60 times a minute, a lung that breathes the air from the surrounding environment, and a liver that breaks down toxic compounds, as well as testicles and a colon.

Although just one-millionth the size of a full-sized adult human organ, these body-on-a-chip" systems are remarkably detailed, complete with their own blood vessel cells, immune system cells, and connective tissue cells. It also contains a microfluidic circuit thats able to circulate a drug throughout the system between organs, just like how a cardiovascular system pumps molecules through the human body in the blood.

Creating microscopic human organs for drug testing was a logical extension of the work we have accomplished in building human-scale organs, said study co-author Thomas Shupe of WFIRM in astatement. Many of the same technologies we have developed at the human-scale level, like including a very natural environment for the cells to live in, also produced excellent results when brought down to the microscopic level.

Don't worry, this isn't scientists creating a tiny "artificial human" the system is barely more thana load of blobs in a petri dish, not a conscious organism.

Organoids are invaluable tools for scientists looking to understand the human body. In one of the most incredible breakthroughs, researchers recently observed brain organoids that began to show signs of brain waves similar to those of preterm infants. Its hoped this kind of research could be used to understand how brain cells develop into the intensely complex organ currently sitting in your head.

They are also extremely useful for testing new pharmaceutical drugs because they react, in theory, just as a real human organ would. Plus, they are safe and relatively low-cost. The newly developed miniature organ model has already been used for a number of tests to assessthetoxicity of some drugs. In some instances, the organ model managed to show adrug might be dangerous or have some undesired effect, thereby potentially preventing harm to humans.

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Progress and Challenges in TB Control Programme – The Daily Star

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Progress and Challenges in TB Control Programme – The Daily Star

CHIEF GUEST:

Prof Dr Md Shamiul Islam, Director, MBDC and Line Director TB-Lep and ASP, Directorate General of Health Services

MODERATOR:

Shamim Ahmed, Doctoral Researcher, University of Toronto

WELCOME SPEECH:

Dr Mahfuza Rifat, Associate Director, TB Control Programme, BRAC

Discussants:

Dr Iqbal Arslan, Professor, Biochemistry and Molecular Biology and Former Dean, BSMMU

M A Faiz, Professor-Medicine, Sir Salimullah Medical College and Former Director, DGHS

Dr Md Akramul Islam, Director-Communicable Diseases and WASH, BRAC

Dr Nazis Arefin Saki, Medical Officer, National Tuberculosis Control Program (NTP), DGHS

Shishir Moral, Journalist, Prothom Alo

Syed Abul Maksud, Writer and Social Activist

Dr Rupali Sisir Banu, National Programme Coordinator, NTP, DGHS

Jewel Aich, Magician

Dr Shakil Ahmed, Professor of Paediatrics, Shaheed Suhrawardy Medical College

Tropa Majumdar, Director, Expressions Ltd

Syed Ishtiaque Reza, Editor in Chief, GTV

Monjurul Ahsan Bulbul, Editor in Chief, TV Today

Dr Ejajul Islam, Head, Department of Nuclear Medicine, Dhaka Medical College

Maya Vandenent, Chief of Health Section, UNICEF Bangladesh

Xeres Sidhwa, Director-Health, USAID

Dr Ahmadul Hasan Khan, Monitoring & Evaluation Expert, National TB Control Programme

Chayanika Chowdhury, Writer and Director (Film and Drama)

Sumaiya Shimu, Actress and Founder & Chairman, Better Future Communication

Dr Asif Mujtaba Mahmud, Consultant, Respiratory Medicine, Asgar Ali Hospital

Dr M A Hamid Salim, Global Fund/MDR-TB Advisor, National Tuberculosis Control Programme (NTP) Bangladesh

Munmun Ahmed, Dance Artist and Actress

Dr Mya Sapal Ngun, Medical Officer-Communicable Diseases Surveillance, World Health Organization, Bangladesh

Dr Sabera Sultana, National Professional Officer-Neglected Tropical Diseases and Hepatitis, World Health Organization, Bangladesh

Prof Dr Md Shahedur Rahman Khan, Director, NIDCH

Dr Mahfuza Rifat, Associate Director, TB Control Programme, BRAC

Tuberculosis (TB) is a global public health issue, with Bangladesh being among the 30 high burden TB countries. TB is not only a clinical concern but also a disease affected by social determinants. National Tuberculosis Control Program (NTP) is working with partners to combat TB. The case detection of TB increased from 40 to more than 70 percent in the last two to three decades, and this change was made by collaborative actions at all levels by engaging different sectors. NGOs such as BRAC, Damien Foundation, came forward to support scaling up of services through community-based approach. We need to work more to reach the last miles of TB control by sustaining the momentum and through engaging different sectors in TB.

Dr Nazis Arefin Saki, Medical Officer, National Tuberculosis Control Program (NTP), DGHS

According to the Global Tuberculosis Report 2019, 47,000 people die of TB in Bangladesh every year. The estimated incidence rate is 221 per 100,000 people. NTP aims to reduce the number of TB deaths in Bangladesh by 35 percent by 2020 (from 72,450 in 2015 to 47,092 in 2020). Bangladesh has already met the 2020 TB mortality target, but the incidence rate is not declining much. Case identification, however, is increasing significantly.

Our recent survey shows that the prevalence of all forms of TB is 260 per 100,000 people. In 2019, we identified 82 percent (292,000) of TB cases, with around 86,000 missing. In 2003, we achieved the global target for treatment success rate and have sustained it until now.

Specialised child TB centres have been established, capacity building is ongoing, and new child-friendly dispersible drugs with fruity flavour have been introduced. The expected trend is that 10 percent of total diagnosed TB cases will be of child TB but in 2019, we only identified 4.22 percent.

In 2017, the GeneXpert services were expanded, resulting in a 40 percent increase in case detection in the past two years. Hence, more drug-resistant TB cases have been diagnosed. Currently, there are two different types of treatments for drug-resistant TB: the shorter regimen of nine months, globally known as the Bangladesh regimen, and the longer regimen. Bangladesh has been maintaining an 80 percent treatment success rate for MDR TB.

Two new drugs, bedaquiline and delamanid, introduced for MDR TB and extensively drug-resistant tuberculosis (XDR TB) management in 2016, have caused treatment success rates to go up from 25 to 81 percent. Challenge remains in human resources and funding.

Shishir Moral, Journalist, Prothom Alo

Private practitioners are not reporting to NTP properly. Many people obtain treatment from outside the formal sector that needs consideration. An estimation of the number of treated patients in the private sector is necessary to understand the scenario.

Syed Abul Maksud, Writer and Social Activist

Extra-pulmonary TB cases such as gland and bone TB are rampant in our country, which requires social awareness.

Since TB is not a reason for mass fear anymore, it is not being talked about much in recent times. District-level hospitals should have separate TB cells. Moreover, contextual research is required, with focus on our socio-economic status relating to TB.

Dr Rupali Sisir Banu, National Programme Coordinator, NTP, DGHS

Diagnosing child TB is difficult since children cannot provide cough for tests and this causes complications in the sputum test of GeneXpert machines. Intensive care management, including gastric lavage, is required at district and upazila levels. Keeping this in mind, NTP has opened five specialised child TB centres in Dhaka Shishu Hospital, Dhaka Medical College Hospital, Institute of Child and Mother Health (ICMH), etc.

The mandatory notification gazette from the Government in 2014 should be used by the private sector to report TB cases.

Jewel Aich, Magician

Child TB could be an area to work on along with other childhood diseases. Also, breaking myths encircling TB is very important. There was a myth about playing the flute, that led to people becoming infected with TB. Coincidentally, the boy I used to learn to play the flute with during my childhood actually was infected with TB. However, I now I believe that his disease was due to his dire living conditions and poor nutrition and not for playing the flute.

Dr Shakil Ahmed, Professor of Paediatrics, Shaheed Suhrawardy Medical College

Nearly 37 to 40 percent of all missing TB cases are childhood TB, which should be addressed more vigorously. The general people should be aware that TB is a disease that affects both adults and children. Children in households living with adult TB patients are also prone to contracting TB and need to be checked. Other family members can prevent being infected by taking a six-month oral medication course, even if they do not display any symptoms.

Tropa Majumdar, Director, Expressions Ltd

We have lost urgency when it comes to the spirit of "It's Time to End TB". Enhancing communication to revive it is necessary. The mass listens when celebrities speak up, but further initiatives are required such as designing communication campaigns and engaging those we wish to address and cure.

Syed Ishtiaque Reza, Editor in Chief, GTV

The health sector creates many simplified TVCs on TB awareness, but other private channels are not interested in running these TVCs. Television owners should be included in future stakeholders' meetings.

Identifying how much investment is going into TB control is important, to make the return on these investments clearer for those involved in journalism.

Monjurul Ahsan Bulbul, Editor in Chief, TV Today

Breaking the culture of secrecy and stigma is very important for increased TB detection. Media engagement can play an important role in message development.

The quality of campaign in social media must be enhanced and the presentation style could be revisited. Effective communication strategy is important in this regard.

Ethical involvement of civil society organisations is also crucial.

Dr Ejajul Islam, Head, Department of Nuclear Medicine, Dhaka Medical College

Advertisers need to be careful about how they present information regarding TB and remind people that they need to be responsible and complete the full course of medication to recover from TB.

Out of 10 pharmacies, only five have qualified pharmacists. Pharmacists need to refer symptomatic patients to Government/NGO designated TB centres. The majority of patients go to pharmacists in unions instead of visiting qualified doctors. The fact that these pharmacists are now treating billions of patients should be under the consideration of NTP.

Maya Vandenent, Chief-Health Section, UNICEF Bangladesh

Bangladesh has a very successful but expensive primary healthcare system. Community clinics, Family Welfare Assistants (FWAs), and Health Assistants (HAs) all reach out to the households approximately every three months. Certain algorithms can be integrated into their protocols to ensure everybody is tested for TB in households with TB cases.

Commodity strengthening and ensuring that the drugs are where they need to be is important. I think it is very well organised in the TB supply chain. Moreover, if we want to ensure child referrals, it is important to ensure that all paediatricians are aware of the issue and are sensitised.

Xerses Sidhwa, Office Director, OPHNE, USAID

We have a very strong public health system in Bangladesh but we need to ensure that we are continuously strengthening it, especially the laboratory and diagnostic space. Ensuring both access and utilisation of those services is important. In addition, we need to make sure to aware the people while we expand services at the community level. In Bangladesh, one of the largest mortalities for children is pneumonia. There might be some cases of child TB and we need to think how we can improve the systems involved.

Starting conversations among communities where people talk and share their stories about TB can play a significant role. In addition, creating a multi-sectoral approach between other ministries can help. For instance, adding examples of TB diagnosis, fighting stigma can be included in national textbooks.

Dr Ahmadul Hasan Khan, Monitoring & Evaluation Expert, National TB Control Programme

If we want to attain the SDGs by 2030, there is no alternative to proper case detection and patient identification. To increase the identification of new patients, we should ensure diagnostic facilities as well as door-to-door access. To achieve this, we are currently designing our action plans keeping the GeneXpert machine in consideration.

Chayanika Chowdhury, Writer and Director (Film and Drama)

A few years back, we had a young female house help who was diagnosed with TB and Hepatitis-B. My family and I ensured that she receive full treatment and after a year, she finally recovered. My message, therefore, is that we should not neglect people if they have TB as they have hope for survival if proper treatment is given. Also, we should be aware that anyone, regardless of his/her social status, can have TB.

Sumaiya Shimu, Actress and Founder & Chairman, Better Future Communication

Disseminate proper information to those who need it the most to achieve the effectiveness of TB control. I agree that media personalities can have a profound effect on mass people by raising awareness because people tend to remember it more.

Prominent social media influencers can also raise awareness on the issue in a comparatively short time span and expense. For example, countries in Africa raise awareness by bringing in influential people or celebrities from different arenas to raise awareness on TB. Celebrities can also join fundraising initiatives for TB.

Dr Asif Mujtaba Mahmud, Consultant, Respiratory Medicine, Asgar Ali Hospital

Patients should be diagnosed early, to break the chain of TB transmission. If we ensure the proper utilisation of and access to GeneXpert machines, we can diagnose a patient early, in case of both TB and drug-resistant TB.

Secondly, we should have a social movement. For example, we can ask celebrities to disseminate simple information such as not spitting anywhere and everywhere. Thirdly, compliance with treatment has to be ensured; patients must complete their full course of medication. Otherwise, there is a chance of developing multi-drug/extensive drug resistant TB.

Finally, latent TB infection (LTBI) cases need to be addressed. NTP's initiatives regarding controlling LTBI need to be widespread.

Dr M A Hamid Salim, Global Fund/MDR-TB Advisor, National Tuberculosis Control Programme (NTP) Bangladesh

292,000 TB cases have been detected in 2019. To detect this number of TB cases, we need to conduct a large number of Presumptive TB tests. We are being able to test only four to five lakh cases with GeneXpert machines. Microscopic machines cannot accurately detect TB, leaving many undetected patients, which is a major problem.

Currently, we have around 228 functional GeneXpert machines and we expect this number to increase to around 400 by the end of this year.

Munmun Ahmed, Dance Artist and Actress

Celebrities are committed to be engaged for social causes.

Sometimes, even after consulting doctors, ailments are not properly diagnosed. My own daughter faced such circumstances both at home and abroad.

Dr Mya Sapal Ngon, Medical Officer-Communicable Diseases Surveillance, World Health Organization Bangladesh

W recently worked with NTP to scale up preventive TB treatment. We are also planning to work on a multi-accountable framework in collaboration with NTP. We also hope that under the framework we can bring in all the partners and identify the responsibilities and functions and thus work together to accelerate the national response and quality services.

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Progress and Challenges in TB Control Programme - The Daily Star

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10 Drugs Expected to Enter the Market This Year Could be Blockbusters, Analysis Says – BioSpace

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on 10 Drugs Expected to Enter the Market This Year Could be Blockbusters, Analysis Says – BioSpace

Over the next six years, 10 drugs that are in the pre-registration phase and expected to launch this year are projected to reach blockbuster status.

GlobalData, a leading data and analytics company, pegged the 10 drugs to hit sales of $1 billion and more per year. The bulk of the treatments that are coming to market are in oncology and disorders of the central nervous system. While most of the medications are considered innovator drugs, that is the first drugs of its kind with a specific active ingredient, at least one is a biosimilar.

The drug expected to have the biggest sales number is Amgen and Allergans biosimilar candidate to Roches Rituxan (rituximab). According to GlobalData, the biosimilar, ABP 798, is projected to generate $4 billion in revenue by 2025. Roches Rituxan, which is sold under the brand name MabThera in Europe, has been approved to treat non-Hodgkins Lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) & microscopic polyangiitis (MPA), and pemphigus vulgaris (PV). It brought in more than $9 billion in 2018. In December 2019, Allergan and Amgen submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration for its biosimilar. Clinical trials confirmed no clinically meaningful differences between ABP 798 and Rituxan, the companies said when they submitted the BLA.

Valentina Gburcik, senior director of Cardiovascular and Metabolic Diseases and Gender Health and Digital at GlobalData said the competitive pricing of the biosimilar drug will help its wider use, and the drug will steal a significant proportion of patient share from the mega-blockbuster Rituxan.

ABP 798 is projected to generate the most revenue out of these 10 drugs. The remaining blockbusters GlobalData predict will become blockbusters are projected to bring in between $1 billion and $2 billion over the next six years.

Bristol Myers Squibbs ozanimod is expected to generate about $2 billion. Ozanimod has been submitted to the U.S. Food and Drug Administration as a potential treatment of people with relapsing forms of multiple sclerosis. The regulatory agency is expected to make a decision on the medication later this month.

Roches risdiplam is set to become the third approved treatment for spinal muscular atrophy. The FDA is expected to make a decision on the drug in May. If the drug is approved, Roche has already stated it will attempt to undercut the price of the other two SMA drugs on the market, Spinraza and Zolgensma, in order to gain traction with patients. GlobalData has pegged annual sales of risdiplam at about $1.5 billion.

BioMarins Valoctocogene roxaparvovec (valrox) is a gene therapy treatment for Hemophilia A. The FDA accepted the companys BLA for valrox in February for priority review. The FDA is expected to make a decision by Aug. 21. If its approved, valrox will be the first gene therapy approved for any type of hemophilia. GlobalData has pegged annual sales of valrox, a potential one-and-done treatment, at about $1.25 billion.

Immunomedics lead product is sacituzumab govitecan for metastatic triple-negative breast cancer. The FDA accepted the companys filing in December and will rule on the medication later in June. GlobalData predicts annual sales of the drug to be about $1 billion if it is approved.

Biohavens Zydist for migraine could generate $1 billion, GlobalData said. Zydist is an orally dissolving tablet for the treatment of acute migraine.

In December, Gilead Sciences submitted an NDA for filgotinib, a potential treatment for rheumatoid arthritis. The drug was submitted under priority review. If approved, GlobalData suggests the medication will bring in about $1 billion annually.

In January, Michigan-based Esperion won approval for its once-daily non-statin LDL-cholesterol lowering drug Nexletol (bempedoic acid). The approval marked the first oral, once-daily, non-statin LDL-C lowering medicine given the green light by the regulatory agency since 2002 for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. GlobalData pegs the drug at $1 billion in annual revenue.

Zogenix could see FDA approval for Fintepla in June. The FDA recently extended the PDUFA date by three months to June 25. Fintepla is being assessed as a treatment for seizures associated with Dravet syndrome. If approved, it could generate $1 billion in annual sales, GlobalData said.

At number 10 on the list, Bristol Myers Squibbs lisocabtagene maraleucel (liso-cel) is a CAR-T cell therapy for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma. If approved, the treatment is expected to bring in about $1 billion annually, according to the analysts.

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Aspiration of spheroids used to 3D print artificial tissues – The Engineer

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Aspiration of spheroids used to 3D print artificial tissues – The Engineer

Aspiration of spheroids, cells and tissue strands is being used to precisely place these biologics in 3D patterns on scaffolding or without to create artificial tissues with natural properties.

According to Penn State Universitys Ibrahim T. Ozbolat, tissue spheroids have been increasingly used as building blocks for fabrication of tissues, but their precise bioprinting has been a major limitation.

In addition, these spheroids have been primarily bioprinted in a scaffold-free manner and could not be applied for fabrication with a scaffold, said Ozbolat, Penn States Hartz Family Career Development Associate Professor of Engineering Science and Mechanics.

Bioprinting breakthrough could lead to artificial tissues on demand

Bioprinting technique gives additive advantage to tissue engineering

Scaffolding is necessary for applications in regenerative medicine and tissue engineering, and in fabrication of microphysiological systems for disease modelling or drug screening.

Ozbolat and his team used aspiration-assisted bioprinting along with conventional micro-valve printing to create homogeneous tissues and tissues containing a variety of cells.

As demonstrated in the video below, aspiration-assisted bioprinting uses suction to move tiny microscopic spheroids. Aspiration-assisted bioprinting picks up the tissue spheroid, holds the suction on the spheroid until it is placed in exactly the proper location and then releases it. The researchers report their findings inScience Advances.

Of course, we have to gently aspirate the spheroids according to their viscoelastic properties, so no damage occurs in transferring the spheroids to the gel substrate, Ozbolat said in a statement. The spheroids need to be structurally intact and biologically viable.

By controlling the exact placement and type of spheroid, the researchers have been able to create samples of heterocellular tissues, those containing different types of cells.

We demonstrated for the first time that by controlling the location and distance between spheroids we can mediate collective capillary sprouting, said Ozbolat.

The researchers created a matrix of spheroids with capillary growth in the desired directions. Capillaries, which are necessary for the creation of tissues that can grow and survive, deliver oxygen and nutrients to the cells. Without capillaries, only the outermost cells will receive oxygen and nutrients.

Precise placement of spheroids also allows creation of heterocellular tissues like bone. Penn State add that by beginning with human mesenchymal stem cells, the cells differentiated and self-assembled bone tissue.

The ability to produce artificial living tissues has applications beyond regenerative medicine, such as in drug testing or the screening of chemical products where specific tissues could be produced for the purpose.

The researchers suggest that this method can be cost-effective because the equipment required costs under $1,000 and is easy to use. They report that the system can be useful in a wide variety of applications, including but not limited to organ-on-a-chip devices, drug testing devices, microfluidic, in vitro human disease models, organoid engineering, biofabrication and tissue engineering, biocomputing and biophysics.

The team note that the system needs improvement to print spheroids in high-throughput to create larger tissues in a shorter time.

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Choose the right colon cancer screening test – Opinion – Rockford Register Star

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Choose the right colon cancer screening test – Opinion – Rockford Register Star

March is Colorectal Cancer Awareness Month. Approximately 140,000 people in the United States will be diagnosed with colon cancer this year. The lifetime risk of developing colon cancer is 1 in 20 and only lung cancer claims more lives each year.

As gastroenterologists, we spend a significant amount of our time and effort working to prevent, diagnose, and treat colon cancer. Because of improved compliance with colon cancer screening, the number of new colon cancer diagnoses and deaths have both decreased by more than 30% over the last 20 years. It is truly one of the success stories in modern medicine.

At the center of this dramatic decline in mortality is colonoscopy. Colonoscopy is the gold standard for both the prevention and diagnosis of colon cancer. The procedure is not only safe and highly accurate, but unlike any other screening test, it allows for the identification and removal of polyps, which are the precursors of colon cancer. Removal of polyps is the main reason that the number of colon cancer diagnoses and deaths are decreasing.

In the last few years, a new test has emerged for colon cancer screening. Stool DNA testing has been combined with testing for microscopic amounts of blood in the stool. This test has been marketed by Exact Sciences as Cologuard and more than 1 million people have utilized this type of screening.

Unfortunately, there are significant limitations to stool DNA tests. In our experience at Rockford Gastroenterology Associates, many patients who have completed stool DNA testing are unaware of these limitations. Many gastroenterologists are concerned that increased use of this test will reverse some of the gains we have made against this deadly disease.

As an informed patient, there are important facts that you need to consider in order to make an educated decision regarding which colon cancer screening test is right for you.

First, stool DNA testing has limited sensitivity for the identification of colon polyps. For advanced polyps 10 millimeters or larger, the sensitivity is less than 50%. That means if you have an advanced polyp with a high risk of progression to colon cancer, this test will detect it less than half the time. For patients who have already developed colon cancer, the test will miss 8% of cases. These numbers are unacceptable given the high accuracy of screening colonoscopy.

Second, stool DNA testing has a significant false positive rate. The initial studies suggested that stool DNA testing has a false positive rate of 14% (normal colonoscopy after abnormal stool DNA test). In our clinical experience, that number has been higher. When combined with the miss rate, stool DNA testing has rather poor accuracy.

Finally, it is important to understand how most medical insurance companies, including Medicare, handle payment for colon cancer screening. The first colon cancer screening test is generally covered, and this includes both colonoscopy and stool DNA testing. However, if you have a positive stool DNA test and then receive a follow-up colonoscopy, you may be responsible for a greater portion of the cost than if you utilized colonoscopy as the first test.

Based on these limitations, the United States Multi-Society Task Force consensus guidelines from 2017 list Cologuard as a Tier 2 test (colonoscopy is Tier 1). The American College of Physicians guidelines from 2019 do not list Cologuard amongst the recommended colon cancer screening tests. Another study from 2019 concluded that it was less effective and more costly than other colon cancer screening tests covered by Medicare.

Armed with this information, you can have meaningful discussions with your primary care provider and choose the colon cancer screening test that is right for you.

Dr. Aaron Shiels is a gastroenterologist and managing partner at Rockford Gastroenterology Associates.

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Curadigm announces the selection of its Nanoprimer technology by the National Cancer Institute for a characterization & development collaboration…

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Curadigm announces the selection of its Nanoprimer technology by the National Cancer Institute for a characterization & development collaboration…

Curadigm, an early-stage nanotechnology company committed to improving treatment outcomes by redefining the therapeutic balance between bioavailability, toxicity, and efficacy, announced the selection of its Nanoprimer technology by the National Cancer Institutes (NCI) Nanotechnology Characterization Laboratory (NCL) for characterization, based on its potential to significantly impact treatments in multiple disease indications, including cancer.

The broad utility of the Nanoprimer technology is due to its unique nanomedicine approach to improve therapeutic action without modifying the therapeutic in any way. Rather, the Nanoprimer is administered intravenously just prior to a therapeutic, specifically and transiently occupying the liver pathways responsible for clearance. This temporarily increases the therapeutics bioavailability and subsequent accumulation in target tissue. This mechanism, targeting the universal upstream pathways involved in intravenous drug clearance, means the Nanoprimer can be used in combination with multiple classes of nanomedicines including nucleic acid and small molecule therapeutics or gene editing technologies.

Through this collaboration, the NCL, a leader in the characterization and development of Nanomedicines, will perform in-depth pre-clinical characterizations. These studies will support the Nanoprimers development, driving advancement toward filing an Investigational New Drug (IND) with the Food and Drug Administration (FDA) and future clinical development. This work will also support ongoing and future collaborations combining the Nanoprimer with therapeutics across diverse clinical indications.

Curadigm is a 2019 Nanobiotix spin-off, that aims to reshape and elevate the efficacy of intravenously administered therapeutics. The Nanoprimer technology is based on engineered, biocompatible nanoparticles that are administered just prior to the therapeutic and acts rapidly to temporarily occupy the Kupffer and liver sinusoidal endothelial (LSEC) cells. This precision-based approach leads to enhanced systemic bioavailability for increased therapeutic action.

The NCL was established to study the use of nanoparticles and nanomedicines to advance cancer research and to accelerate the development of promising and safe nanotechnology-based cancer therapeutics. The program provides pre-clinical testing and services on a competitive acceptance basis to companies, such as Curadigm, and is working in concert with other US agencies such as the FDA to accelerate the use of nanomedicines from early-stage development to clinical applications.

The selection of our nanoprimer by the NCL is a major step for Curadigm, said Matthieu Germain, CEO of Curadigm. The standardized cascade assay developed by the NCL is a great opportunity to accelerate the development of the Nanoprimer by providing additional data about its physico-chemical properties, safety and mechanism of action that will facilitate regulatory review. The results generated through this collaboration will also be instrumental in supporting our discussions with partners to develop their therapeutics with the Nanoprimer.

About Curadigm

Curadigm, a Nanobiotix Corp spin-off, is an early-stage nanotechnology company dedicated to improving outcomes for patients by shifting the therapeutic delivery paradigm. Curadigms Nanoprimer technology increases drug bioavailability while decreasing unintended off-target effects, specifically liver & spleen toxicities. The platform can be used with most intravenous (IV) therapeutics across multiple drug classes. Curadigm is dedicated to advancing therapeutic development based on our deep understanding of how drugs interact with the body, to impact both known and novel drugs across multiple clinical indications.

For more information about Curadigm visit http://www.curadigm.com

View source version on businesswire.com: https://www.businesswire.com/news/home/20200309005732/en/

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Coronavirus: truth and myth on personal risk perception – The European Sting

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Coronavirus: truth and myth on personal risk perception – The European Sting

(CDC, Unsplash)

This article was exclusively written forThe European Sting by Ms. Paula Pacheco Rocha, a student of the sixth period of Medicine of the Pontifical Catholic University of Campinas- PUC Campinas. She is affiliated to the International Federation of Medical Students Associations (IFMSA), cordial partner of The Sting. The opinions expressed in this piece belong strictly to the writer and do not necessarily reflect IFMSAs view on the topic, nor The European Stings one.

The epidemic is already predicted as a possibility and aggressive measures are being taken by governments worldwide. Recent history on this kind of virus (Severe acute respiratory syndrome coronavirus (SARS-Cov) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012) suggest low risk of catastrophe.

Governments and control organs should face the potential risk of epidemics so that they not spread undesirably. Nevertheless, rationally, there is a huge difference on individual perception risk compared to populational perception risk.

It is a cognitive misunderstanding to say individual risk of lethality is high for the Coronavirus. Epidemiology analysis is important to face some facts and let the fake news panic aside. First of all, the new Coronavirus has a lethality around 2%, while 2002 SARS had around 10% lethality.

Speaking of epidemiology still, the risk for dissemination is different from risk of lethality and most times they go opposite ways: smaller pathogenicity of a virus increases the chances of dissemination, as people do not skip work or stay at home due to light symptoms. That is why the risk of dissemination of Coronavirus is high and there are measures to try to isolate people with mild symptomatology. The measures took upon isolating people look, intuitively, for the layman on the subject, as directed to a very lethal disease- which is not the case. Community-acquired pneumonia can reach 13% lethality among hospitalized patients and we have not seen any panic around that.

It is indeed necessary that there is professional and governmental worry around coronavirus, but, for the common individual, the panic is unjustifiable. On the matter of individual worries, people around the world have much more important problems to worry about, like the situation of their own country public health. Emerging infectious diseases occur and have been occurring for thousands of years, but, nowadays, the speed on which they spread is the biggest worry, turning a red light on diseases being globalized already, but not the public health coverage.

A Globalizao da doena. Rev. Sade Pblica, So Paulo , v. 37, n. 3, p. 273-274, June 2003 . Available from <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0034-89102003000300001&lng=en&nrm=iso>. access on 31 Jan. 2020. http://dx.doi.org/10.1590/S0034-89102003000300001.

PERALTA, Rogelio MD et al. Community-acquired Pneumonia: A Potentially Lethal Emergency?. Clinical Pulmonary Medicine, [S. l.], v. 20, n. 4, p. 166-171, 1 jul. 2013.

About the author

Paula Pacheco Rocha is a student of the sixth period of Medicine of the Pontifical Catholic University of Campinas- PUC Campinas. Class monitor of Microbiology, assisting the Professor Dr. Maria Magali Stelato. Member of IFMSA Brazil- PUC Campinas as LEO-in (Local Exchange Officer for incoming students) and LORA-D (Director of the Standing Committee of Sexual and Reproductive Health including HIV and AIDS). She believes immensely in Global Cooperation for the future of human health on Earth, with the development of technologies like AI and nanomedicine backed by ethical, human intercultural knowledge exchange.

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The Promising Future of Nanomedicine and… – The Doctor Weighs In

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on The Promising Future of Nanomedicine and… – The Doctor Weighs In

Cancer, unfortunately, is widespread throughout the world. It affects millions of lives, in many different ways, on a daily basis. Before we dive into the topic of nanomedicine and nanoparticles, lets first look at the current state of cancer treatment.

Most therapeutic options for cancer are detrimental to the body They dont just kill cancer cells, they can also damage healthy tissues causing serious side effects.

Cancer chemotherapy drugs suffer from poor biodistribution and, therefore, require high doses. [1] Resistance can also develop to one or more of the drugs being used on a regular basis. This means that oncologists must continually develop new drug cocktails to keep treating their patients.

Some of the drugs used, particularly in later rounds of chemotherapy, may also be relatively ineffective.

So far, the benefits of chemotherapy have outweighed the risks but with the dawn of the age of nanomedicine and nanoparticles, the situation may soon change.

Nanomedicine is the medical application of nanotechnology. According to Johns Hopkins:

Nanomedicine can include a wide range of applications, including biosensors, tissue engineering, diagnostic devices, and many others. [It involves]harnessing nanotechnology to more effectively diagnose, treat, and prevent various diseases.

It also involves the development of new approaches to more efficiently deliver medications to the site of action with the aim of improving outcomes with less medication (and fewer medication side effects).

Nanoparticles are amongst the most promising treatment options in oncology, They have the potential to revolutionize the usual therapies by improving the usage and delivery of chemotherapy drugs [2].

The ability to control nanoparticle shape, size, and surface, as well as their ability to transport and deliver drugs to specific locations in the body, make nanoparticles highly useful in oncology[3].

Nanoparticles use has also spread to other areas of the medical world,[4] including:

Almost. Cancer is often debilitating with few treatment options that include surgery, chemotherapy, radiation, and immunotherapy. The side effects of these treatments can be detrimental to a patients way of living. They can often experience insomnia, nausea, vomiting, and weight loss among a long list of other adverse reactions [5].

With a cancer diagnosis and treatment, a patients quality of life can quickly nose-dive. But with nanomedicine, patients may experience a dramatic decrease in chemotherapy side effects, including a reduction of toxicity from the drugs used [6]. This, combined with all the other possible advantages of administering nanoparticles, makes nanomedicine an attractive new cancer therapy option.

Nanoparticles are attractive treatment options because their outer surfaces can be modified to attack specific cancer cells. They are biocompatible and biodegradable. They also offer increased stability to their drug payload[7].

Other possible advantages include:

There are three main types of nanoparticles [8] as follows:

Lipid-based nanoparticles have many advantages over other variations of nanoparticles. This accounts for their increased use in the delivery of drugs. Lipid-based nanoparticles have better biocompatibility than other nanoparticles. This means they work better with living tissue. Lipid-based nanoparticles are also more versatile, making them a better option in many therapies, like cancer treatments.

Liposomes are formulated with a wide range of natural, synthetic, and modified lipids to help them deliver drugs as well as contrast agents for medical imaging. Liposomes are used to treat cancer, fungal infections, vaccines, and more.

Polymeric nanoparticles are currently used for the following:

Polymer-based nanoparticles improve the efficiency of drugs as well as decrease drug side effects and toxicity.

Efficiently. The purpose of nanoparticles is to deliver drugs directly to the cancer cells and not the rest of the body. They are administered intravenously and are then moved around the body by the circulatory system.

Nanoparticles are designed to locate and then accumulate on the cancer tissue, penetrating through the walls of a tumor to deliver the chemotherapy drug they carry [8]. This way, the chemotherapy drug is delivered directly to the site of cancer versus distributed throughout the body. Mass distribution to both diseased and healthy tissues is usually the cause of drug side effects.

There are different methods of releasing the drugs being administered via nanomedicine [9]:

Nanoparticles can also be designed to transform under different conditions to either release or hold onto their drugs.

While widely used for cancer therapies, nanoparticles are also used for diagnostics, a type of nanomedicine referred to as nanodiagnostics[10]. Several nanoparticle formulations have already been designed for diagnostic use only. Though currently in limited use, nanodiagnostics is a growing field with imaging applications, such as use in magnetic resonance monitoring of tumor blood vessels and coronary arteries in patients.

On top of diagnostics, nanoparticles are also used in research opportunities, the treatment of cardiovascular diseases[11], and theranostics, which is a term used to describe pre-clinical research and trials of drug therapies and other treatments[12].

The production and use of nanoparticles face many challenges [13], including:

The creation process for lipid-based nanoparticles has a significant variation between each batch developed.

The manufacturing process is challenging to develop and maintain to the point that significant, quality nanoparticles can be produced.

The production of nanoparticles is time-consuming and extremely labor-intensive, requiring specialized knowledge and tools.

Nanoparticles are intended to maximize the benefit/risk ratio of therapies. Rather than causing many debilitating symptoms in the hopes of curing one disease, like current cancer treatments, nanoparticles are designed to minimize any side effects while treating that same disease.

But the technology isnt 100 percent ready for prime time yet. More research is needed and more dollars must be spent on analyzing both the effectiveness of nanomedicine as well as the long-term effects on the body.

While lipid-based nanoparticles are the most promising prospect because they are made of natural elements and have more advantages than other types of nanoparticles, they are not yet a perfect solution for drug delivery. We need more significant investments in clinical trials in both the government and private sectors to advance the technology.

Nanomedicine is used to treat a variety of different diseases and conditions, but it is in the oncology segment where nanoparticles see the most use and the most promise. To date, there are 51 nanopharmaceuticals approved for use in clinical practice[14]. More are being studied in clinical trials for cancer and other diseases.

Clearly, nanomedicine is a field to watch closely. I believe with continual research, trials, and advancements, the future of nanomedicine and nanoparticles is bright.

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Related content: Why Drug Discovery is So Hard and High Risk

References:

[1] Torchilin, V.P. and Lukyanov, A.N., 2003. Peptide and protein drug delivery to and into tumors: challenges and solutions. Drug discovery today, 8(6), pp.259-266..

[2]Shi, J., Kantoff, P.W., Wooster, R. and Farokhzad, O.C., 2017. Cancer nanomedicine: progress, challenges and opportunities. Nature Reviews Cancer, 17(1), p.20.

[3] Cho, K., Wang, X.U., Nie, S. and Shin, D.M., 2008. Therapeutic nanoparticles for drug delivery in cancer. Clinical cancer research, 14(5), pp.1310-1316.

[4] Heiligtag, F.J. and Niederberger, M., 2013. The fascinating world of nanoparticle research. Materials Today, 16(7-8), pp.262-271.

[5] Griffin, A.M., Butow, P.N., Coates, A.S., Childs, A.M., Ellis, P.M., Dunn, S.M. and Tattersall, M.H.N., 1996. On the receiving end V: patient perceptions of the side effects of cancer chemotherapy in 1993. Annals of oncology, 7(2), pp.189-195.

[6] Landesman-Milo, D., Ramishetti, S. and Peer, D., 2015. Nanomedicine as an emerging platform for metastatic lung cancer therapy. Cancer and Metastasis Reviews, 34(2), pp.291-301.

[7] Doane, T.L. and Burda, C., 2012. The unique role of nanoparticles in nanomedicine: imaging, drug delivery and therapy. Chemical Society Reviews, 41(7), pp.2885-2911.

[8] Singh, R. and Lillard Jr, J.W., 2009. Nanoparticle-based targeted drug delivery. Experimental and molecular pathology, 86(3), pp.215-223.

[9] Mura, S., Nicolas, J. and Couvreur, P., 2013. Stimuli-responsive nanocarriers for drug delivery. Nature materials, 12(11), pp.991-1003.

[10] Baetke, S.C., Lammers, T.G.G.M. and Kiessling, F., 2015. Applications of nanoparticles for diagnosis and therapy of cancer. The British journal of radiology, 88(1054), p.20150207.

[11] Godin, B., Sakamoto, J.H., Serda, R.E., Grattoni, A., Bouamrani, A. and Ferrari, M., 2010. Emerging applications of nanomedicine for the diagnosis and treatment of cardiovascular diseases. Trends in pharmacological sciences, 31(5), pp.199-205.

[12] Lammers, T., Aime, S., Hennink, W.E., Storm, G. and Kiessling, F., 2011. Theranostic nanomedicine. Accounts of chemical research, 44(10), pp.1029-1038.

[13] Prabhakar, U., Maeda, H., Jain, R.K., Sevick-Muraca, E.M., Zamboni, W., Farokhzad, O.C., Barry, S.T., Gabizon, A., Grodzinski, P. and Blakey, D.C., 2013. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology.

[14] Bobo, D., Robinson, K.J., Islam, J., Thurecht, K.J. and Corrie, S.R., 2016. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharmaceutical research, 33(10), pp.2373-2387.

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Clean the soles of your shoes of CoV. Why China disinfects streets. – Feminine-Perspective Magazine (FPMag)

§ March 9th, 2020 § Filed under Nano Medicine Comments Off on Clean the soles of your shoes of CoV. Why China disinfects streets. – Feminine-Perspective Magazine (FPMag)

Microscopic bugs blow in the wind and stick to your feet. Disinfecting the floor and our feet deactivates CoV and that is why many countries are spraying the streets.

We sometimes refer to a virus as a bug. It actually isnt a bug but it certainly falls into the category of parasites among other things humans dislike. We can kill bugs but viruses need deactivation wherever they occur, even on the floor.

Human-to-human transmissions of the COVID-19 in many epidemic regions have been described by clinicians as having incubation times between 2-10 days, facilitating the virus spread via human emitted water droplets, or contaminated hands and other surfaces. A recent evaluation of 22 scientific reports of all CoVs suggests the CoVID-19 can be active on surfaces for longer than its incubation period, nine days and more.

FPMag has called the COVID-19 virus a protein sack of nucleic acid and a bag of single or multiple stranded DNS/RNA; or bug. Using the common word bug triggers an alarm awareness in computer programming and healthcare vernacular. Its a bug in our systems.

by Micheal John and Sharon Santiago (The authors of this article are both medical professionals but do not offer medical advice in this article. See your doctor or public health officials for your jurisdiction. Check citations herein.)

Viruses are bundles of RNA, sometimes DNA and they are programmed to reproduce. (Cite: Molecular Cell Biology. 4th edition, Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.)

Viruses accomplish propagation by finding a living species organic cells and using the functional apparatus of those cells to make millions of copies of itself. The virus will connect to any target cell it can find but it has preferences. Each virus type has its own set of preferences and behaviours.

Most viruses have eitherRNAorDNAas their genetic material. Thenucleic acidmay be single- or double-stranded. The entire infectious virus particle, called avirion, consists of the nucleic acid and an outer shell ofprotein. The simplest viruses contain only enough RNA or DNA to encode four proteins. The most complex can encode 100 200 proteins. Cite: Molecular Cell Biology. 4th edition, Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.

The cells they choose are important to scientists and to the infected persons. The COVID-19 tends to go after pulmonary receptors. Thats why persons who are elderly or have underlying weaknesses are especially vulnerable to the SARS-CoV-2 virus. Otherwise the human body does not make those cells available. Thats an oversimplification but its the basic point. Protect the elderly and the vulnerable members of your family.

Wash your hands (soap and water for minimally 20 seconds or use an alcohol-based (70% to 90% hand cleaner) while you read this and wash them often. Make that your new life habit. Use a clean disposable paper towel (not allowed for scrub-in) or better yet, air dry your hands. If you are using a spray bottle of 70% to 90% alcohol, spray your keyboard and mouse too and allow a moment or two to dry.

(Advice for healthcare professionals can be found at this site.)

My Foot! Actually, a virus can be tracked around by your peds. Click the image ti watch a 15 second video.Thats why in China, South Korea and Iran, governments spray streets. Photo Credit, Sara Qin. Photo Art/Cropping/Enhancement: Rosa Yamamoto FPMag

HCoV can persist on inanimate surfaces like metal, glass or plastic for up to 9 days, but can be efficiently inactivated by surface disinfection procedures with 6271% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute, says Dr. Kampf of the University Medicine Greifswald, Institute for Hygiene and Environmental Medicine. See below for study results.

Why in China, South Korea and Iran, governments disinfect the streets. Photo Credit: Xinhua.

The headline of this article reads, Clean the soles of your shoes of COVID-19, and unless you are wearing blue booties which you can discard with your protective gloves after removal of first bootie and then glove, your feet have tracked in things you dont want in your home.

This photograph illustrates what we know and do in everyday life in our clinics about things like viruses that can stick to our feet and be tracked around to eventually infect people.

And this is why China, South Korea, Italy and Iran are spraying disinfectant on streets and concrete buildings.

Micheals feet with personal protection equipment aka blue booties. Photo credit Sharon Santiago. Doctors, nurses, cleaning staff, and visitors to clinics, hospital units, or rooms where infection might be a threat to patients health, or COVID-19 isolation rooms. Visitors might be required to wear blue booties an isolation gown, a mask, and gloves in these areas and discard them before they leave. In epidemic regions should you take extra precautions before and after leaving public places? Yes. Photo Art/Cropping/Enhancement: Rosa Yamamoto FPMag

The emergence of a novel human coronavirus, also known as SARS-CoV-2, has awakened many people in the public domain to things that medical professionals have always known for at least the past century.

The COVID-19 also called the SARS-CoV-2, has become a global health threat causing severe respiratory tract infections and lower respiratory failure in humans.

Human-to-human transmissions in China, South Korea, Iran and Italy have been described with incubation times between 2-10 days, facilitating its spread via droplets, contaminated hands or surfaces.

SARS CoV Spike Protein can be valid from two to 28 days depending on the environment. Most often it remains actiive for nine days says study of 22 scientific reports on the various CoVs. Photo credit: Captured from video and redrawn. Photo Art/Cropping/Enhancement: Rosa Yamamoto FPMag

On different types of materials it [COVID-19] can remain infectious for from 2 hours up to 9 days. A higher temperature such as 30C or 40C reduced the duration of persistence of highly pathogenic MERS-CoV, TGEV and MHV. However, at 4C persistence of TGEV and MHV can be increased to = 28 days. Few comparative data obtained with SARS-CoV indicate that persistence was longer with higher inocula (Table I). In addition it was shown at room temperature that HCoV-229E persists better at 50% compared to 30% relative humidity. See: PIIS0195670120300463

We reviewed the literature on all available information about the persistence of human and veterinary coronaviruses on inanimate surfaces as well as inactivation strategies with biocidal agents used for chemical disinfection, e.g. in healthcare facilities, notes Dr. Kampf of the University Medicine Greifswald, Institute for Hygiene and Environmental Medicine.

Analysis of 22 studies reveals that human coronaviruses such as Severe Acute Respiratory Syndrome (SARS) coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus or endemic human coronaviruses (HCoV) can persist on inanimate surfaces like metal, glass or plastic for up to 9 days, but can be efficiently inactivated by surface disinfection procedures with 6271% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute, says the report.

Bleach

According to Dr. Anderson of The RINJ Foundation, The Nurses Without Bordershave been using hyrdrogen-peroxide-based sanitization that they mix themselves or commercial products like D7 as a cleaner in clinics they have run or worked at in war zones and in highly infectious camps around the world.

Every number has a face. Photo Credit: Melissa Hemingway / FPMAG

The following sources are available to readers. FPMag and The Nurses Without Borders make direct contact and interview colleagues and sources close to the information around the world to track events and statistics.

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Clean the soles of your shoes of CoV. Why China disinfects streets. - Feminine-Perspective Magazine (FPMag)

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Choose the right colon cancer screening test – Freeport Journal-Standard

§ March 8th, 2020 § Filed under Nano Medicine Comments Off on Choose the right colon cancer screening test – Freeport Journal-Standard

March is Colorectal Cancer Awareness Month. Approximately 140,000 people in the United States will be diagnosed with colon cancer this year. The lifetime risk of developing colon cancer is 1 in 20 and only lung cancer claims more lives each year.

As gastroenterologists, we spend a significant amount of our time and effort working to prevent, diagnose, and treat colon cancer. Because of improved compliance with colon cancer screening, the number of new colon cancer diagnoses and deaths have both decreased by more than 30% over the last 20 years. It is truly one of the success stories in modern medicine.

At the center of this dramatic decline in mortality is colonoscopy. Colonoscopy is the gold standard for both the prevention and diagnosis of colon cancer. The procedure is not only safe and highly accurate, but unlike any other screening test, it allows for the identification and removal of polyps, which are the precursors of colon cancer. Removal of polyps is the main reason that the number of colon cancer diagnoses and deaths are decreasing.

In the last few years, a new test has emerged for colon cancer screening. Stool DNA testing has been combined with testing for microscopic amounts of blood in the stool. This test has been marketed by Exact Sciences as Cologuard and more than 1 million people have utilized this type of screening.

Unfortunately, there are significant limitations to stool DNA tests. In our experience at Rockford Gastroenterology Associates, many patients who have completed stool DNA testing are unaware of these limitations. Many gastroenterologists are concerned that increased use of this test will reverse some of the gains we have made against this deadly disease.

As an informed patient, there are important facts that you need to consider in order to make an educated decision regarding which colon cancer screening test is right for you.

First, stool DNA testing has limited sensitivity for the identification of colon polyps. For advanced polyps 10 millimeters or larger, the sensitivity is less than 50%. That means if you have an advanced polyp with a high risk of progression to colon cancer, this test will detect it less than half the time. For patients who have already developed colon cancer, the test will miss 8% of cases. These numbers are unacceptable given the high accuracy of screening colonoscopy.

Second, stool DNA testing has a significant false positive rate. The initial studies suggested that stool DNA testing has a false positive rate of 14% (normal colonoscopy after abnormal stool DNA test). In our clinical experience, that number has been higher. When combined with the miss rate, stool DNA testing has rather poor accuracy.

Finally, it is important to understand how most medical insurance companies, including Medicare, handle payment for colon cancer screening. The first colon cancer screening test is generally covered, and this includes both colonoscopy and stool DNA testing. However, if you have a positive stool DNA test and then receive a follow-up colonoscopy, you may be responsible for a greater portion of the cost than if you utilized colonoscopy as the first test.

Based on these limitations, the United States Multi-Society Task Force consensus guidelines from 2017 list Cologuard as a Tier 2 test (colonoscopy is Tier 1). The American College of Physicians guidelines from 2019 do not list Cologuard amongst the recommended colon cancer screening tests. Another study from 2019 concluded that it was less effective and more costly than other colon cancer screening tests covered by Medicare.

Armed with this information, you can have meaningful discussions with your primary care provider and choose the colon cancer screening test that is right for you.

Dr. Aaron Shiels is a gastroenterologist and managing partner at Rockford Gastroenterology Associates.

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Cancer researcher Maria Kavallaris named NSW Woman of the Year – SBS News

§ March 8th, 2020 § Filed under Nano Medicine Comments Off on Cancer researcher Maria Kavallaris named NSW Woman of the Year – SBS News

Renowned scientist Maria Kavallaris has received the top honour at the NSW Premier's Woman of the Year Awards.

Professor Kavallaris, the founding director of the Australian Centre for NanoMedicine at the University of New South Wales, received the gong at an awards ceremony in Sydney on Thursday.

"Maria is a remarkable achiever whose ground-breaking research has led to more effective therapies for aggressive childhood cancers," Premier Gladys Berejiklian said in a statement.

Another six women from across NSW were honoured in categories including community hero, lifetime achievement and businesswoman of the year.

Children's author, poet, playwright and artist Kirli Saunders was named Aboriginal woman of the year, while Southern Tablelands volunteer firefighter Kystaal Hinds was named regional woman of the year.

"Congratulations to all the incredible women who have deservedly been recognised; their achievements are an inspiration to women who want to make a difference," Ms Berejiklian said.

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CRISPR Used To Edit Genes Inside A Patient With A Rare Form Of Blindness : Shots – Health News – NPR

§ March 7th, 2020 § Filed under Nano Medicine Comments Off on CRISPR Used To Edit Genes Inside A Patient With A Rare Form Of Blindness : Shots – Health News – NPR

Scientists at the Casey Eye Institute, in Portland, Ore., have have injected a harmless virus containing CRISPR gene-editing instructions inside the retinal cells of a patient with a rare form of genetic blindness. KTSDesign/Science Photo Library/Getty Images hide caption

Scientists at the Casey Eye Institute, in Portland, Ore., have have injected a harmless virus containing CRISPR gene-editing instructions inside the retinal cells of a patient with a rare form of genetic blindness.

For the first time, scientists have used the gene-editing technique CRISPR to try to edit a gene while the DNA is still inside a person's body.

The groundbreaking procedure involved injecting the microscopic gene-editing tool into the eye of a patient blinded by a rare genetic disorder, in hopes of enabling the volunteer to see. They hope to know within weeks whether the approach is working and, if so, to know within two or three months how much vision will be restored.

"We're really excited about this," says Dr. Eric Pierce, a professor of ophthalmology at Harvard Medical School and director of the Inherited Retinal Disorders Service at Massachusetts Eye and Ear. Pierce is leading a study that the procedure launched.

"We're helping open, potentially, an era of gene-editing for therapeutic use that could have impact in many aspects of medicine," Pierce tells NPR.

The CRISPR gene-editing technique has been revolutionizing scientific research by making it much easier to rewrite the genetic code. It's also raising high hopes of curing many diseases.

Before this step, doctors had only used CRISPR to try to treat a small number of patients who have cancer, or the rare blood disorders sickle cell anemia or beta-thalassemia. While some of the initial results have been promising, it's still too soon to know whether the strategy is working.

In those other cases, doctors removed cells from patients' bodies, edited genes in the cells with CRISPR in the lab and then infused the modified cells back into the volunteers' bodies to either attack their cancer or produce a protein their bodies are missing.

In this new experiment, doctors at the Casey Eye Institute in Portland, Ore., injected (into the eye of a patient who is nearly blind from a condition called Leber congenital amaurosis) microscopic droplets carrying a harmless virus that had been engineered to deliver the instructions to manufacture the CRISPR gene-editing machinery.

Beginning in infancy, the rare genetic condition progressively destroys light-sensing cells in the retina that are necessary for vision. Vision impairment with LCA varies widely, but most patients are legally blind and are only able to differentiate between light and dark or perhaps to detect movement.

"The majority of people affected by this disease have the most severe end of the spectrum, in terms of how poor their vision is," Pierce says. "They're functionally blind."

The goal is that once the virus carrying the CRISPR instructions has been infused into the eye, the gene-editing tool will slice out the genetic defect that caused the blindness. That would, the researchers hope, restore production of a crucial protein and prevent the death of cells in the retina, as well as revive other cells enabling patients to regain at least some vision.

"It's the first time the CRISPR gene-editing is used directly in a patient," Pierce says. "We're really optimistic that this has a good chance of being effective."

The study is being sponsored by Editas Medicine, of Cambridge, Mass., and Allergan, based in Dublin. It will eventually involve a total of 18 patients, including some as young as ages 3 to 17, who will receive three different doses.

"We're very excited about this. This is the first time we're doing editing inside the body," says Charles Albright, the chief scientific officer at Editas.

"We believe that the ability to edit inside the body is going to open entire new areas of medicine and lead to a whole new class of therapies for diseases that are not treatable any other way," Albright says.

Francis Collins, director of the National Institutes of Health, calls the advance "a significant moment."

"All of us dream that a time might be coming where we could apply this approach for thousands of diseases," Collins tells NPR. "This is the first time that's being tried in a human being. And it gives us hope that we could extend that to lots of other diseases if it works and if it's safe."

Pierce, Albright and others stressed that only one patient has been treated so far and that the study, still at a very early stage, is designed primarily to determine whether injecting the gene-editing tool directly into the eye is safe.

To that end, the researchers are starting with lowest dose and the oldest patients, who have already suffered extensive damage to their vision. And doctors are only treating one eye in each patient. All of those steps are being taken in case the treatment somehow backfires, causing more damage instead of being helpful.

"CRISPR has never been used directly inside a patient before," Pierce says. "We want to make sure we're doing it right."

Still, he says, if the underlying defect can be repaired in this patient and others with advanced damage, "we have the potential to restore vision to people who never had normal vision before. It would indeed be amazing."

The study involves a form of Leber congenital amaurosis known as Type 10, which is caused by a defect in the CEP290 gene.

If the approach appears to be safe and effective, the researchers will start treating younger patients.

"We believe children have the potential to have the most benefit from their therapy, because we know their visual pathways are still intact," Albright explains.

The procedure, which takes about an hour to perform, involves making tiny incisions that enable access to the back of the eye. That allows a surgeon to inject three droplets of fluid containing billions of copies of the virus that has been engineered to carry the CRISPR gene-editing instructions under the retina.

The idea is that once there, the CRISPR editing elements would snip out the mutation that causes a defect in CEP290. The hope is that this would be a one-time treatment that would correct vision for a lifetime.

If it works, the volunteers in the study might be able to have the procedure repeated on the other eye later.

"If we can do this safely, that opens the possibility to treat many other diseases where it's not possible to remove the cells from the body and do the treatment outside," Pierce says.

The list of such conditions might include some brain disorders, such Huntington's disease and inherited forms of dementia, as well as muscle diseases, such as muscular dystrophy and myotonic dystrophy, according to Pierce and Albright.

"Inherited retinal diseases are a good choice in terms of gene-based therapies," says Artur Cideciyan, a professor of ophthalmology at the University of Pennsylvania, given that the retina is easily accessible.

But Cideciyan cautions that other approaches for these conditions are also showing promise, and it remains unclear which will turn out to be the best.

"The gene-editing approach is hypothesized to be a 'forever fix,' " he says. "However, that's not known. And the data will have to be evaluated to see the durability of that. We'll have to see what happens."

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Biochemical and structural cues of 3D-printed matrix synergistically direct MSC differentiation for functional sweat gland regeneration – Science…

§ March 7th, 2020 § Filed under Nano Medicine Comments Off on Biochemical and structural cues of 3D-printed matrix synergistically direct MSC differentiation for functional sweat gland regeneration – Science…

Abstract

Mesenchymal stem cells (MSCs) encapsulation by three-dimensionally (3D) printed matrices were believed to provide a biomimetic microenvironment to drive differentiation into tissue-specific progeny, which made them a great therapeutic potential for regenerative medicine. Despite this potential, the underlying mechanisms of controlling cell fate in 3D microenvironments remained relatively unexplored. Here, we bioprinted a sweat gland (SG)like matrix to direct the conversion of MSC into functional SGs and facilitated SGs recovery in mice. By extracellular matrix differential protein expression analysis, we identified that CTHRC1 was a critical biochemical regulator for SG specification. Our findings showed that Hmox1 could respond to the 3D structure activation and also be involved in MSC differentiation. Using inhibition and activation assay, CTHRC1 and Hmox1 synergistically boosted SG gene expression profile. Together, these findings indicated that biochemical and structural cues served as two critical impacts of 3D-printed matrix on MSC fate decision into the glandular lineage and functional SG recovery.

Mesenchymal stem cells (MSCs) hold great promise for therapeutic tissue engineering and regenerative medicine, largely because of their capacity for self-renewal and multipotent properties (1). However, their uncertain fate has a major impact on their envisioned therapeutic use. Cell fate regulation requires specific transcription programs in response to environmental cues (2, 3). Once stem cells are removed from their microenvironment, their response to environmental cues, phenotype, and functionality could often be altered (4, 5). In contrast to growing information concerning transcriptional regulation, guidance from the extracellular matrix (ECM) governing MSC identity and fate determination is not well understood. It remains an active area of investigation and may provide previously unidentified avenues for MSC-based therapy.

Over the past decade, engineering three-dimensional (3D) ECM to direct MSC differentiation has demonstrated great potential of MSCs in regenerative medicine (6). 3D ECM has been found to be useful in providing both biochemical and biophysical cues and to stabilize newly formed tissues (7). Culturing cells in 3D ECM radically alters the interfacial interactions with the ECM as compared with 2D ECM, where cells are flattened and may lose their differentiated phenotype (8). However, one limitation of 3D materials as compared to 2D approaches was the lack of spatial control over chemistry with 3D materials. One possible solution to this limitation is 3D bioprinting, which could be used to design the custom scaffolds and tissues (9).

In contrast to traditional engineering techniques, 3D cell printing technology is especially advantageous because it can integrate multiple biophysical and biochemical cues spatially for cellular regulation and ensure complex structures with precise control and high reproducibility. In particular, for our final goal of clinical practice, extrusion-based bioprinting may be more appropriate for translational application. In addition, as a widely used bioink for extrusion bioprinting, alginate-based hydrogel could maintain stemness of MSC due to the bioinert property and improve biological activity and printability by combining gelatin (10).

Sweat glands (SGs) play a vital role in thermal regulation, and absent or malfunctioning SGs in a hot environment can lead to hyperthermia, stroke, and even death in mammals (11, 12). Each SG is a single tube consisting of a functionally distinctive duct and secretory portions. It has low regenerative potential in response to deep dermal injury, which poses a challenge for restitution of lost cells after wound (13). A major obstacle in SG regeneration, similar to the regeneration of most other glandular tissues, is the paucity of viable cells capable of regenerating multiple tissue phenotypes (12). Several reports have described SG regeneration in vitro; however, dynamic morphogenesis was not identified nor was the overall function of the formed tissues explored (1416). Recent advances in bioprinting and tissue engineering led to the complexities in the matrix design and fabrication with appropriate biochemical cues and biophysical guidance for SG regeneration (1719).

Here, we adopted 3D bioprinting technique to mimic the regenerative microenvironment that directed the specific SG differentiation of MSCs and ultimately guided the formation and function of glandular tissue. We used alginate/gelatin hydrogel as bioinks in this present study due to its good cytocompatibility, printability, and structural maintenance in long-time culture. Although the profound effects of ECM on cell differentiation was well recognized, the importance of biochemical and structural cues of 3D-printed matrix that determined the cell fate of MSCs remained unknown; thus, the present study demonstrated the role of 3D-printed matrix cues on cellular behavior and tissue morphogenesis and might help in developing strategies for MSC-based tissue regeneration or directing stem cell lineage specification by 3D bioprinting.

The procedure for printing the 3D MSC-loaded construct incorporating a specific SG ECM (mouse plantar region dermis, PD) was shown schematically in Fig. 1A. A 3D cellular construct with cross section 30 mm 30 mm and height of 3 mm was fabricated by using the optimized process parameter (20). The 3D construct demonstrated a macroporous grid structure with hydrogel fibers evenly distributed according to the computer design. Both the width of the fibers and the gap between the fibers were homogeneous, and MSCs were embedded uniformly in the hydrogel matrix fibers to result in a specific 3D microenvironment. (Fig. 1B).

(A) Schematic description of the approach. (B) Full view of the cellular construct and representative microscopic and fluorescent images and the quantitative parameters of 3D-printed construct (scale bars, 200 m). Photo credit: Bin Yao, Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA. (C) Representative microscopy images of cell aggregates and tissue morphology at 3, 7, and 14 days of culture (scale bars, 50 m) and scanning electron microscopy (sem) images of 3D structure (scale bars, 20 m). PD+/PD, 3D construct with and without PD. (D) DNA contents, collagen, and GAGs of native tissue and PD. (E) Proliferating cells were detected through Ki67 stain at 3, 7, and 14 days of culture. (F) Live/dead assay show cell viability at days 3, 7, and 14. *P < 0.05.

During the maintenance of constructs for stem cell expansion, MSCs proliferated to form aggregates of cells but self-assembled to an SG-like structure only with PD administration (Fig. 1C and fig. S1, A to C). We carried out DNA quantification assay to evaluate the cellular content in PD and found the cellular matrix with up to 90% reduction, only 3.4 0.7 ng of DNA per milligram tissue remaining in the ECM. We also estimated the proportions of collagen and glycosaminoglycans (GAGs) in ECM through hydroxyproline assay and dimethylmethylene blue assay, the collagen contents could increase to 112.6 11.3%, and GAGs were well retained to 81 9.6% (Fig. 1D). Encapsulated cells were viable, with negligible cell death apparent during extrusion and ink gelation by ionic cross-linking, persisting through extended culture in excess of 14 days. The fluorescence intensity of Ki67 of MSCs cultured in 2D condition decreased from days 3 (152.7 13.4) to 14 (29.4 12.9), while maintaining higher intensity of MSCs in 3D construct (such as 211.8 19.4 of PD+3D group and 209.1 22.1 of PD3D group at day 14). And the cell viability in 3D construct was found to be sufficiently high (>80%) when examined on days 3, 7, and 14. The phenomenon of cell aggregate formation and increased cell proliferation implied the excellent cell compatibility of the hydrogel-based construct and promotion of tissue development of 3D architectural guides, which did not depend on the presence or absence of PD (Fig. 1, E and F).

The capability of 3D-printed construct with PD directing MSC to SGs in vitro was investigated. The 3D construct was dissolved, and cells were isolated at days 3, 7, and 14 for transcriptional analysis. Expression of the SG markers K8 and K18 was higher from the 3D construct with (3D/PD+) than without PD (3D/PD); K8 and K18 expression in the 3D/PD construct was similar to with control that MSCs cultured in 2D condition, which implied the key role of PD in SG specification. As compared with the 2D culture condition, 3D administration (PD+) up-regulated SG markers, which indicated that the 3D structure synergistically boosted the MSC differentiation (Fig. 2A).

(A) Transcriptional expression of K8, K18, Fxyd2, Aqp5, and ATP1a1 in 3D-bioprinted cells with and without PD in days 3, 7, and 14 culture by quantitative real-time polymerase chain reaction (qRT-PCR). Data are means SEM. (B) Comparison of SG-specific markers K8 and K18 in 3D-bioprinted cells with and without PD (K8 and K18, red; DAPI, blue; scale bars, 50 m). (C and D) Comparison of SG secretion-related markers ATP1a1 (C) and Ca2+ (D) in 3D-bioprinted cells with and without PD [ATP1a1 and Ca2+, red; 4,6-diamidino-2-phenylindole (DAPI), blue; scale bars, 50 m].

In addition, we tested secretion-related genes to evaluate the function of induced SG cells (iSGCs). Although levels of the ion channel factors of Fxyd2 and ATP1a1 were increased notably in 2D culture with PD and ATP1a1 up-regulated in the 3D/PD construct, all the secretory genes of Fxyd2, ATP1a1, and water transporter Aqp5 showed the highest expression level in the 3D/PD+ construct (Fig. 2A). Considering the remarkable impact, further analysis focused on 3D constructs.

Immunofluorescence staining confirmed the progression of MSC differentiation. At day 7, cells in the 3D/PD+ construct began to express K8 and K18, which was increased at day 14, whereas cells in the 3D/PD construct did not express K8 and K18 all the time (Fig. 2B and fig. S2A). However, the expression of ATP1a1 (ATPase Na+/K+ transporting subunit alpha 1) and free Ca2+ concentration did not differ between cells in the 3D/PD+ and 3D/PD constructs (Fig. 2, C and D). By placing MSCs in such a 3D environment, secretion might be stimulated by rapid cell aggregation without the need for SG lineage differentiation. Cell aggregationimproved secretion might be due to the benefit of cell-cell contact (fig. S2B) (21, 22).

To map the cell fate changes during the differentiation between MSCs and SG cells, we monitored the mRNA levels of epithelial markers such as E-cadherin, occludin, Id2, and Mgat3 and mesenchymal markers N-cadherin, vimentin, Twist1, and Zeb2. The cells transitioned from a mesenchymal status to a typical epithelial-like status accompanied by mesenchymal-epithelial transition (MET), then epithelial-mesenchymal transition (EMT) occurred during the further differentiation of epithelial lineages to SG cells (fig. S3A). In addition, MET-related genes were dynamically regulated during the SG differentiation of MSCs. For example, the mesenchymal markers N-cadherin and vimentin were down-regulated from days 1 to 7, which suggested cells losing their mesenchymal phenotype, then were gradually up-regulated from days 7 to 10 in their response to the SG phenotype and decreased at day 14. The epithelial markers E-cadherin and occludin showed an opposite expression pattern: up-regulated from days 1 to 5, then down-regulated from days 7 to 10 and up-regulated again at day 14. The mesenchymal transcriptional factors ZEB2 and Twist1 and epithelial transcriptional factors Id2 and Mgat3 were also dynamically regulated.

We further analyzed the expression of these genes at the protein level by immunofluorescence staining (figs. S3B and S4). N-cadherin was down-regulated from days 3 to 7 and reestablished at day 14, whereas E-cadherin level was increased from days 3 to 7 and down-regulated at day 14. Together, these results indicated that a sequential and dynamic MET-EMT process underlie the differentiation of MSCs to an SG phenotype, perhaps driving differentiation more efficiently (23). However, the occurrence of the MET-EMT process did not depend on the presence of PD. Thus, a 3D structural factor might also participate in the MSC-specific differentiation (fig. S3C).

To investigate the underlying mechanism of biochemical cues in lineage-specific cell fate, we used quantitative proteomics analysis to screen the ECM factors differentially expressed between PD and dorsal region dermis (DD) because mice had eccrine SGs exclusively present in the pads of their paws, and the trunk skin lacks SGs. In total, quantitative proteomics analyses showed higher expression levels of 291 proteins in PD than DD. Overall, 66 were ECM factors: 23 were significantly up-regulated (>2-fold change in expression). We initially determined the level of proteins with the most significant difference after removing keratins and fibrin: collagen triple helix repeat containing 1 (CTHRC1) and thrombospondin 1 (TSP1) (fig. S5). Western blotting was performed to further confirm the expression level of CTHRC1 and TSP1, and we then confirmed that immunofluorescence staining at different developmental stages in mice revealed increased expression of CTHRC1 in PD with SG development but only slight expression in DD at postnatal day 28, while TSP1 was continuously expressed in DD and PD during development (Fig. 3, A to C). Therefore, TSP1 was required for the lineage-specific function during the differentiation in mice but was not dispensable for SG development.

(A and B) Differential expression of CTHRC1 and TSP1in PD and back dermis (DD) ECM of mice by proteomics analysis (A) and Western blotting (B). (C) CTHRC1 and TSP1 expression in back and plantar skin of mice at different developmental times. (Cthrc1/TSP1, red; DAPI, blue; scale bars, 50 m).

According to previous results of the changes of SG markers, 3D structure and PD were both critical to SG fate. Then, we focused on elucidating the mechanisms that underlie the significant differences observed in 2D and 3D conditions with or without PD treatment. To this end, we performed transcriptomics analysis of MSCs, MSCs treated with PD, MSCs cultured in 3D construct, and MSC cultured in 3D construct with PD after 3-day treatment. We noted that the expression profiles of MSCs treated with 3D, PD, or 3D/PD were distinct from the profiles of MSCs (Fig. 4A). Through Gene Ontology (GO) enrichment analysis of differentially expressed genes, it was shown that PD treatment in 2D condition induced up-regulation of ECM and inflammatory response term, and the top GO term for MSCs in 3D construct was ECM organization and extracellular structure organization. However, for the MSCs with 3D/PD treatment, we found very significant overrepresentation of GO term related to branching morphogenesis of an epithelial tube and morphogenesis of a branching structure, which suggested that 3D structure cues and biochemical cues synergistically initiate the branching of gland lineage (fig S6). Heat maps of differentially expressed ECM organization, cell division, gland morphogenesis, and branch morphogenesis-associated genes were shown in fig. S7. To find the specific genes response to 3D structure cues facilitating MSC reprogramming, we analyzed the differentially expressed genes of four groups of cells (Fig. 4B). The expression of Vwa1, Vsig1, and Hmox1 were only up-regulated with 3D structure stimulation, especially the expression of Hmox1 showed a most significant increase and even showed a higher expression addition with PD, which implied that Hmox1 might be the transcriptional driver of MSC differentiation response to 3D structure cues. Differential expression of several genes was confirmed by quantitative polymerase chain reaction (qPCR): Mmp9, Ptges, and Il10 were up-regulated in all the treated groups. Likewise, genes involving gland morphogenesis and branch morphogenesis such as Bmp2, Tgm2, and Sox9 showed higher expression in 3D/PD-treated group. Bmp2 was up-regulated only in 3D/PD-treated group, combined with the results of GO analysis, we assumed that Bmp2 initiated SG fate through inducing branch morphogenesis and gland differentiation (Fig. 4C).

(A) Gene expression file of four groups of cells (R2DC, MSCs; R2DT, MSC with PD treatment; R3DC, MSC cultured in 3D construct; and R3DT, MSC treated with 3D/PD). (B) Up-regulated genes after treatment (2DC, MSCs; 2DT, MSC with PD treatment; 3DC, MSC cultured in 3D construct; and 3DT, MSC treated with 3D/PD). (C) Differentially expressed genes were further validated by RT-PCR analysis. [For all RT-PCR analyses, gene expression was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with 40 cycles, data are represented as the means SEM, and n = 3].

To validate the role of HMOX1 and CTHRC1 in the differentiation of MSCs to SG lineages, we analyzed the gene expression of Bmp2 by regulating the expression of Hmox1 and CTHRC1 based on the 3D/PD-treated MSCs. The effects of caffeic acid phenethyl ester (CAPE) and tin protoporphyrin IX dichloride (Snpp) on the expression of Hmox1 were evaluated by quantitative real-time (qRT)PCR. Hmox1 expression was significantly activated by CAPE and reduced by Snpp. Concentration of CTHRC1 was increased with recombinant CTHRC1 and decreased with CTHRC1 antibody. That is, it was negligible of the effects of activator and inhibitor of Hmox1 and CTHRC1 on cell proliferation (fig. S8, A and B). Hmox1 inhibition or CTHRC1 neutralization could significantly reduce the expression of Bmp2, while Hmox1 activation or increased CTHRC1 both activated Bmp2 expression. Furthermore, Bmp2 showed highest expression by up-regulation of Hmox1 and CTHRC1 simultaneously and sharply decreased with down-regulation of Hmox1 and CTHRC1 at the same time (Fig. 5A). Immunofluorescent staining revealed that the expression of bone morphogenetic protein 2 (BMP2) at the translational level with CTHRC1 and Hmox1 regulation showed a similar trend with transcriptional changes (Fig. 5B). Likewise, the expression of K8 and K18 at transcriptional and translational level changed similarly with CTHRC1 and Hmox1 regulation (fig. S9, A and B). These results suggested that CTHRC1 and Hmox1 played an essential role in SG fate separately, and they synergistically induced SG direction from MSCs (Fig. 5C).

(A and B) Transcriptional analysis (A) and translational analysis (PD, MSCs; PD+, MSCs with 3D/PD treatment; CAPE, MSCs treated with 3D/PD and Hmox1 activator; Snpp, MSCs treated with 3D/PD and Hmox1 inhibitor; Cthrc1, MSCs treated with 3D/PD and recombinant CTHRC1; anti, MSCs treated with 3D/PD and CTHRC1 antibody: +/+, MSCs treated with 3D/PD and Hmox1 activator and recombinant CTHRC1; and /, MSCs treated with 3D/PD and Hmox1 inhibitor and CTHRC1 antibody. Data are represented as the means SEM and n = 3) (B) of bmp2 with regulation of CTHRC1 and Hmox1. (C) The graphic illustration of 3D-bioprinted matrix directed MSC differentiation. CTHRC1 is the main biochemical cues during SG development, and structural cues up-regulated the expression of Hmox1 synergistically initiated branching morphogenesis of SG. *P < 0.05.

Next, we sought to assess the repair capacity of iSGCs for in vivo implications, the 3D-printed construct with green fluorescent protein (GFP)labeled MSCs was transplanted in burned paws of mice (Fig. 6A). We measured the SG repair effects by iodine/starch-based sweat test at day 14. Only mice with 3D/PD treatment showed black dots on foot pads (representing sweating), and the number increased within 10 min; however, no black dots were observed on untreated and single MSC-transplanted mouse foot pads even after 15 min (Fig. 6B). Likewise, hematoxylin and eosin staining analysis revealed SG regeneration in 3D/PD-treated mice (Fig. 6C). GFP-positive cells were characterized as secretory lumen expressing K8, K18, and K19. Of note, the GFP-positive cells were highly distributed in K14-positive myoepithelial cells of SGs but were absent in K14-positive repaired epidermal wounds (Fig. 6, D and E). Thus, differentiated MSCs enabled directed restitution of damaged SG tissues both at the morphological and functional level.

(A) Schematic illustration of approaches for engineering iSGCs and transplantation. (B) Sweat test of mice treated with different cells. Photo credit: Bin Yao, Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA. (C) Histology of plantar region without treatment and transplantation of MSCs and iSGCs (scale bars, 200 m). (D) Involvement of GFP-labeled iSGCs in directed regeneration of SG tissue in thermal-injured mouse model (K14, red; GFP, green; DAPI, blue; scale bar, 200 m). (E) SG-specific markers K14, K19, K8, and K18 detected in regenerated SG tissue (arrows). (K14, K19, K8, and K18, red; GFP, green; scale bars, 50 m).

A potential gap in MSC-based therapy still exists between current understandings of MSC performance in vivo in their microenvironment and their intractability outside of that microenvironment (24). To regulate MSCs differentiation into the right phenotype, an appropriate microenvironment should be created in a precisely controlled spatial and temporal manner (25). Recent advances in innovative technologies such as bioprinting have enabled the complexities in the matrix design and fabrication of regenerative microenvironments (26). Our findings demonstrated that directed differentiation of MSCs into SGs in a 3D-printed matrix both in vitro and in vivo was feasible. In contrast to conventional tissue-engineering strategies of SG regeneration, the present 3D-printing approach for SG regeneration with overall morphology and function offered a rapid and accurate approach that may represent a ready-to-use therapeutic tool.

Furthermore, bioprinting MSCs successfully repaired the damaged SG in vivo, suggesting that it can improve the regenerative potential of exogenous differentiated MSCs, thereby leading to translational applications. Notably, the GFP-labeled MSC-derived glandular cells were highly distributed in K14-positive myoepithelial cells of newly formed SGs but were absent in K14-positive repaired epidermal wounds. Compared with no black dots were observed on single MSC-transplanted mouse foot pads, the black dots (representing sweating function) can be observed throughout the entire examination period, and the number increased within 10 min on MSC-bioprinted mouse foot pads. Thus, differentiated MSCs by 3D bioprinting enabled exclusive restitution of damaged SG tissues morphologically and functionally.

Although several studies indicated that engineering 3D microenvironments enabled better control of stem cell fates and effective regeneration of functional tissues (2730), there were no studies concerning the establishment of 3D-bioprinted microenvironments that can preferentially induce MSCs differentiating into glandular cells with multiple tissue phenotypes and overall functional tissue. To find an optimal microenvironment for promoting MSC differentiation into specialized progeny, biochemical properties are considered as the first parameter to ensure SG specification. In this study, we used mouse PD as the main composition of a tissue-specific ECM. As expected, this 3D-printed PD+ microenvironment drove the MSC fate decision to enhance the SG phenotypic profile of the differentiated cells. By ECM differential protein expression analysis, we identified that CTHRC1 was a critical biochemical regulator of 3D-printed matrix for SG specification. TSP1 was required for the lineage-specific function during the differentiation in mice but was not dispensable for SG development. Thus, we identified CTHRC1 as a specific factor during SG development. To our knowledge, this is the first demonstration of CTHRC1 involvement in dictating MSC differentiation to SG, highlighting a potential therapeutic tool for SG injury.

The 3D-printed matrix also provided architectural guides for further SG morphogenesis. Our results clearly show that the 3D spatial dimensionality allows for better cell proliferation and aggregation and affect the characteristics of phenotypic marker expression. Notably, the importance of 3D structural cues on MSC differentiation was further proved by MET-EMT process during differentiation, where the influences did not depend on the presence of biochemical cues. To fully elucidate the underlying mechanisms, we first examined how 3D structure regulating stem cell fate choices. According to our data, Hmox1 is highly up-regulated in 3D construct, which were supposed to response to hypoxia, with a previously documented role in MSC differentiation (31, 32). It is suggested that 3D microenvironment induced rapid cell aggregation leading to hypoxia and then activated the expression of Hmox1.

Through regulation of the expression of Hmox1 and addition or of CTHRC1 in the matrix, we confirmed that each of them is critical for SG reprogramming, respectively. Thus, biochemical and structural cues of 3D-printed matrix synergistically creating a microenvironment could enhance the accuracy and efficiency of MSC differentiation, thereby leading to resulting SG formation. Although we further need a more extensive study examining the role of other multiple cues and their possible overlap function in regulating MSC differentiation, our findings suggest that CTHRC1 and Hmox1 provide important signals that cooperatively modulate MSC lineage specification toward sweat glandular lineage. The 3D structure combined with PD stimulated the GO functional item of branch morphogenesis and gland formation, which might be induce by up-regulation of Bmp2 based on the verification of qPCR results. Although our results could not rule out the involvement of other factors and their possible overlapping role in regulating MSC lineage specification toward SGs, our findings together with several literatures suggested that BMP2 plays a critical role in inducing branch morphogenesis and gland formation (3335).

In summary, our findings represented a novel strategy of directing MSC differentiation for functional SG regeneration by using 3D bioprinting and pave the way for a potential therapeutic tool for other complex glandular tissues as well as further investigation into directed differentiation in 3D conditions. Specifically, we showed that biochemical and structural cues of 3D-printed matrix synergistically direct MSC differentiation, and our results highlighted the importance of 3D-printed matrix cues as regulators of MSC fate decisions. This avenue opens up the intriguing possibility of shifting from genetic to microenvironmental manipulations of cell fate, which would be of particular interest for clinical applications of MSC-based therapies.

The main aim and design of the study was first to determine whether by using 3D-printed microenvironments, MSCs can be directed to differentiate and regenerate SGs both morphologically and functionally. Then, to investigate the underlying molecular mechanism of biochemical and structural cues of 3D-printed matrix involved in MSCs reprogramming. The primary aims of the study design were as follows: (i) cell aggregation and proliferation in a 3D-bioprinted construct; (ii) differentiation of MSCs at the cellular phenotype and functional levels in the 3D-bioprinted construct; (iii) the MET-EMT process during differentiation; (iv) differential protein expression of the SG niche in mice; (v) differential genes expression of MSCs in 3D-bioprinted construct; (vi) the key role of CTHRC1 and HMOX1 in MSCs reprogramming to SGCs; and (vii) functional properties of regenerated SG in vivo.

Gelatin (Sigma-Aldrich, USA) and sodium alginate (Sigma-Aldrich, USA) were dissolved in phosphate-buffered saline (PBS) at 15 and 1% (w/v), respectively. Both solutions were sterilized under 70C for 30 min three times at an interval of 30 min. The sterilized solutions were packed into 50-ml centrifuge tubes, stored at 4C, and incubated at 37C before use.

From wild-type C57/B16 mice (Huafukang Co., Beijing) aged 5 days old, dermal homogenates were prepared by homogenizing freshly collected hairless mouse PD with isotonic phosphate buffer (pH 7.4) for 20 min in an ice bath to obtain 25% (w/v) tissue suspension. The supernatant was obtained after centrifugation at 4C for 20 min at 10,000g. The DNA content was determined using Hoechst 33258 assay (Beyotime, Beijing). The fluorescence intensity was measured to assess the amount of remaining DNA within the decellularized ECMs and the native tissue using a fluorescence spectrophotometer (Thermo Scientific, Evolution 260 Bio, USA). The GAGs content was estimated via 1,9-dimethylmethylene blue solution staining. The absorbance was measured with microplate reader at wavelength of 492 nm. The standard curve was made using chondroitin sulfate A. The total COL (Collagen) content was determined via hydroxyproline assay. The absorbance of the samples was measured at 550 nm and quantified by referring to a standard curve made with hydroxyproline.

MSCs were bioprinted with matrix materials by using an extrusion-based 3D bioprinter (Regenovo Co., Bio-Architect PRO, Hangzhou). Briefly, 10 ml of gelatin solution (10% w/v) and 5 ml of alginate solution (2% w/v) were warmed under 37C for 20 min, gently mixed as bioink and used within 30 min. MSCs were collected from 100-mm dishes, dispersed into single cells, and 200 l of cell suspension was gently mixed with matrix material under room temperature with cell density 1 million ml1. PD (58 g/ml) was then gently mixed with bioink. Petri dishes at 60 mm were used as collecting plates in the 3D bioprinting process. Within a temperature-controlled chamber of the bioprinter, with temperature set within the gelation region of gelatin, the mixture of MSCs and matrix materials was bioprinted into a cylindrical construct layer by layer. The nozzle-insulation temperature and printing chamber temperature were set at 18 and 10C, respectively; nozzles with an inner diameter of 260 m were chosen for printing. The diameter of the cylindrical construct was 30 mm, with six layers in height. After the temperature-controlled bioprinting process, the printed 3D constructs were immersed in 100-mM calcium chloride (Sigma-Aldrich, USA) for 3 min for cross-linking, then washed with Dulbeccos modified Eagle medium (DMEM) (Gibco, USA) medium for three times. The whole printing process was finished in 10 min. The 3D cross-linked construct was cultured in DMEM in an atmosphere of 5% CO2 at 37C. The culture medium was changed to SG medium [contains 50% DMEM (Gibco, New York, NY) and 50% F12 (Gibco) supplemented with 5% fetal calf serum (Gibco), 1 ml/100 ml penicillin-streptomycin solution, 2 ng/ml liothyronine sodium (Gibco), 0.4 g/ml hydrocortisone succinate (Gibco), 10 ng/ml epidermal growth factor (PeproTech, Rocky Hill, NJ), and 1 ml/100 ml insulin-transferrin-selenium (Gibco)] 2 days later. The cell morphology was examined and recorded under an optical microscope (Olympus, CX40, Japan).

Fluorescent live/dead staining was used to determine cell viability in the 3D cell-loaded constructs according to the manufacturers instructions (Sigma-Aldrich, USA). Briefly, samples were gently washed in PBS three times. An amount of 1 M calcein acetoxymethyl (calcein AM) ester (Sigma-Aldrich, USA) and 2 M propidium iodide (Sigma-Aldrich, USA) was used to stain live cells (green) and dead cells (red) for 15 min while avoiding light. A laser scanning confocal microscopy system (Leica, TCSSP8, Germany) was used for image acquisition.

The cell-printed structure was harvested and fixed with a solution of 4% paraformaldehyde. The structure was embedded in optimal cutting temperature (OCT) compound (Sigma-Aldrich, USA) and sectioned 10-mm thick by using a cryotome (Leica, CM1950, Germany). The sliced samples were washed repeatedly with PBS solution to remove OCT compound and then permeabilized with a solution of 0.1% Triton X-100 (Sigma-Aldrich, USA) in PBS for 5 min. To reduce nonspecific background, sections were treated with 0.2% bovine serum albumin (Sigma-Aldrich, USA) solution in PBS for 20 min. To visualize iSGCs, sections were incubated with primary antibody overnight at 4C for anti-K8 (1:300), anti-K14 (1:300), anti-K18 (1:300), anti-K19 (1:300), anti-ATP1a1 (1:300), anti-Ki67 (1:300), antiN-cadherin (1:300), antiE-cadherin (1:300), anti-CTHRC1 (1:300), or anti-TSP1 (1:300; all Abcam, UK) and then incubated with secondary antibody for 2 hours at room temperature: Alexa Fluor 594 goat anti-rabbit (1:300), fluorescein isothiocyanate (FITC) goat anti-rabbit (1:300), FITC goat anti-mouse (1:300), or Alexa Fluor 594 goat anti-mouse (1:300; all Invitrogen, CA). Sections were also stained with 4,6-diamidino-2-phenylindole (Beyotime, Beijing) for 15 min. Stained samples were visualized, and images were captured under a confocal microscope.

To harvest the cells in the construct, the 3D constructs were dissolved by adding 55 mM sodium citrate and 20 mM EDTA (Sigma-Aldrich, USA) in 150 mM sodium chloride (Sigma-Aldrich, USA) for 5 min while gently shaking the petri dish for better dissolving. After transfer to 15-ml centrifuge tubes, the cell suspensions were centrifuged at 200 rpm for 3 min, and the supernatant liquid was removed to harvest cells for further analysis.

Total RNA was isolated from cells by using TRIzol reagent (Invitrogen, USA) following the manufacturers protocol. RNA concentration was measured by using a NanoPhotometer (Implen GmbH, P-330-31, Germany). Reverse transcription involved use of a complementary DNA synthesis kit (Takara, China). Gene expression was analyzed quantitatively by using SYBR green with the 7500 Real-Time PCR System (Takara, China). The primers and probes for genes were designed on the basis of published gene sequences (table S1) (National Center for Biotechnology Information and PubMed). The expression of each gene was normalized to that for glyceraldehyde-3-phosphate dehydrogenase and analyzed by the 2-CT method. Each sample was assessed in triplicate.

The culture medium was changed to SG medium with 2 mM CaCl2 for at least 24 hours, and cells were loaded with fluo-3/AM (Invitrogen, CA) at a final concentration of 5 M for 30 min at room temperature. After three washes with calcium-free PBS, 10 M acetylcholine (Sigma-Aldrich, USA) was added to cells. The change in the Fluo 3 fluorescent signal was recorded under a laser scanning confocal microscopy.

Cell proliferation was evaluated through CCK-8 (Cell counting kit-8) assay. Briefly, cells were seeded in 96-well plates at the appropriate concentration and cultured at 37C in an incubator for 4 hours. When cells were adhered, 10 l of CCK-8 working buffer was added into the 96-well plates and incubated at 37C for 1 hour. Absorbance at 450 nm was measured with a microplate reader (Tecan, SPARK 10M, Austria).

Proteomics of mouse PD and DD involved use of isobaric tags for relative and absolute quantification (iTRAQ) in BGI Company, with differentially expressed proteins detected in PD versus DD. Twofold greater difference in expression was considered significant for further study.

Tissues were grinded and lysed in radioimmunoprecipitation assay buffer (Beyotime, Nanjing). Proteins were separated by 12% SDSpolyacrylamide gel electrophoresis and transferred to a methanol-activated polyvinylidene difluoride membrane (GE Healthcare, USA). The membrane was blocked for 1 hour in PBS with Tween 20 containing 5% bovine serum albumin (Sigma-Aldrich, USA) and probed with the antibodies anti-CTHRC1 (1:1000) and anti-TSP1 (1:1000; both Abcam, UK) overnight at 4C. After 2 hours of incubation with goat anti-rabbit horseradish peroxidaseconjugated secondary antibody (Santa Cruz Biotechnology, CA), the protein bands were detected by using luminal reagent (GE Healthcare, ImageQuant LAS 4000, USA).

Total RNA was prepared with TRIzol (Invitrogen), and RNA sequencing was performed using HiSeq 2500 (Illumina). Genes with false discovery rate < 0.05, fold difference > 2.0, and mean log intensity > 2.0 were considered to be significant.

CAPE or Snpp was gently mixed with bioink at a concentration of 10 M. Physiological concentration of CTHRC1 was measured by enzyme linked immunosorbent assay (ELISA) (80 ng/ml), and then recombinant CTHRC1 or CTHRC1 antibody was added into the bioink at a concentration of 0.4 g/ml. The effect of inhibitor and activator was estimated by qRT-PCR or ELISA.

Mice were anesthetized with pentobarbital (100 mg/kg) and received subcutaneous buprenorphine (0.1 mg/kg) preoperatively. Full-thickness scald injuries were created on paw pads with soldering station (Weller, WSD81, Germany). Mice recovered in clean cages with paper bedding to prevent irritation or infection. Mice were monitored daily and euthanized at 30 days after wounding. Mice were maintained in an Association for Assessment and Accreditation of Laboratory Animal Careaccredited animal facility, and procedures were performed with Institutional Animal Care and Use Committeeapproved protocols.

MSCs in 3D-printed constructs with PD were cultured with DMEM for 2 days and then replaced with SG medium. The SG medium was changed every 2 days, and cells were harvested on day 12. The K18+ iSGCs were sorting through flow cytometry and injected into the paw pads (1 106 cells/50 l) of the mouse burn model by using Microliter syringes (Hamilton, 7655-01, USA). Then, mice were euthanized after 14 days; feet were excised and fixed with 10% formalin (Sigma-Aldrich, USA) overnight for paraffin sections and immunohistological analysis.

The foot pads of anesthetized treated mice were first painted with 2% (w/v) iodine/ethanol solution then with starch/castor oil solution (1 g/ml) (Sigma-Aldrich, USA). After drying, 50 l of 100 M acetylcholine (Sigma-Aldrich, USA) was injected subcutaneously into paws of mice. Pictures of the mouse foot pads were taken after 5, 10, and 15 min.

All data were presented as means SEM. Statistical analyses were performed using GraphPad Prism7 statistical software (GraphPad, USA). Significant differences were calculated by analysis of variance (ANOVA), followed by the Bonferroni test when performing multiple comparisons between groups. P < 0.05 was considered as a statistically significant difference.

Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/6/10/eaaz1094/DC1

Fig. S1. Biocompatibility of 3D-bioprinted construct and cellular morphology in 2D monolayer culture.

Fig. S2. Expression of SG-specific and secretion-related markers in MSCs and SG cells in vitro.

Fig. S3. Transcriptional and translational expression of epithelial and mesenchymal markers in 3D-bioprinted cells with and without PD.

Fig. S4. Expression of N- and E-cadherin in MSCs and SG cells in 2D monolayer culture.

Fig. S5. Proteomic microarray assay of differential gene expression between PD and DD ECM in postnatal mice.

Fig. S6. GO term analysis of differentially expressed pathways.

Fig. S7. Heat maps illustrating differential expression of genes implicated in ECM organization, cell division, and gland and branch morphogenesis.

Fig. S8. The expression of Hmox1 and the concentration of CTHRC1 on treatment and the related effects on cell proliferation.

Fig. S9. The expression of K8 and K18 with Hmox1 and CTHRC1 regulation.

Table S1. Primers for qRT-PCR of all the genes.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This study was supported in part by the National Nature Science Foundation of China (81571909, 81701906, 81830064, and 81721092), the National Key Research Development Plan (2017YFC1103300), Military Logistics Research Key Project (AWS17J005), and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund (2017-JQPY-002). Author contributions: B.Y. and S.H. were responsible for the design and primary technical process, conducted the experiments, collected and analyzed data, and wrote the manuscript. Y.W. and R.W. helped perform the main experiments. Y.Z. and T.H. participated in the 3D printing. W.S. and Z.L. participated in cell experiments and postexamination. S.H. and X.F. collectively oversaw the collection of data and data interpretation and revised the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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