StemCell Therapy

What was long suspected was quietly confirmed last month: Montrealers who live in the city's poorest neighbourhoods were more likely to die from COVID-19 at the height of the pandemic.

Now community organizers and experts are turning to how to best address the underlying issues that contributed to the disproportionate impact of the pandemic on the city's lower income, more racialized neighbourhoods.

"It really sheds light on the fact that social inequalities here since long before the pandemic are still here and need to be addressed," said Vronique Nadeau-Grenier, the lead researcher on the study conducted by Montreal public health.

The study, released Oct. 13, found a clear correlation between a neighbourhood's material advantages a metric which includes education and income levels and COVID-19 mortality rates.

The public health agency recommended a multitude of changes to address the underlying disparity in the city.

Some of them can be addressed by the City of Montreal, which is set to hold its municipal electionNov. 6 and 7, and others are more complex issues that involve several levels of government.

They include an increase in pay for low-wage workers and the fostering of more stable workplaces (movement between healthcare workplaces was an early contributor to the spread of COVID-19 in Quebec), increase to the availability of affordable quality housing and improved access to social and health services in disadvantaged areas.

The findings underscore those laid out in a CBC News analysis last year after the city's first wave.

Vulnerable populations, such as people living in low-income households, with precarious employment and in underprivileged neighbourhoods, represented both the most cases and deaths linked to COVID-19.

On average, underprivileged neighbourhoods had twice the number of cases and deaths than more affluent ones.

Marjorie Villefranche, the head of Maison d'Haiti, a community organization in Montral-Nord, said the numbers confirm what she has been saying for more than a year.

"We kept saying it and no one was listening," she said. Villefranche said the pandemic highlighted the lack of services in the area.

Montral-Nord, the report found, has the highest mortality rate of any sector: three times higher than some parts of the West Island.

The borough also has the highest per capita case count in the city: 12,079 cases per 100,000 people, as of Oct. 28.

Parole d'excluEs and Hoodstock, both of which have been calling for more research on pandemic impacts, released their own survey of residents. The report found a gap in health and mental health services, and the need for improved communication with residents.

"What all this highlights is that there needs to be a massive investment for community-based organizations in these poorer neighbourhoods that would lead to better access to health care and social services," said Olivier Bonnet, head of Parole d'excluEs.

Mabel Carabali,an assistant professor in the department of social and preventative medicine at University of Montreal, who holds adjunct position at the Dalla Lana School of Public Health at the University of Toronto, said such dynamics are visible in many cities.

She said the underlying issues have been "neglected for too long" and they need to be put under the microscope long after the municipal election cycle.

In Montreal, the disparity played out during the first three waves of COVID-19. By the summer of 2021, according to the report, the disparity had subsided with the spread of COVID-19 on the decline.

Nicholas King, a professor at McGill University who conducts research in public health ethics and policy, said it would be useful to dig deeper into the causes of that levelling off.

"That may give us some clues for us intervening in the future to try to reduce inequalities in health," he said.

In the meantime, he said the government should commit to more quickly and consistently reporting on health and social inequality.

King touted community groups in the province for stepping up and into the breach by producing the data themselves when they noticed the lag.

He said while experts and governments rely on public health authorities to understand what should be done next, community groups can benefit from the data themselves.

"Often some of the most effective interventions against inequalities are bottom up."

Originally posted here:
The pandemic exposed Montreal's inequalities, and residents say it's time to tackle root causes - CBC.ca

In 2009, the U.S. Special Operations Command announced that Humans are more important than hardware. But with wearables revolutionizing sports medicine and athletics, the distinction between humans and hardware is less relevant than ever. This means that investing in wearable technology for special operations forces is now the best way to put humans first.

What might this look like? With a small population of elite warfighters in high-stress environments, Special Operations Command can lead the force in determining which wearable devices are worth the investment. The Preservation of the Force and Family program, which is already in place to improve the holistic health of special operations forces, can spearhead efforts to distribute, monitor, test, and best utilize wearables for the entire military.

A Wearable Revolution

In the last two decades, sports medicine and sports science have advanced dramatically. Athletes are now bigger, faster, and stronger due, in part, to advancements in technologies that allow them to train smarter. A critical facet of this revolution is wearable technology that offers athletes immediate and continuous feedback on an increasing number of health and performance metrics. The wearable trend started with simple Global Positioning System-enabled devices measuring steps taken in a day and heart-rate monitors allowing users to train in specific heart-rate zones. However, wearable technology is now quickly outpacing older, more expensive, and more invasive technologies. New Apple Watches, for example, allow users to bypass hospital visits by serving as both an electrocardiogram to monitor heart health and a pulse oximeter to measure blood oxygen levels in 10 seconds. Wearables rapid development is providing valuable new tools for physical therapists and healthcare professionals and eliciting optimism about the future of individualized self-care.

This revolution hasnt gone unnoticed by the Department of Defense, which is testing wearables across different military branches. The U.S. Air Force recently began using the Oura Ring, a technology worn on your finger, to more accurately determine pilots flight readiness in the morning based on their overall sleep score. Previously, pilots flight readiness was determined by hours in bed rather than the quality of sleep. However, Oura Rings offer the ability to both measure sleep quality and potentially improve sleep, making pilots fitter to fly. Additionally, the U.S. Navy regularly tests various wearable devices at the Naval Postgraduate School Human and Systems Integration laboratory to study and improve crew rest, while the U.S. Army tests wearables to study soldiers resiliency in harsh winter conditions. As wearable technology continues to progress, so do the applications and opportunities to improve service members sleep, fitness, and overall health.

Wearables Potential in Special Operations

In 2012, Special Operations Command adopted the Preservation of the Force and Family strategy. The goal was to optimize and sustain mission readiness, longevity, and performance, thereby maximizing the estimated $1.5 million investment that the military makes in each member of special operations. The strategy seeks to provide precise preventative interventions and emphasisizes holistic health across five domains: physical, cognitive, psychological, social and family, and spiritual.

Wearable technology is already improving individual physical fitness and should be a critical component in enhancing operator health across every all of these domains. Wearables currently track a host of physical and biological metrics and use algorithms to generate useful approximations of additional metrics, including sleep quality, readiness, and stress. Many wearable interfaces offer coaching to nudge users towards healthier behaviors. Leading wearables, including the Oura Ring, Apple Watch, and Whoop Strap, offer nuanced sleep and activity coaching based on users unique metrics and trends. Put simply, wearables can tell you when you are overworked and need a break.

In an organization like Special Operations Command, which demands long hours under highly stressful conditions, having a tool that provides an objective measurement of readiness is uniquely valuable. Operators are specially selected and trained for resilience to adverse physical and mental conditions. Constant adaptation to a changing environment, however, comes at a cost. But this advantageous adaptation can produce allostatic load, leading to chronic physical maladies including pain, fatigue, and compromised immunity. Reduction of allostatic load first requires identification of increased stress. Enter wearables. Wearables can provide feedback on a host of biological metrics correlated with stress, including heart-rate variability, resting heart rate, and sleep quality. This makes it possible to identify chronic physiological stress, implement nuanced interventions, and prevent the difficulties associated with allostatic overload.

Wearables can also bring benefits in the cognitive and psychological domains. The Oura Ring encourages users to monitor body signals through practices such as guided mindfulness and breathing protocols. As shown by ongoing studies at Texas A&M, mindfulness meditations and associated breathing exercises can reduce stress and improve mental health. This can be particularly useful to special operations forces in reducing combat mental illness. Paired with blast gauge data or baseline cognitive tests such as the Automated Neuropsychological Assessment Metrics, wearables may also allow the early identification and treatment of traumatic brain injury.

Mitigating Concerns

In a profession where chronic stress is so abundant that it produced the term operator syndrome, why are wearable technologies not already commonplace? For one thing, there isnt a one-size-fits-all wearable. While one wearable specializes in sleep, for example, it may not be as effective at measuring physical activity. Concerns over operational security also dampen wearable enthusiasm in the Defence Department. And for good reasons in 2018, the fitness and location tracking application Strava infamously illuminated the location of multiple overseas military bases. Similarly, privacy risks regarding collected data can cause hesitation in an increasingly connected and data-driven world. Data security and patient confidentiality are paramount concerns with aggregated health information collected from wearables, and have legal implications under the Health Insurance Portability and Accountability Act. While data is routinely stripped of identifiers, including names and addresses, it can become re-identifiable when correlated with other datasets.

Special Operations Command has an important role to play in helping to address these security and privacy concerns. Letting the Preservation of the Force and Family program lead the development of wearables can help by removing military commanders from the loop, preventing mandatory use and giving participants the power of consent. Personnel associated with this program are also trained and certified to handle protected health information, reducing the risk of a Health Insurance Portability and Accountability Act violation and relieving military commanders of such a burden. Assigning random user identifications can help to avoid the disclosure of personal data. Preservation of the Force and Family personnel can further prevent the re-identification of anonymous users by isolating the wearables data, thereby preventing their merging with larger military data sets.

While there are simple ways to mitigate the known concerns over wearables, there will always be risks, especially with the early adoption of technology. These risks should be explored, preferably in a small and competent population, to best identify and understand wearables capabilities and limitations. Implementation and open dialogue will enable the force to exploit wearables significant potential to improve holistic health.

Wearables Are Coming!

In any technological revolution, there will be resistance to adopting new technology, especially in large organizations like Special Operations Command. Nevertheless, wearable technology has taken the world by storm. Large corporations have adopted wearables into healthcare policies, and wearable tech is an $81.5 billion industry. With a smaller population that is often presented with high chronic stress, Special Operations Command has the opportunity to lead the U.S. military in the use of wearable technology. By leveraging the recent revolution in wearables, programs such as Preservation of the Force and Family can bring humans and hardware together in the safest and smartest way possible.

Maj. Kevin Butler and Maj. Frank Foss are Army Special Forces officers currently pursuing a masters in Defense Analysis at the Naval Postgraduate School. Between them, they have over a dozen combat and operational deployments to the Central Command and Southern Command.

Disclaimer: The views expressed in this article are the views of the authors alone. They do not reflect the official position of the Naval Postgraduate School, the U.S. Army, the Department of Defense, or any other entity within the U.S. government and the authors are not authorized to provide any official position of these entities.

Image: U.S. Army (Photo by Sgt. Apolonia Gaspar)

Originally posted here:
Humans and Hardware: How Special Operations Can Pioneer Wearable Technology - War on the Rocks

Nearly two years into the global pandemic, there remain a handful of approved therapies to treat COVID-19.

Dr. Dermot Kelleher

And with emerging variants threatening the effectiveness of existing vaccines, there is an ever-pressing need to find new treatment approaches to fight the disease.

At UBCs faculty of medicine, researchers Dr. Dermot Kelleher and Dr. Shane Duggan are tackling this challenge head on, redirecting elements of their groundbreaking research on esophageal disease to develop a novel aerosol treatment for COVID-19.

The global effort to intervene in the spread and severity of COVID-19 has produced several effective vaccines, but there is still a pressing need for new treatments for people who contract the virus and to safeguard the health and well-being of those who are most vulnerable to disease transmission, says Dr. Kelleher, dean of the faculty of medicine and vice-president, health at UBC.

The proposed therapyset to be delivered to the lungs as an aerosol using a handheld nebulizerwould be designed to stop the virus from replicating, halting the progression of COVID-19 in an effort to reduce harmful health effects and save lives.

The global effort to intervene in the spread and severity of COVID-19 has produced several effective vaccines, but there is still a pressing need for new treatments for people who contract the virus and to safeguard the health and well-being of those who are most vulnerable to disease transmission. Dr. Dermot Kelleher

The researchers are hopeful that the treatment could help reduce hospitalizations and one day delay or even eliminate the need for mechanical ventilators for patients who contract the disease. They also see great potential for the therapy to be used as a prophylactic, or preventative treatment, capable of temporarily reducing the risk of infection and protecting healthcare workers on the frontlines as well as others at increased risk.

This is an excellent example of the world-class biomedical research taking place at UBCs Academy of Translational Medicine (ATM), says Dr. Poul Sorensen, director of the ATM. The ATM is a powerful innovation hub dedicated to accelerating the translation of scientific discoveries into clinical practice, rapidly solving some of lifes most pressing health challengesfrom COVID-19 and cancer to diabetes and dementiabringing real and lasting hope to everyone.

This research also nicely complements the groundbreaking work underway in Dr. Josef Penningers laboratory at UBCs Life Sciences Institute (LSI), where they are examining the use of an inhalable form of the ACE2 protein to bind the virus and halt COVID-19, adds Dr. Sorensen.

Within UBCs Life Sciences Institutethe largest biomedical research institute of its kind in Canadathe research team is already hard at work in the Kelleher lab, using cutting-edge technology to identify and design molecules to target SARS-CoV-2, the virus that causes COVID-19.

Once inhaled, these specialized molecules, known as GapmeRs, would stick to the virus and degrade its DNA, thereby preventing the virus from replicating further, while limiting infection and further transmission.

Dr. Shane Duggan

Ultimately, by embracing GapmeR technology and a simple delivery system, such as a nebulizer that doesnt rely on specialized equipment, the researchers believe their approach could represent a much more cost-effective means of combatting COVID-19 and saving lives around the worldincluding harder-to-reach regions.

Its our duty as researchers to use every tool in our toolkit to advance knowledge of COVID-19 and rapidly rethink our current treatment approaches to make a direct impact on patient lives both here in Canada and around the world. Dr. Shane Duggan

Treatments based on GapmeR technology are relatively easy to manufacture and require no specialized storage or transport, which make them ideal for distributing to vulnerable communities in need, says Dr. Duggan, a research associate in the division of gastroenterology.

In the coming months, the research team, which has recently grown to include two postdoctoral fellows with expertise in virology, will begin rapidly identifying molecular candidates with the highest chance of success. Following this, they will begin working with the live virus.

In an effort to accelerate the development of the new treatment, the UBC research team will also collaborate with a group of scientists with expertise in GapmeR technologies led by Dr. Navin Verma at the Lee Kong Chian School of Medicine, Nanyang Technological University in Singapore. Through this international partnership, the team hopes to bolster the studies needed to turn their research into a clinical reality, ultimately expediting the path from bench to bedside.

Beyond COVID-19, the treatment approach has the potential to be rapidly mobilized and tailored to fight future viral outbreaksand could one day be used to help tackle other diseases, including some forms of cancer.

The beauty behind this technology is that it holds tremendous potential because its readily translatable and scalable, says Dr. Duggan.

But right now, with COVID-19 forecasted to remain for the foreseeable future, the research team remains focused on the current pandemic and accelerating an aerosol treatment to save lives.

COVID-19 has already claimed the lives of millions and impacted millions more around the world, says Dr. Duggan, who, after losing a family member to a combination of COVID-19 and liver dysfunction last year, understands the high stakes at hand more than most.

Its our duty as researchers to use every tool in our toolkit to advance knowledge of COVID-19 and rapidly rethink our current treatment approaches to make a direct impact on patient lives both here in Canada and around the world.

At UBC, this is hope, accelerated.

Read the original post:
Halting COVID-19 in its tracks - UBC Faculty of Medicine

2004 Saint Anselm alum Greg Grappone had his lifes ambitions and virtues memorialized in the form of a institute for humanities situated behind Alumni Hall.

At age 35, Grappone passed on May 1, 2015 in Seattle after complications from a graft-versus-host disease succeeding a stem cell transplant for a rare form of cancer. Grappone led his life as a father, a husband, and a son, and after graduating he found himself as the owner of his familys car dealership that stretches Route 3A in Bow, New Hampshire. The Grappone company was said to have been built upon a philanthropic reputation which parallelled the way in which Greg Grappone held himself. Grappone held a deep passion regarding cultural, social and political issues. He relished in his own personal pursuit for truth regarding these subjects, and it was because of this that he was seen as an inspiration to all. Grappone, as this type of intellect, spent much of his life grounded by lifes unanswerable questions.

Grappones consistent search to understand the world around him demonstrated a clear path in becoming a Great Books major for the Saint Anselm class of 2004. His adventures saturated in curiosity were accompanied by the stories the Great Books told; to which he viewed them as life companions rather than just educational implements Grappone luxuriated in the wisdom that these books provided and the questions and conversations that they provoked. One of Grappones professors, Father John, depicted the extent of Grappones intellectual curiosity by explaining how [Greg was] very interested in learning and eager to discuss the Great Books we read not only for their content but also for how they could help him be a better person. As a professor, it is always a pleasure to work with a student whose primary focus is learning, not grades. This pursuit of higher intellect was bolstered by Grappones person as a whole, as he was praised for, His great attitude and kindly, gentlemanly manner.

Grappones fascination for the humanities had fostered the foundation for a permanent home for the cultivation of intellect on the Saint Anselm campus. In an article to the Concord Monitor, Gregs parents, Robert and Beverly discussed how they were searching for a meaningful way to honor their sons memory, and it was at this time where Saint Anselm College was in search of enlivening their humanities department. The brevity of Grappones life ended with daily correspondence with his father and American filmmaker Ken Burns. The three would engage in conversation surrounding wisdom laid forth by Russian author and philosopher Leo Tolstoy. Because of the relationship that Grappone and Burns shared, Burns served as the honorary chair of the new humanities building campaign on campus. Grappones parents, in recognition of the importance in further the development of higher education stated, We believe that now more than ever we all need to do what we can to enlighten our minds, feed our souls and lift our spirits and those of others by heeding the instructions of Tolstoy: you have to embrace what the wisdom of humanity, your intellect and your heart tell you: that the meaning of life is to serve the force that sent you into the world. Then life becomes a joy.

Father John, in acknowledging the life lessons that Grappone exemplified as a student, stated that students could take away this lesson: Focus on learning, not on grades! Strive to be a better person today than you were yesterday. It is because based upon this mindset, that Grappone will forever be remembered at the Saint Anselm campus.

Donations can be made to the following causes that were identified as meaningful to the Grappone name, found in the Concord Monitor 2015:

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Namesake of new center a young man in love with the pursuit of knowledge - The Saint Anselm Crier

Success Story of Extracorporeal Shock Wave Therapy (ESWT)

Successful for over 40 years in urology for the disintegration of kidney stones, with high efficiency and hardly any side effects worth mentioning.

How does the shock wave work?

Without causing mechanical damage, shockwaves trigger a biological response in the treated tissue through their compressive, tensile and shear forces (mechanotransduction). Genes are activated in the cell nucleus starting to produce proteins (including growth factors) responsible for the healing process. This also causes increased ingrowth of newly formed blood vessels, which improves local metabolism. The additional modulation of the inflammation necessary for healing enables regeneration of pathological tissue.

Recent studies prove.

Shockwaves also trigger the production of messenger substances to the cell nucleus, which mobilize the body's own stem cells from the bone marrow, stimulating them to migrate to the treated tissue, settle there and develop into the required tissue (e.g. heart muscle cells). Instead of conventional stem cell transplantation shockwaves make it possible to initiate the body's own regeneration without risk of complications.

Therapy for a wide variety of tissues.

Since the underlying pathology can be treated with these methods, shockwave therapy is being used in more and more medical disciplines.

This creates a tool that opens up completely new possibilities in tissue regeneration without triggering significant side effects. Since conventional medicine has not been able to offer any significant therapeutic options to date, the present results of shockwave therapy are of particular importance and are therefore applied in the following areas. It can be assumed that shockwave therapy can be used in practically all medical specialties.

Spinal cord injury/cross-sectional lesion.

What was long considered unthinkable is now one of the major hopes for causal therapy: shockwave has also made great progress in the treatment of paraplegia. Since November 2020, the first patients have been included in an Austria-wide study. Due to the COVID pandemic, the initiation of the individual study centers has been somewhat delayed, but so far eight patients have already been enrolled in the study. In addition, the Unfallkrankenhaus Berlin, one of the most important centers for spinal cord injury in Germany, will participate in the study.

Dr. Wolfgang Schaden, adj. Prof., President of ISMST, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Deputy Medical Director of AUVA, Austria

Cardiac Surgery.

Regeneration of heart muscle after myocardial infarction has long remained a dream of modern medicine. Despite extensive efforts to develop stem cell and gene therapies, none of these methods could be brought into clinical routine. Cardiac shockwave therapy brings a scientific breakthrough: Cardiac function is improved, and impressive results show the increase of patients' quality of life. Shockwave therapy in cardiac surgery has a favorable side effect profile and is on the verge of bringing cardiac regeneration into daily clinical practice.

PD Dr. Johannes Holfeld, University Department of Cardiac Surgery, Innsbruck Medical University, Austria.

Sexual Medicine.

Low-energy shockwave therapy has been a fabulous addition to sexual medicine armamentarium for men and women with various forms of sexual dysfunction, e.g. erectile dysfunction, premature ejaculation, persistent genital arousal disorder PGAD/genito-pelvic dysesthesia GPD. Many patients (and their partners) describe these comfortable and quick shockwave treatments as life changing.

Prof. Dr. Irwin Goldstein, Alvarado Hospital, San Diego, CA, USA

Aesthetic-, hand-, burn- and reconstructive surgery.

Shockwave medicine can support these four pillars of surgery noninvasively. Two significant examples: In aesthetic surgery with significant improvement in cellulite with shockwave therapy after six to eight sessions, lasting for a period of about one year. In burns, shockwave therapy can accelerate epithelialization (healing) of superficial burn injuries clinically relevant by three days, with a significant reduction in infections and hospitalization.

Prof. Dr. Karsten Knobloch, SportPraxis Prof. Knobloch, Hanover, Secretary General of the German Shockwave Society DIGEST.

Sports Medicine.

After more than 30 years of experience, shock wave treatment is now a standard in sports medicine and rehabilitation facilities worldwide.

Leprosy.

Shockwaves used in a similar way as for diabetic foot ulcers have also led to the healing of wounds in leprosy patients and significantly improved the quality of life of these patients. This work, carried out in Agua de Dios, Colombia, by the Bosque University group in Bogot, is now being used in several medical centers around the world with very positive results.

Prof. Dr. Carlos Leal, Bosque University, Fenway Medical, Bogot, Colombia.

Wound healing.

Chronic wounds are challenging for patients concerned and practitioners and will have an increasing impact on health care systems. Treatment with shockwaves has a positive conditioning influence on the wounds and in a high proportion for healing, independent of otherwise aggravating factors (e.g. diabetes mellitus, immunosuppression, cortisone therapy, and other exacerbating factors).

With an average treatment frequency of one treatment every second week, in addition to the established wound therapy, healing was observed in more than 70% of the cases of ulcers and other wound healing disorders.The therapy is free of side effects and helps to reduce the burden of the health care system due to the enormous savings potential.

Rainer Mittermayr, MD, MBA, assoc. Prof., Treasurer of the ISMST and Conference Secretary, Senior Surgeon Orthopedic and Traumatology, AUVA (Austrian Workers Compensation Board, Vienna, Austria)

Originally posted here:
Shockwave therapy brings new healing opportunities for heart attack patients and hope for people with spinal cord injuries - KULR-TV

RICHMOND, Ind. The next Red Cross blood drive is focusing on the fight against sickle cell disease.

The local blood drive will participate in the national effort, according to Dana Mollenkopf, who has been with the local Red Cross nine years. The drive will be noon-5 p.m. Dec. 21 in the lower-level multipurpose room at Central United Methodist Church, 1425 E. Main St.

COVID-19 protocols will be followed during the blood drive, and blood samples will be tested for COVID antibodies, according to Mollenkopf. Blood samples from Black donors also will be tested for sickle cell traits, with results available to donors in one to two weeks.

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About 10% of Black people carry the sickle cell trait, according to the American Society of Hematology. Although sickle cell disease disproportionately impacts Black people, only 3% of blood donors nationwide are Black, Mollenkopf said, andBlack donors are encouraged to register for the Dec. 21 drive to help fulfill the need for blood.

Appointments may be made at redcrossblood.org with the CUMCRICH code.

As an organization dedicated to alleviating suffering, the Red Cross is committed to the health and well-being of all communities, and a diverse blood supply is critical to improving health outcomes for all patients especially those with sickle cell disease," said Gail McGovern, CEO and president of the Red Cross, in a news release. For someone facing a sickle cell crisis, a blood transfusion can make a lifesaving difference.

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Sickle cell is the most common genetic blood disease in the United States, according to the Red Cross. Patients often rely on regular blood transfusions to avoid complications such as organ and tissue damage, severe pain and strokes. The disease is only cured by stem cell or bone marrow transplants or emerging gene therapy, but such treatments are not widely available.

The blood used in those transfusions must be the most compatible match possible, which usually comes from someone of the same race or from a similar ethnicity. Donated blood will also be utilized for other emergency uses.

Go here to see the original:
Red Cross blood drive focuses on sickle cell disease fight - Palladium-Item

Discover the future of medicine

The Master of Science degree program invites you to chart the course for the medicine of the futureregenerative medicine. This is one of the first masters programs in stem cell biology and regenerative medicine in the United States.

Our one-year program offers courses in cutting-edge biomedical science, including developmental biology, human embryology, regenerative medicine, and the translational and therapeutic aspects of stem cell technology. The program also provides practical hands-on laboratory experience with the growth and differentiation of stem cells. Although not required, students are encouraged to engage in laboratory research during the year, with one of the 80+ lab groups that constitute USC Stem Cell. At the completion of the first year, students may informally continue to conduct research in their labs after receiving the MS diploma, or can petition to continue research with a guided and structured second research year culminating in a capstone thesis project.

After completing this program, you will be poised to apply to medical or PhD programs, enter the growing stem cell pharmaceutical domain, or engage in other academic, clinical or business efforts. You will possess a unique understanding of how the bodys own developmental and repair mechanisms can restore damaged cells, tissues and organsproviding new opportunities to treat conditions ranging from blindness to cancer, from organ failure to HIV/AIDS.

To apply, visit gradadm.usc.edu.

Please note that the application portal for Fall 2022 will open October 15th, 2021. The deadline to apply will be April 1st, 2022.

For questions, e-mail us at scrm@usc.edu or call (323) 865 1266.

Read more from the original source:
MS in Stem Cell Biology and Regenerative Medicine

Int J Cell Biol. 2016; 2016: 6940283.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Academic Editor: Paul J. Higgins

Received 2016 Mar 13; Accepted 2016 Jun 5.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of specific tissue and/or organ of the patients suffering with severe injuries or chronic disease conditions, in the state where bodies own regenerative responses do not suffice [1]. In the present scenario donated tissues and organs cannot meet the transplantation demands of aged and diseased populations that have driven the thrust for search for the alternatives. Stem cells are endorsed with indefinite cell division potential, can transdifferentiate into other types of cells, and have emerged as frontline regenerative medicine source in recent time, for reparation of tissues and organs anomalies occurring due to congenital defects, disease, and age associated effects [1]. Stem cells pave foundation for all tissue and organ system of the body and mediates diverse role in disease progression, development, and tissue repair processes in host. On the basis of transdifferentiation potential, stem cells are of four types, that is, (1) unipotent, (2) multipotent, (3) pluripotent, and (4) totipotent [2]. Zygote, the only totipotent stem cell in human body, can give rise to whole organism through the process of transdifferentiation, while cells from inner cells mass (ICM) of embryo are pluripotent in their nature and can differentiate into cells representing three germ layers but do not differentiate into cells of extraembryonic tissue [2]. Stemness and transdifferentiation potential of the embryonic, extraembryonic, fetal, or adult stem cells depend on functional status of pluripotency factors like OCT4, cMYC, KLF44, NANOG, SOX2, and so forth [35]. Ectopic expression or functional restoration of endogenous pluripotency factors epigenetically transforms terminally differentiated cells into ESCs-like cells [3], known as induced pluripotent stem cells (iPSCs) [3, 4]. On the basis of regenerative applications, stem cells can be categorized as embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and iPSCs (; ). The transplantation of stem cells can be autologous, allogenic, and syngeneic for induction of tissue regeneration and immunolysis of pathogen or malignant cells. For avoiding the consequences of host-versus-graft rejections, tissue typing of human leucocyte antigens (HLA) for tissue and organ transplant as well as use of immune suppressant is recommended [6]. Stem cells express major histocompatibility complex (MHC) receptor in low and secret chemokine that recruitment of endothelial and immune cells is enabling tissue tolerance at graft site [6]. The current stem cell regenerative medicine approaches are founded onto tissue engineering technologies that combine the principles of cell transplantation, material science, and microengineering for development of organoid; those can be used for physiological restoration of damaged tissue and organs. The tissue engineering technology generates nascent tissue on biodegradable 3D-scaffolds [7, 8]. The ideal scaffolds support cell adhesion and ingrowths, mimic mechanics of target tissue, support angiogenesis and neovascularisation for appropriate tissue perfusion, and, being nonimmunogenic to host, do not require systemic immune suppressant [9]. Stem cells number in tissue transplant impacts upon regenerative outcome [10]; in that case prior ex vivo expansion of transplantable stem cells is required [11]. For successful regenerative outcomes, transplanted stem cells must survive, proliferate, and differentiate in site specific manner and integrate into host circulatory system [12]. This review provides framework of most recent (; Figures ) advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells as the tool of regenerative applications in wildlife conservation.

Promises of stem cells in regenerative medicine: the six classes of stem cells, that is, embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and induced pluripotent stem cells (iPSCs), have many promises in regenerative medicine and disease therapeutics.

ESCs in regenerative medicine: ESCs, sourced from ICM of gastrula, have tremendous promises in regenerative medicine. These cells can differentiate into more than 200 types of cells representing three germ layers. With defined culture conditions, ESCs can be transformed into hepatocytes, retinal ganglion cells, chondrocytes, pancreatic progenitor cells, cone cells, cardiomyocytes, pacemaker cells, eggs, and sperms which can be used in regeneration of tissue and treatment of disease in tissue specific manner.

TSPSCs in regenerative medicine: tissue specific stem and progenitor cells have potential to differentiate into other cells of the tissue. Characteristically inner ear stem cells can be transformed into auditory hair cells, skin progenitors into vascular smooth muscle cells, mesoangioblasts into tibialis anterior muscles, and dental pulp stem cells into serotonin cells. The 3D-culture of TSPSCs in complex biomaterial gives rise to tissue organoids, such as pancreatic organoid from pancreatic progenitor, intestinal tissue organoids from intestinal progenitor cells, and fallopian tube organoids from fallopian tube epithelial cells. Transplantation of TSPSCs regenerates targets tissue such as regeneration of tibialis muscles from mesoangioblasts, cardiac tissue from AdSCs, and corneal tissue from limbal stem cells. Cell growth and transformation factors secreted by TSPSCs can change cells fate to become other types of cell, such that SSCs coculture with skin, prostate, and intestine mesenchyme transforms these cells from MSCs into epithelial cells fate.

MSCs in regenerative medicine: mesenchymal stem cells are CD73+, CD90+, CD105+, CD34, CD45, CD11b, CD14, CD19, and CD79a cells, also known as stromal cells. These bodily MSCs represented here do not account for MSCs of bone marrow and umbilical cord. Upon transplantation and transdifferentiation these bodily MSCs regenerate into cartilage, bones, and muscles tissue. Heart scar formed after heart attack and liver cirrhosis can be treated from MSCs. ECM coating provides the niche environment for MSCs to regenerate into hair follicle, stimulating hair growth.

UCSCs in regenerative medicine: umbilical cord, the readily available source of stem cells, has emerged as futuristic source for personalized stem cell therapy. Transplantation of UCSCs to Krabbe's disease patients regenerates myelin tissue and recovers neuroblastoma patients through restoring tissue homeostasis. The UCSCs organoids are readily available tissue source for treatment of neurodegenerative disease. Peritoneal fibrosis caused by long term dialysis, tendon tissue degeneration, and defective hyaline cartilage can be regenerated by UCSCs. Intravenous injection of UCSCs enables treatment of diabetes, spinal myelitis, systemic lupus erythematosus, Hodgkin's lymphoma, and congenital neuropathies. Cord blood stem cells banking avails long lasting source of stem cells for personalized therapy and regenerative medicine.

BMSCs in regenerative medicine: bone marrow, the soft sponge bone tissue that consisted of stromal, hematopoietic, and mesenchymal and progenitor stem cells, is responsible for blood formation. Even halo-HLA matched BMSCs can cure from disease and regenerate tissue. BMSCs can regenerate craniofacial tissue, brain tissue, diaphragm tissue, and liver tissue and restore erectile function and transdifferentiation monocytes. These multipotent stem cells can cure host from cancer and infection of HIV and HCV.

iPSCs in regenerative medicine: using the edge of iPSCs technology, skin fibroblasts and other adult tissues derived, terminally differentiated cells can be transformed into ESCs-like cells. It is possible that adult cells can be transformed into cells of distinct lineages bypassing the phase of pluripotency. The tissue specific defined culture can transform skin cells to become trophoblast, heart valve cells, photoreceptor cells, immune cells, melanocytes, and so forth. ECM complexation with iPSCs enables generation of tissue organoids for lung, kidney, brain, and other organs of the body. Similar to ESCs, iPSCs also can be transformed into cells representing three germ layers such as pacemaker cells and serotonin cells.

Stem cells in wildlife conservation: tissue biopsies obtained from dead and live wild animals can be either cryopreserved or transdifferentiated to other types of cells, through culture in defined culture medium or in vivo maturation. Stem cells and adult tissue derived iPSCs have great potential of regenerative medicine and disease therapeutics. Gonadal tissue procured from dead wild animals can be matured, ex vivo and in vivo for generation of sperm and egg, which can be used for assistive reproductive technology oriented captive breeding of wild animals or even for resurrection of wildlife.

Application of stem cells in regenerative medicine: stem cells (ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs) have diverse applications in tissue regeneration and disease therapeutics.

For the first time in 1998, Thomson isolated human ESCs (hESCs) [13]. ESCs are pluripotent in their nature and can give rise to more than 200 types of cells and promises for the treatment of any kinds of disease [13]. The pluripotency fate of ESCs is governed by functional dynamics of transcription factors OCT4, SOX2, NANOG, and so forth, which are termed as pluripotency factors. The two alleles of the OCT4 are held apart in pluripotency state in ESCs; phase through homologues pairing during embryogenesis and transdifferentiation processes [14] has been considered as critical regulatory switch for lineage commitment of ESCs. The diverse lineage commitment potential represents ESCs as ideal model for regenerative therapeutics of disease and tissue anomalies. This section of review on ESCs discusses transplantation and transdifferentiation of ESCs into retinal ganglion, hepatocytes, cardiomyocytes, pancreatic progenitors, chondrocytes, cones, egg sperm, and pacemaker cells (; ). Infection, cancer treatment, and accidents can cause spinal cord injuries (SCIs). The transplantation of hESCs to paraplegic or quadriplegic SCI patients improves body control, balance, sensation, and limbal movements [15], where transplanted stem cells do homing to injury sites. By birth, humans have fixed numbers of cone cells; degeneration of retinal pigment epithelium (RPE) of macula in central retina causes age-related macular degeneration (ARMD). The genomic incorporation of COCO gene (expressed during embryogenesis) in the developing embryo leads lineage commitment of ESCs into cone cells, through suppression of TGF, BMP, and Wnt signalling pathways. Transplantation of these cone cells to eye recovers individual from ARMD phenomenon, where transplanted cone cells migrate and form sheet-like structure in host retina [16]. However, establishment of missing neuronal connection of retinal ganglion cells (RGCs), cones, and PRE is the most challenging aspect of ARMD therapeutics. Recently, Donald Z Jacks group at John Hopkins University School of Medicine has generated RGCs from CRISPER-Cas9-m-Cherry reporter ESCs [17]. During ESCs transdifferentiation process, CRIPER-Cas9 directs the knock-in of m-Cherry reporter into 3UTR of BRN3B gene, which is specifically expressed in RGCs and can be used for purification of generated RGCs from other cells [17]. Furthermore, incorporation of forskolin in transdifferentiation regime boosts generation of RGCs. Coaxing of these RGCs into biomaterial scaffolds directs axonal differentiation of RGCs. Further modification in RGCs generation regime and composition of biomaterial scaffolds might enable restoration of vision for ARMD and glaucoma patients [17]. Globally, especially in India, cardiovascular problems are a more common cause of human death, where biomedical therapeutics require immediate restoration of heart functions for the very survival of the patient. Regeneration of cardiac tissue can be achieved by transplantation of cardiomyocytes, ESCs-derived cardiovascular progenitors, and bone marrow derived mononuclear cells (BMDMNCs); however healing by cardiomyocytes and progenitor cells is superior to BMDMNCs but mature cardiomyocytes have higher tissue healing potential, suppress heart arrhythmias, couple electromagnetically into hearts functions, and provide mechanical and electrical repair without any associated tumorigenic effects [18, 19]. Like CM differentiation, ESCs derived liver stem cells can be transformed into Cytp450-hepatocytes, mediating chemical modification and catabolism of toxic xenobiotic drugs [20]. Even today, availability and variability of functional hepatocytes are a major a challenge for testing drug toxicity [20]. Stimulation of ESCs and ex vivo VitK12 and lithocholic acid (a by-product of intestinal flora regulating drug metabolism during infancy) activates pregnane X receptor (PXR), CYP3A4, and CYP2C9, which leads to differentiation of ESCs into hepatocytes; those are functionally similar to primary hepatocytes, for their ability to produce albumin and apolipoprotein B100 [20]. These hepatocytes are excellent source for the endpoint screening of drugs for accurate prediction of clinical outcomes [20]. Generation of hepatic cells from ESCs can be achieved in multiple ways, as serum-free differentiation [21], chemical approaches [20, 22], and genetic transformation [23, 24]. These ESCs-derived hepatocytes are long lasting source for treatment of liver injuries and high throughput screening of drugs [20, 23, 24]. Transplantation of the inert biomaterial encapsulated hESCs-derived pancreatic progenitors (CD24+, CD49+, and CD133+) differentiates into -cells, minimizing high fat diet induced glycemic and obesity effects in mice [25] (). Addition of antidiabetic drugs into transdifferentiation regime can boost ESCs conservation into -cells [25], which theoretically can cure T2DM permanently [25]. ESCs can be differentiated directly into insulin secreting -cells (marked with GLUT2, INS1, GCK, and PDX1) which can be achieved through PDX1 mediated epigenetic reprogramming [26]. Globally, osteoarthritis affects millions of people and occurs when cartilage at joints wears away, causing stiffness of the joints. The available therapeutics for arthritis relieve symptoms but do not initiate reverse generation of cartilage. For young individuals and athletes replacement of joints is not feasible like old populations; in that case transplantation of stem cells represents an alternative for healing cartilage injuries [27]. Chondrocytes, the cartilage forming cells derived from hESC, embedded in fibrin gel effectively heal defective cartilage within 12 weeks, when transplanted to focal cartilage defects of knee joints in mice without any negative effect [27]. Transplanted chondrocytes form cell aggregates, positive for SOX9 and collagen II, and defined chondrocytes are active for more than 12wks at transplantation site, advocating clinical suitability of chondrocytes for treatment of cartilage lesions [27]. The integrity of ESCs to integrate and differentiate into electrophysiologically active cells provides a means for natural regulation of heart rhythm as biological pacemaker. Coaxing of ESCs into inert biomaterial as well as propagation in defined culture conditions leads to transdifferentiation of ESCs to become sinoatrial node (SAN) pacemaker cells (PCs) [28]. Genomic incorporation TBox3 into ESCs ex vivo leads to generation of PCs-like cells; those express activated leukocyte cells adhesion molecules (ALCAM) and exhibit similarity to PCs for gene expression and immune functions [28]. Transplantation of PCs can restore pacemaker functions of the ailing heart [28]. In summary, ESCs can be transdifferentiated into any kinds of cells representing three germ layers of the body, being most promising source of regenerative medicine for tissue regeneration and disease therapy (). Ethical concerns limit the applications of ESCs, where set guidelines need to be followed; in that case TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs can be explored as alternatives.

TSPSCs maintain tissue homeostasis through continuous cell division, but, unlike ESCs, TSPSCs retain stem cells plasticity and differentiation in tissue specific manner, giving rise to few types of cells (). The number of TSPSCs population to total cells population is too low; in that case their harvesting as well as in vitro manipulation is really a tricky task [29], to explore them for therapeutic scale. Human body has foundation from various types of TSPSCs; discussing the therapeutic application for all types is not feasible. This section of review discusses therapeutic application of pancreatic progenitor cells (PPCs), dental pulp stem cells (DPSCs), inner ear stem cells (IESCs), intestinal progenitor cells (IPCs), limbal progenitor stem cells (LPSCs), epithelial progenitor stem cells (EPSCs), mesoangioblasts (MABs), spermatogonial stem cells (SSCs), the skin derived precursors (SKPs), and adipose derived stem cells (AdSCs) (; ). During embryogenesis PPCs give rise to insulin-producing -cells. The differentiation of PPCs to become -cells is negatively regulated by insulin [30]. PPCs require active FGF and Notch signalling; growing more rapidly in community than in single cell populations advocates the functional importance of niche effect in self-renewal and transdifferentiation processes. In 3D-scaffold culture system, mice embryo derived PPCs grow into hollow organoid spheres; those finally differentiate into insulin-producing -cell clusters [29]. The DSPSCs, responsible for maintenance of teeth health status, can be sourced from apical papilla, deciduous teeth, dental follicle, and periodontal ligaments, have emerged as regenerative medicine candidate, and might be explored for treatment of various kinds of disease including restoration neurogenic functions in teeth [31, 32]. Expansion of DSPSCs in chemically defined neuronal culture medium transforms them into a mixed population of cholinergic, GABAergic, and glutaminergic neurons; those are known to respond towards acetylcholine, GABA, and glutamine stimulations in vivo. These transformed neuronal cells express nestin, glial fibrillary acidic protein (GFAP), III-tubulin, and voltage gated L-type Ca2+ channels [32]. However, absence of Na+ and K+ channels does not support spontaneous action potential generation, necessary for response generation against environmental stimulus. All together, these primordial neuronal stem cells have possible therapeutic potential for treatment of neurodental problems [32]. Sometimes, brain tumor chemotherapy can cause neurodegeneration mediated cognitive impairment, a condition known as chemobrain [33]. The intrahippocampal transplantation of human derived neuronal stem cells to cyclophosphamide behavioural decremented mice restores cognitive functions in a month time. Here the transplanted stem cells differentiate into neuronal and astroglial lineage, reduce neuroinflammation, and restore microglial functions [33]. Furthermore, transplantation of stem cells, followed by chemotherapy, directs pyramidal and granule-cell neurons of the gyrus and CA1 subfields of hippocampus which leads to reduction in spine and dendritic cell density in the brain. These findings suggest that transplantation of stem cells to cranium restores cognitive functions of the chemobrain [33]. The hair cells of the auditory system produced during development are not postmitotic; loss of hair cells cannot be replaced by inner ear stem cells, due to active state of the Notch signalling [34]. Stimulation of inner ear progenitors with -secretase inhibitor ({"type":"entrez-nucleotide","attrs":{"text":"LY411575","term_id":"1257853995","term_text":"LY411575"}}LY411575) abrogates Notch signalling through activation of transcription factor atonal homologue 1 (Atoh1) and directs transdifferentiation of progenitors into cochlear hair cells [34]. Transplantation of in vitro generated hair cells restores acoustic functions in mice, which can be the potential regenerative medicine candidates for the treatment of deafness [34]. Generation of the hair cells also can be achieved through overexpression of -catenin and Atoh1 in Lrg5+ cells in vivo [35]. Similar to ear progenitors, intestine of the digestive tract also has its own tissue specific progenitor stem cells, mediating regeneration of the intestinal tissue [34, 36]. Dysregulation of the common stem cells signalling pathways, Notch/BMP/TGF-/Wnt, in the intestinal tissue leads to disease. Information on these signalling pathways [37] is critically important in designing therapeutics. Coaxing of the intestinal tissue specific progenitors with immune cells (macrophages), connective tissue cells (myofibroblasts), and probiotic bacteria into 3D-scaffolds of inert biomaterial, crafting biological environment, is suitable for differentiation of progenitors to occupy the crypt-villi structures into these scaffolds [36]. Omental implementation of these crypt-villi structures to dogs enhances intestinal mucosa through regeneration of goblet cells containing intestinal tissue [36]. These intestinal scaffolds are close approach for generation of implantable intestinal tissue, divested by infection, trauma, cancer, necrotizing enterocolitis (NEC), and so forth [36]. In vitro culture conditions cause differentiation of intestinal stem cells to become other types of cells, whereas incorporation of valproic acid and CHIR-99021 in culture conditions avoids differentiation of intestinal stem cells, enabling generation of indefinite pool of stem cells to be used for regenerative applications [38]. The limbal stem cells of the basal limbal epithelium, marked with ABCB5, are essential for regeneration and maintenance of corneal tissue [39]. Functional status of ABCB5 is critical for survival and functional integrity of limbal stem cells, protecting them from apoptotic cell death [39]. Limbal stem cells deficiency leads to replacement of corneal epithelium with visually dead conjunctival tissue, which can be contributed by burns, inflammation, and genetic factors [40]. Transplanted human cornea stem cells to mice regrown into fully functional human cornea, possibly supported by blood eye barrier phenomena, can be used for treatment of eye diseases, where regeneration of corneal tissue is critically required for vision restoration [39]. Muscle degenerative disease like duchenne muscular dystrophy (DMD) can cause extensive thrashing of muscle tissue, where tissue engineering technology can be deployed for functional restoration of tissue through regeneration [41]. Encapsulation of mouse or human derived MABs (engineered to express placental derived growth factor (PDGF)) into polyethylene glycol (PEG) fibrinogen hydrogel and their transplantation beneath the skin at ablated tibialis anterior form artificial muscles, which are functionally similar to those of normal tibialis anterior muscles [41]. The PDGF attracts various cell types of vasculogenic and neurogenic potential to the site of transplantation, supporting transdifferentiation of mesoangioblasts to become muscle fibrils [41]. The therapeutic application of MABs in skeletal muscle regeneration and other therapeutic outcomes has been reviewed by others [42]. One of the most important tissue specific stem cells, the male germline stem cells or spermatogonial stem cells (SSCs), produces spermatogenic lineage through mesenchymal and epithets cells [43] which itself creates niche effect on other cells. In vivo transplantation of SSCs with prostate, skin, and uterine mesenchyme leads to differentiation of these cells to become epithelia of the tissue of origin [43]. These newly formed tissues exhibit all physical and physiological characteristics of prostate and skin and the physical characteristics of prostate, skin, and uterus, express tissue specific markers, and suggest that factors secreted from SSCs lead to lineage conservation which defines the importance of niche effect in regenerative medicine [43]. According to an estimate, more than 100 million people are suffering from the condition of diabetic retinopathy, a progressive dropout of vascularisation in retina that leads to loss of vision [44]. The intravitreal injection of adipose derived stem cells (AdSCs) to the eye restores microvascular capillary bed in mice. The AdSCs from healthy donor produce higher amounts of vasoprotective factors compared to glycemic mice, enabling superior vascularisation [44]. However use of AdSCs for disease therapeutics needs further standardization for cell counts in dose of transplant and monitoring of therapeutic outcomes at population scale [44]. Apart from AdSCs, other kinds of stem cells also have therapeutic potential in regenerative medicine for treatment of eye defects, which has been reviewed by others [45]. Fallopian tubes, connecting ovaries to uterus, are the sites where fertilization of the egg takes place. Infection in fallopian tubes can lead to inflammation, tissue scarring, and closure of the fallopian tube which often leads to infertility and ectopic pregnancies. Fallopian is also the site where onset of ovarian cancer takes place. The studies on origin and etiology of ovarian cancer are restricted due to lack of technical advancement for culture of epithelial cells. The in vitro 3D organoid culture of clinically obtained fallopian tube epithelial cells retains their tissue specificity, keeps cells alive, which differentiate into typical ciliated and secretory cells of fallopian tube, and advocates that ectopic examination of fallopian tube in organoid culture settings might be the ideal approach for screening of cancer [46]. The sustained growth and differentiation of fallopian TSPSCs into fallopian tube organoid depend both on the active state of the Wnt and on paracrine Notch signalling [46]. Similar to fallopian tube stem cells, subcutaneous visceral tissue specific cardiac adipose (CA) derived stem cells (AdSCs) have the potential of differentiation into cardiovascular tissue [47]. Systemic infusion of CA-AdSCs into ischemic myocardium of mice regenerates heart tissue and improves cardiac function through differentiation to endothelial cells, vascular smooth cells, and cardiomyocytes and vascular smooth cells. The differentiation and heart regeneration potential of CA-AdSCs are higher than AdSCs [48], representing CA-AdSCs as potent regenerative medicine candidates for myocardial ischemic therapy [47]. The skin derived precursors (SKPs), the progenitors of dermal papilla/hair/hair sheath, give rise to multiple tissues of mesodermal and/or ectodermal origin such as neurons, Schwann cells, adipocytes, chondrocytes, and vascular smooth muscle cells (VSMCs). VSMCs mediate wound healing and angiogenesis process can be derived from human foreskin progenitor SKPs, suggesting that SKPs derived VSMCs are potential regenerative medicine candidates for wound healing and vasculature injuries treatments [49]. In summary, TSPSCs are potentiated with tissue regeneration, where advancement in organoid culture (; ) technologies defines the importance of niche effect in tissue regeneration and therapeutic outcomes of ex vivo expanded stem cells.

MSCs, the multilineage stem cells, differentiate only to tissue of mesodermal origin, which includes tendons, bone, cartilage, ligaments, muscles, and neurons [50]. MSCs are the cells which express combination of markers: CD73+, CD90+, CD105+, CD11b, CD14, CD19, CD34, CD45, CD79a, and HLA-DR, reviewed elsewhere [50]. The application of MSCs in regenerative medicine can be generalized from ongoing clinical trials, phasing through different state of completions, reviewed elsewhere [90]. This section of review outlines the most recent representative applications of MSCs (; ). The anatomical and physiological characteristics of both donor and receiver have equal impact on therapeutic outcomes. The bone marrow derived MSCs (BMDMSCs) from baboon are morphologically and phenotypically similar to those of bladder stem cells and can be used in regeneration of bladder tissue. The BMDMSCs (CD105+, CD73+, CD34, and CD45), expressing GFP reporter, coaxed with small intestinal submucosa (SIS) scaffolds, augment healing of degenerated bladder tissue within 10wks of the transplantation [51]. The combinatorial CD characterized MACs are functionally active at transplantation site, which suggests that CD characterization of donor MSCs yields superior regenerative outcomes [51]. MSCs also have potential to regenerate liver tissue and treat liver cirrhosis, reviewed elsewhere [91]. The regenerative medicinal application of MSCs utilizes cells in two formats as direct transplantation or first transdifferentiation and then transplantation; ex vivo transdifferentiation of MSCs deploys retroviral delivery system that can cause oncogenic effect on cells. Nonviral, NanoScript technology, comprising utility of transcription factors (TFs) functionalized gold nanoparticles, can target specific regulatory site in the genome effectively and direct differentiation of MSCs into another cell fate, depending on regime of TFs. For example, myogenic regulatory factor containing NanoScript-MRF differentiates the adipose tissue derived MSCs into muscle cells [92]. The multipotency characteristics represent MSCs as promising candidate for obtaining stable tissue constructs through coaxed 3D organoid culture; however heterogeneous distribution of MSCs slows down cell proliferation, rendering therapeutic applications of MSCs. Adopting two-step culture system for MSCs can yield homogeneous distribution of MSCs in biomaterial scaffolds. For example, fetal-MSCs coaxed in biomaterial when cultured first in rotating bioreactor followed with static culture lead to homogeneous distribution of MSCs in ECM components [7]. Occurrence of dental carries, periodontal disease, and tooth injury can impact individual's health, where bioengineering of teeth can be the alternative option. Coaxing of epithelial-MSCs with dental stem cells into synthetic polymer gives rise to mature teeth unit, which consisted of mature teeth and oral tissue, offering multiple regenerative therapeutics, reviewed elsewhere [52]. Like the tooth decay, both human and animals are prone to orthopedic injuries, affecting bones, joint, tendon, muscles, cartilage, and so forth. Although natural healing potential of bone is sufficient to heal the common injuries, severe trauma and tumor-recession can abrogate germinal potential of bone-forming stem cells. In vitro chondrogenic, osteogenic, and adipogenic potential of MSCs advocates therapeutic applications of MSCs in orthopedic injuries [53]. Seeding of MSCs, coaxed into biomaterial scaffolds, at defective bone tissue, regenerates defective bone tissues, within fourwks of transplantation; by the end of 32wks newly formed tissues integrate into old bone [54]. Osteoblasts, the bone-forming cells, have lesser actin cytoskeleton compared to adipocytes and MSCs. Treatment of MSCs with cytochalasin-D causes rapid transportation of G-actin, leading to osteogenic transformation of MSCs. Furthermore, injection of cytochalasin-D to mice tibia also promotes bone formation within a wk time frame [55]. The bone formation processes in mice, dog, and human are fundamentally similar, so outcomes of research on mice and dogs can be directional for regenerative application to human. Injection of MSCs to femur head of Legg-Calve-Perthes suffering dog heals the bone very fast and reduces the injury associated pain [55]. Degeneration of skeletal muscle and muscle cramps are very common to sledge dogs, animals, and individuals involved in adventurous athletics activities. Direct injection of adipose tissue derived MSCs to tear-site of semitendinosus muscle in dogs heals injuries much faster than traditional therapies [56]. Damage effect treatment for heart muscle regeneration is much more complex than regeneration of skeletal muscles, which needs high grade fine-tuned coordination of neurons with muscles. Coaxing of MSCs into alginate gel increases cell retention time that leads to releasing of tissue repairing factors in controlled manner. Transplantation of alginate encapsulated cells to mice heart reduces scar size and increases vascularisation, which leads to restoration of heart functions. Furthermore, transplanted MSCs face host inhospitable inflammatory immune responses and other mechanical forces at transplantation site, where encapsulation of cells keeps them away from all sorts of mechanical forces and enables sensing of host tissue microenvironment, and respond accordingly [57]. Ageing, disease, and medicine consumption can cause hair loss, known as alopecia. Although alopecia has no life threatening effects, emotional catchments can lead to psychological disturbance. The available treatments for alopecia include hair transplantation and use of drugs, where drugs are expensive to afford and generation of new hair follicle is challenging. Dermal papillary cells (DPCs), the specialized MSCs localized in hair follicle, are responsible for morphogenesis of hair follicle and hair cycling. The layer-by-layer coating of DPCs, called GAG coating, consists of coating of geletin as outer layer, middle layer of fibroblast growth factor 2 (FGF2) loaded alginate, and innermost layer of geletin. GAG coating creates tissue microenvironment for DPCs that can sustain immunological and mechanical obstacles, supporting generation of hair follicle. Transplantation of GAG-coated DPCs leads to abundant hair growth and maturation of hair follicle, where GAG coating serves as ECM, enhancing intrinsic therapeutic potential of DPCs [58]. During infection, the inflammatory cytokines secreted from host immune cells attract MSCs to the site of inflammation, which modulates inflammatory responses, representing MSCs as key candidate of regenerative medicine for infectious disease therapeutics. Coculture of macrophages (M) and adipose derived MSCs from Leishmania major (LM) susceptible and resistant mice demonstrates that AD-MSCs educate M against LM infection, differentially inducing M1 and M2 phenotype that represents AD-MSC as therapeutic agent for leishmanial therapy [93]. In summary, the multilineage differentiation potential of MSCs, as well as adoption of next-generation organoid culture system, avails MSCs as ideal regenerative medicine candidate.

Umbilical cord, generally thrown at the time of child birth, is the best known source for stem cells, procured in noninvasive manner, having lesser ethical constraints than ESCs. Umbilical cord is rich source of hematopoietic stem cells (HSCs) and MSCs, which possess enormous regeneration potential [94] (; ). The HSCs of cord blood are responsible for constant renewal of all types of blood cells and protective immune cells. The proliferation of HSCs is regulated by Musashi-2 protein mediated attenuation of Aryl hydrocarbon receptor (AHR) signalling in stem cells [95]. UCSCs can be cryopreserved at stem cells banks (; ), in operation by both private and public sector organization. Public stem cells banks operate on donation formats and perform rigorous screening for HLA typing and donated UCSCs remain available to anyone in need, whereas private stem cell banks operation is more personalized, availing cells according to donor consent. Stem cell banking is not so common, even in developed countries. Survey studies find that educated women are more eager to donate UCSCs, but willingness for donation decreases with subsequent deliveries, due to associated cost and safety concerns for preservation [96]. FDA has approved five HSCs for treatment of blood and other immunological complications [97]. The amniotic fluid, drawn during pregnancy for standard diagnostic purposes, is generally discarded without considering its vasculogenic potential. UCSCs are the best alternatives for those patients who lack donors with fully matched HLA typing for peripheral blood and PBMCs and bone marrow [98]. One major issue with UCSCs is number of cells in transplant, fewer cells in transplant require more time for engraftment to mature, and there are also risks of infection and mortality; in that case ex vivo propagation of UCSCs can meet the demand of desired outcomes. There are diverse protocols, available for ex vivo expansion of UCSCs, reviewed elsewhere [99]. Amniotic fluid stem cells (AFSCs), coaxed to fibrin (required for blood clotting, ECM interactions, wound healing, and angiogenesis) hydrogel and PEG supplemented with vascular endothelial growth factor (VEGF), give rise to vascularised tissue, when grafted to mice, suggesting that organoid cultures of UCSCs have promise for generation of biocompatible tissue patches, for treating infants born with congenital heart defects [59]. Retroviral integration of OCT4, KLF4, cMYC, and SOX2 transforms AFSCs into pluripotency stem cells known as AFiPSCs which can be directed to differentiate into extraembryonic trophoblast by BMP2 and BMP4 stimulation, which can be used for regeneration of placental tissues [60]. Wharton's jelly (WJ), the gelatinous substance inside umbilical cord, is rich in mucopolysaccharides, fibroblast, macrophages, and stem cells. The stem cells from UCB and WJ can be transdifferentiated into -cells. Homogeneous nature of WJ-SCs enables better differentiation into -cells; transplantation of these cells to streptozotocin induced diabetic mice efficiently brings glucose level to normal [7]. Easy access and expansion potential and plasticity to differentiate into multiple cell lineages represent WJ as an ideal candidate for regenerative medicine but cells viability changes with passages with maximum viable population at 5th-6th passages. So it is suggested to perform controlled expansion of WJ-MSCS for desired regenerative outcomes [9]. Study suggests that CD34+ expression leads to the best regenerative outcomes, with less chance of host-versus-graft rejection. In vitro expansion of UCSCs, in presence of StemRegenin-1 (SR-1), conditionally expands CD34+ cells [61]. In type I diabetic mellitus (T1DM), T-cell mediated autoimmune destruction of pancreatic -cells occurs, which has been considered as tough to treat. Transplantation of WJ-SCs to recent onset-T1DM patients restores pancreatic function, suggesting that WJ-MSCs are effective in regeneration of pancreatic tissue anomalies [62]. WJ-MSCs also have therapeutic importance for treatment of T2DM. A non-placebo controlled phase I/II clinical trial demonstrates that intravenous and intrapancreatic endovascular injection of WJ-MSCs to T2DM patients controls fasting glucose and glycated haemoglobin through improvement of -cells functions, evidenced by enhanced c-peptides and reduced inflammatory cytokines (IL-1 and IL-6) and T-cells counts [63]. Like diabetes, systematic lupus erythematosus (SLE) also can be treated with WJ-MSCs transplantation. During progression of SLE host immune system targets its own tissue leading to degeneration of renal, cardiovascular, neuronal, and musculoskeletal tissues. A non-placebo controlled follow-up study on 40 SLE patients demonstrates that intravenous infusion of WJ-MSC improves renal functions and decreases systematic lupus erythematosus disease activity index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), and repeated infusion of WJ-MSCs protects the patient from relapse of the disease [64]. Sometimes, host inflammatory immune responses can be detrimental for HSCs transplantation and blood transfusion procedures. Infusion of WJ-MSC to patients, who had allogenic HSCs transplantation, reduces haemorrhage inflammation (HI) of bladder, suggesting that WJ-MSCs are potential stem cells adjuvant in HSCs transplantation and blood transfusion based therapies [100]. Apart from WJ, umbilical cord perivascular space and cord vein are also rich source for obtaining MSCs. The perivascular MSCs of umbilical cord are more primitive than WJ-MSCs and other MSCs from cord suggest that perivascular MSCs might be used as alternatives for WJ-MSCs for regenerative therapeutics outcome [101]. Based on origin, MSCs exhibit differential in vitro and in vivo properties and advocate functional characterization of MSCs, prior to regenerative applications. Emerging evidence suggests that UCSCs can heal brain injuries, caused by neurodegenerative diseases like Alzheimer's, Krabbe's disease, and so forth. Krabbe's disease, the infantile lysosomal storage disease, occurs due to deficiency of myelin synthesizing enzyme (MSE), affecting brain development and cognitive functions. Progression of neurodegeneration finally leads to death of babies aged two. Investigation shows that healing of peripheral nervous system (PNS) and central nervous system (CNS) tissues with Krabbe's disease can be achieved by allogenic UCSCs. UCSCs transplantation to asymptomatic infants with subsequent monitoring for 46 years reveals that UCSCs recover babies from MSE deficiency, improving myelination and cognitive functions, compared to those of symptomatic babies. The survival rate of transplanted UCSCs in asymptomatic and symptomatic infants was 100% and 43%, respectively, suggesting that early diagnosis and timely treatment are critical for UCSCs acceptance for desired therapeutic outcomes. UCSCs are more primitive than BMSCs, so perfect HLA typing is not critically required, representing UCSCs as an excellent source for treatment of all the diseases involving lysosomal defects, like Krabbe's disease, hurler syndrome, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Tay-Sachs disease (TSD), and Sandhoff disease [65]. Brain injuries often lead to cavities formation, which can be treated from neuronal parenchyma, generated ex vivo from UCSCs. Coaxing of UCSCs into human originated biodegradable matrix scaffold and in vitro expansion of cells in defined culture conditions lead to formation of neuronal organoids, within threewks' time frame. These organoids structurally resemble brain tissue and consisted of neuroblasts (GFAP+, Nestin+, and Ki67+) and immature stem cells (OCT4+ and SOX2+). The neuroblasts of these organoids further can be differentiated into mature neurons (MAP2+ and TUJ1+) [66]. Administration of high dose of drugs in divesting neuroblastoma therapeutics requires immediate restoration of hematopoiesis. Although BMSCs had been promising in restoration of hematopoiesis UCSCs are sparely used in clinical settings. A case study demonstrates that neuroblastoma patients who received autologous UCSCs survive without any associated side effects [12]. During radiation therapy of neoplasm, spinal cord myelitis can occur, although occurrence of myelitis is a rare event and usually such neurodegenerative complication of spinal cord occurs 624 years after exposure to radiations. Transplantation of allogenic UC-MSCs in laryngeal patients undergoing radiation therapy restores myelination [102]. For treatment of neurodegenerative disease like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), traumatic brain injuries (TBI), Parkinson's, SCI, stroke, and so forth, distribution of transplanted UCSCs is critical for therapeutic outcomes. In mice and rat, injection of UCSCs and subsequent MRI scanning show that transplanted UCSCs migrate to CNS and multiple peripheral organs [67]. For immunomodulation of tumor cells disease recovery, transplantation of allogenic DCs is required. The CD11c+DCs, derived from UCB, are morphologically and phenotypically similar to those of peripheral blood derived CTLs-DCs, suggesting that UCB-DCs can be used for personalized medicine of cancer patient, in need for DCs transplantation [103]. Coculture of UCSCs with radiation exposed human lung fibroblast stops their transdifferentiation, which suggests that factors secreted from UCSCs may restore niche identity of fibroblast, if they are transplanted to lung after radiation therapy [104]. Tearing of shoulder cuff tendon can cause severe pain and functional disability, whereas ultrasound guided transplantation of UCB-MSCs in rabbit regenerates subscapularis tendon in fourwks' time frame, suggesting that UCB-MSCs are effective enough to treat tendons injuries when injected to focal points of tear-site [68]. Furthermore, transplantation of UCB-MSCs to chondral cartilage injuries site in pig knee along with HA hydrogel composite regenerates hyaline cartilage [69], suggesting that UCB-MSCs are effective regenerative medicine candidate for treating cartilage and ligament injuries. Physiologically circulatory systems of brain, placenta, and lungs are similar. Infusion of UCB-MSCs to preeclampsia (PE) induced hypertension mice reduces the endotoxic effect, suggesting that UC-MSCs are potential source for treatment of endotoxin induced hypertension during pregnancy, drug abuse, and other kinds of inflammatory shocks [105]. Transplantation of UCSCs to severe congenital neutropenia (SCN) patients restores neutrophils count from donor cells without any side effect, representing UCSCs as potential alternative for SCN therapy, when HLA matched bone marrow donors are not accessible [106]. In clinical settings, the success of myocardial infarction (MI) treatment depends on ageing, systemic inflammation in host, and processing of cells for infusion. Infusion of human hyaluronan hydrogel coaxed UCSCs in pigs induces angiogenesis, decreases scar area, improves cardiac function at preclinical level, and suggests that the same strategy might be effective for human [107]. In stem cells therapeutics, UCSCs transplantation can be either autologous or allogenic. Sometimes, the autologous UCSCs transplants cannot combat over tumor relapse, observed in Hodgkin's lymphoma (HL), which might require second dose transplantation of allogenic stem cells, but efficacy and tolerance of stem cells transplant need to be addressed, where tumor replace occurs. A case study demonstrates that second dose allogenic transplants of UCSCs effective for HL patients, who had heavy dose in prior transplant, increase the long term survival chances by 30% [10]. Patients undergoing long term peritoneal renal dialysis are prone to peritoneal fibrosis and can change peritoneal structure and failure of ultrafiltration processes. The intraperitoneal (IP) injection of WJ-MSCs prevents methylglyoxal induced programmed cell death and peritoneal wall thickening and fibrosis, suggesting that WJ-MSCs are effective in therapeutics of encapsulating peritoneal fibrosis [70]. In summary, UCB-HSCs, WJ-MSCs, perivascular MSCs, and UCB-MSCs have tissue regeneration potential.

Bone marrow found in soft spongy bones is responsible for formation of all peripheral blood and comprises hematopoietic stem cells (producing blood cells) and stromal cells (producing fat, cartilage, and bones) [108] (; ). Visually bone marrow has two types, red marrow (myeloid tissue; producing RBC, platelets, and most of WBC) and yellow marrow (producing fat cells and some WBC) [108]. Imbalance in marrow composition can culminate to the diseased condition. Since 1980, bone marrow transplantation is widely accepted for cancer therapeutics [109]. In order to avoid graft rejection, HLA typing of donors is a must, but completely matched donors are limited to family members, which hampers allogenic transplantation applications. Since matching of all HLA antigens is not critically required, in that case defining the critical antigens for haploidentical allogenic donor for patients, who cannot find fully matched donor, might relieve from donor constraints. Two-step administration of lymphoid and myeloid BMSCs from haploidentical donor to the patients of aplastic anaemia and haematological malignancies reconstructs host immune system and the outcomes are almost similar to fully matched transplants, which recommends that profiling of critically important HLA is sufficient for successful outcomes of BMSCs transplantation. Haploidentical HLA matching protocol is the major process for minorities and others who do not have access to matched donor [71]. Furthermore, antigen profiling is not the sole concern for BMSCs based therapeutics. For example, restriction of HIV1 (human immune deficiency virus) infection is not feasible through BMSCs transplantation because HIV1 infection is mediated through CD4+ receptors, chemokine CXC motif receptor 4 (CXCR4), and chemokine receptor 5 (CCR5) for infecting and propagating into T helper (Th), monocytes, macrophages, and dendritic cells (DCs). Genetic variation in CCR2 and CCR5 receptors is also a contributory factor; mediating protection against infection has been reviewed elsewhere [110]. Engineering of hematopoietic stem and progenitor cells (HSPCs) derived CD4+ cells to express HIV1 antagonistic RNA, specifically designed for targeting HIV1 genome, can restrict HIV1 infection, through immune elimination of latently infected CD4+ cells. A single dose infusion of genetically modified (GM), HIV1 resistant HSPCs can be the alternative of HIV1 retroviral therapy. In the present scenario stem cells source, patient selection, transplantation-conditioning regimen, and postinfusion follow-up studies are the major factors, which can limit application of HIV1 resistant GM-HSPCs (CD4+) cells application in AIDS therapy [72, 73]. Platelets, essential for blood clotting, are formed from megakaryocytes inside the bone marrow [74]. Due to infection, trauma, and cancer, there are chances of bone marrow failure. To an extent, spongy bone marrow microenvironment responsible for lineage commitment can be reconstructed ex vivo [75]. The ex vivo constructed 3D-scaffolds consisted of microtubule and silk sponge, flooded with chemically defined organ culture medium, which mimics bone marrow environment. The coculture of megakaryocytes and embryonic stem cells (ESCs) in this microenvironment leads to generation of functional platelets from megakaryocytes [75]. The ex vivo 3D-scaffolds of bone microenvironment can stride the path for generation of platelets in therapeutic quantities for regenerative medication of burns [75] and blood clotting associated defects. Accidents, traumatic injuries, and brain stroke can deplete neuronal stem cells (NSCs), responsible for generation of neurons, astrocytes, and oligodendrocytes. Brain does not repopulate NSCs and heal traumatic injuries itself and transplantation of BMSCs also can heal neurodegeneration alone. Lipoic acid (LA), a known pharmacological antioxidant compound used in treatment of diabetic and multiple sclerosis neuropathy when combined with BMSCs, induces neovascularisation at focal cerebral injuries, within 8wks of transplantation. Vascularisation further attracts microglia and induces their colonization into scaffold, which leads to differentiation of BMSCs to become brain tissue, within 16wks of transplantation. In this approach, healing of tissue directly depends on number of BMSCs in transplantation dose [76]. Dental caries and periodontal disease are common craniofacial disease, often requiring jaw bone reconstruction after removal of the teeth. Traditional therapy focuses on functional and structural restoration of oral tissue, bone, and teeth rather than biological restoration, but BMSCs based therapies promise for regeneration of craniofacial bone defects, enabling replacement of missing teeth in restored bones with dental implants. Bone marrow derived CD14+ and CD90+ stem and progenitor cells, termed as tissue repair cells (TRC), accelerate alveolar bone regeneration and reconstruction of jaw bone when transplanted in damaged craniofacial tissue, earlier to oral implants. Hence, TRC therapy reduces the need of secondary bone grafts, best suited for severe defects in oral bone, skin, and gum, resulting from trauma, disease, or birth defects [77]. Overall, HSCs have great value in regenerative medicine, where stem cells transplantation strategies explore importance of niche in tissue regeneration. Prior to transplantation of BMSCs, clearance of original niche from target tissue is necessary for generation of organoid and organs without host-versus-graft rejection events. Some genetic defects can lead to disorganization of niche, leading to developmental errors. Complementation with human blastocyst derived primary cells can restore niche function of pancreas in pigs and rats, which defines the concept for generation of clinical grade human pancreas in mice and pigs [111]. Similar to other organs, diaphragm also has its own niche. Congenital defects in diaphragm can affect diaphragm functions. In the present scenario functional restoration of congenital diaphragm defects by surgical repair has risk of reoccurrence of defects or incomplete restoration [8]. Decellularization of donor derived diaphragm offers a way for reconstruction of new and functionally compatible diaphragm through niche modulation. Tissue engineering technology based decellularization of diaphragm and simultaneous perfusion of bone marrow mesenchymal stem cells (BM-MSCs) facilitates regeneration of functional scaffolds of diaphragm tissues [8]. In vivo replacement of hemidiaphragm in rats with reseeded scaffolds possesses similar myography and spirometry as it has in vivo in donor rats. These scaffolds retaining natural architecture are devoid of immune cells, retaining intact extracellular matrix that supports adhesion, proliferation, and differentiation of seeded cells [8]. These findings suggest that cadaver obtained diaphragm, seeded with BM-MSCs, can be used for curing patients in need for restoration of diaphragm functions (; ). However, BMSCs are heterogeneous population, which might result in differential outcomes in clinical settings; however clonal expansion of BMSCs yields homogenous cells population for therapeutic application [8]. One study also finds that intracavernous delivery of single clone BMSCs can restore erectile function in diabetic mice [112] and the same strategy might be explored for adult human individuals. The infection of hepatitis C virus (HCV) can cause liver cirrhosis and degeneration of hepatic tissue. The intraparenchymal transplantation of bone marrow mononuclear cells (BMMNCs) into liver tissue decreases aspartate aminotransferase (AST), alanine transaminase (ALT), bilirubin, CD34, and -SMA, suggesting that transplanted BMSCs restore hepatic functions through regeneration of hepatic tissues [113]. In order to meet the growing demand for stem cells transplantation therapy, donor encouragement is always required [8]. The stem cells donation procedure is very simple; with consent donor gets an injection of granulocyte-colony stimulating factor (G-CSF) that increases BMSCs population. Bone marrow collection is done from hip bone using syringe in 4-5hrs, requiring local anaesthesia and within a wk time frame donor gets recovered donation associated weakness.

The field of iPSCs technology and research is new to all other stem cells research, emerging in 2006 when, for the first time, Takahashi and Yamanaka generated ESCs-like cells through genetic incorporation of four factors, Sox2, Oct3/4, Klf4, and c-Myc, into skin fibroblast [3]. Due to extensive nuclear reprogramming, generated iPSCs are indistinguishable from ESCs, for their transcriptome profiling, epigenetic markings, and functional competence [3], but use of retrovirus in transdifferentiation approach has questioned iPSCs technology. Technological advancement has enabled generation of iPSCs from various kinds of adult cells phasing through ESCs or direct transdifferentiation. This section of review outlines most recent advancement in iPSC technology and regenerative applications (; ). Using the new edge of iPSCs technology, terminally differentiated skin cells directly can be transformed into kidney organoids [114], which are functionally and structurally similar to those of kidney tissue in vivo. Up to certain extent kidneys heal themselves; however natural regeneration potential cannot meet healing for severe injuries. During kidneys healing process, a progenitor stem cell needs to become 20 types of cells, required for waste excretion, pH regulation, and restoration of water and electrolytic ions. The procedure for generation of kidney organoids ex vivo, containing functional nephrons, has been identified for human. These ex vivo kidney organoids are similar to fetal first-trimester kidneys for their structure and physiology. Such kidney organoids can serve as model for nephrotoxicity screening of drugs, disease modelling, and organ transplantation. However generation of fully functional kidneys is a far seen event with today's scientific technologies [114]. Loss of neurons in age-related macular degeneration (ARMD) is the common cause of blindness. At preclinical level, transplantation of iPSCs derived neuronal progenitor cells (NPCs) in rat limits progression of disease through generation of 5-6 layers of photoreceptor nuclei, restoring visual acuity [78]. The various approaches of iPSCs mediated retinal regeneration including ARMD have been reviewed elsewhere [79]. Placenta, the cordial connection between mother and developing fetus, gets degenerated in certain pathophysiological conditions. Nuclear programming of OCT4 knock-out (KO) and wild type (WT) mice fibroblast through transient expression of GATA3, EOMES, TFAP2C, and +/ cMYC generates transgene independent trophoblast stem-like cells (iTSCs), which are highly similar to blastocyst derived TSCs for DNA methylation, H3K7ac, nucleosome deposition of H2A.X, and other epigenetic markings. Chimeric differentiation of iTSCs specifically gives rise to haemorrhagic lineages and placental tissue, bypassing pluripotency phase, opening an avenue for generation of fully functional placenta for human [115]. Neurodegenerative disease like Alzheimer's and obstinate epilepsies can degenerate cerebrum, controlling excitatory and inhibitory signals of the brain. The inhibitory tones in cerebral cortex and hippocampus are accounted by -amino butyric acid secreting (GABAergic) interneurons (INs). Loss of these neurons often leads to progressive neurodegeneration. Genomic integration of Ascl1, Dlx5, Foxg1, and Lhx6 to mice and human fibroblast transforms these adult cells into GABAergic-INs (iGABA-INs). These cells have molecular signature of telencephalic INs, release GABA, and show inhibition to host granule neuronal activity [81]. Transplantation of these INs in developing embryo cures from genetic and acquired seizures, where transplanted cells disperse and mature into functional neuronal circuits as local INs [82]. Dorsomorphin and SB-431542 mediated inhibition of TGF- and BMP signalling direct transformation of human iPSCs into cortical spheroids. These cortical spheroids consisted of both peripheral and cortical neurons, surrounded by astrocytes, displaying transcription profiling and electrophysiology similarity with developing fetal brain and mature neurons, respectively [83]. The underlying complex biology and lack of clear etiology and genetic reprogramming and difficulty in recapitulation of brain development have barred understanding of pathophysiology of autism spectrum disorder (ASD) and schizophrenia. 3D organoid cultures of ASD patient derived iPSC generate miniature brain organoid, resembling fetal brain few months after gestation. The idiopathic conditions of these organoids are similar with brain of ASD patients; both possess higher inhibitory GABAergic neurons with imbalanced neuronal connection. Furthermore these organoids express forkhead Box G1 (FOXG1) much higher than normal brain tissue, which explains that FOXG1 might be the leading cause of ASD [84]. Degeneration of other organs and tissues also has been reported, like degeneration of lungs which might occur due to tuberculosis infection, fibrosis, and cancer. The underlying etiology for lung degeneration can be explained through organoid culture. Coaxing of iPSC into inert biomaterial and defined culture leads to formation of lung organoids that consisted of epithelial and mesenchymal cells, which can survive in culture for months. These organoids are miniature lung, resemble tissues of large airways and alveoli, and can be used for lung developmental studies and screening of antituberculosis and anticancer drugs [87]. The conventional multistep reprogramming for iPSCs consumes months of time, while CRISPER-Cas9 system based episomal reprogramming system that combines two steps together enables generation of ESCs-like cells in less than twowks, reducing the chances of culture associated genetic abrasions and unwanted epigenetic [80]. This approach can yield single step ESCs-like cells in more personalized way from adults with retinal degradation and infants with severe immunodeficiency, involving correction for genetic mutation of OCT4 and DNMT3B [80]. The iPSCs expressing anti-CCR5-RNA, which can be differentiated into HIV1 resistant macrophages, have applications in AIDS therapeutics [88]. The diversified immunotherapeutic application of iPSCs has been reviewed elsewhere [89]. The -1 antitrypsin deficiency (A1AD) encoded by serpin peptidase inhibitor clade A member 1 (SERPINA1) protein synthesized in liver protects lungs from neutrophils elastase, the enzyme causing disruption of lungs connective tissue. A1AD deficiency is common cause of both lung and liver disease like chronic obstructive pulmonary disease (COPD) and liver cirrhosis. Patient specific iPSCs from lung and liver cells might explain pathophysiology of A1AD deficiency. COPD patient derived iPSCs show sensitivity to toxic drugs which explains that actual patient might be sensitive in similar fashion. It is known that A1AD deficiency is caused by single base pair mutation and correction of this mutation fixes the A1AD deficiency in hepatic-iPSCs [85]. The high order brain functions, like emotions, anxiety, sleep, depression, appetite, breathing heartbeats, and so forth, are regulated by serotonin neurons. Generation of serotonin neurons occurs prior to birth, which are postmitotic in their nature. Any sort of developmental defect and degeneration of serotonin neurons might lead to neuronal disorders like bipolar disorder, depression, and schizophrenia-like psychiatric conditions. Manipulation of Wnt signalling in human iPSCs in defined culture conditions leads to an in vitro differentiation of iPSCs to serotonin-like neurons. These iPSCs-neurons primarily localize to rhombomere 2-3 segment of rostral raphe nucleus, exhibit electrophysiological properties similar to serotonin neurons, express hydroxylase 2, the developmental marker, and release serotonin in dose and time dependent manner. Transplantation of these neurons might cure from schizophrenia, bipolar disorder, and other neuropathological conditions [116]. The iPSCs technology mediated somatic cell reprogramming of ventricular monocytes results in generation of cells, similar in morphology and functionality with PCs. SA note transplantation of PCs to large animals improves rhythmic heart functions. Pacemaker needs very reliable and robust performance so understanding of transformation process and site of transplantation are the critical aspect for therapeutic validation of iPSCs derived PCs [28]. Diabetes is a major health concern in modern world, and generation of -cells from adult tissue is challenging. Direct reprogramming of skin cells into pancreatic cells, bypassing pluripotency phase, can yield clinical grade -cells. This reprogramming strategy involves transformation of skin cells into definitive endodermal progenitors (cDE) and foregut like progenitor cells (cPF) intermediates and subsequent in vitro expansion of these intermediates to become pancreatic -cells (cPB). The first step is chemically complex and can be understood as nonepisomal reprogramming on day one with pluripotency factors (OCT4, SOX2, KLF4, and hair pin RNA against p53), then supplementation with GFs and chemical supplements on day seven (EGF, bFGF, CHIR, NECA, NaB, Par, and RG), and two weeks later (Activin-A, CHIR, NECA, NaB, and RG) yielding DE and cPF [86]. Transplantation of cPB yields into glucose stimulated secretion of insulin in diabetic mice defines that such cells can be explored for treatment of T1DM and T2DM in more personalized manner [86]. iPSCs represent underrated opportunities for drug industries and clinical research laboratories for development of therapeutics, but safety concerns might limit transplantation applications (; ) [117]. Transplantation of human iPSCs into mice gastrula leads to colonization and differentiation of cells into three germ layers, evidenced with clinical developmental fat measurements. The acceptance of human iPSCs by mice gastrula suggests that correct timing and appropriate reprogramming regime might delimit human mice species barrier. Using this fact of species barrier, generation of human organs in closely associated primates might be possible, which can be used for treatment of genetic factors governed disease at embryo level itself [118]. In summary, iPSCs are safe and effective for treatment of regenerative medicine.

The unstable growth of human population threatens the existence of wildlife, through overexploitation of natural habitats and illegal killing of wild animals, leading many species to face the fate of being endangered and go for extinction. For wildlife conservation, the concept of creation of frozen zoo involves preservation of gene pool and germ plasm from threatened and endangered species (). The frozen zoo tissue samples collection from dead or live animal can be DNA, sperms, eggs, embryos, gonads, skin, or any other tissue of the body [119]. Preserved tissue can be reprogrammed or transdifferentiated to become other types of tissues and cells, which opens an avenue for conservation of endangered species and resurrection of life (). The gonadal tissue from young individuals harbouring immature tissue can be matured in vivo and ex vivo for generation of functional gametes. Transplantation of SSCs to testis of male from the same different species can give rise to spermatozoa of donor cells [120], which might be used for IVF based captive breeding of wild animals. The most dangerous fact in wildlife conservation is low genetic diversity, too few reproductively capable animals which cannot maintain adequate genetic diversity in wild or captivity. Using the edge of iPSC technology, pluripotent stem cells can be generated from skin cells. For endangered drill, Mandrillus leucophaeus, and nearly extinct white rhinoceros, Ceratotherium simum cottoni, iPSC has been generated in 2011 [121]. The endangered animal drill (Mandrillus leucophaeus) is genetically very close to human and often suffers from diabetes, while rhinos are genetically far removed from other primates. The progress in iPSCs, from the human point of view, might be transformed for animal research for recapturing reproductive potential and health in wild animals. However, stem cells based interventions in wild animals are much more complex than classical conservation planning and biomedical research has to face. Conversion of iPSC into egg or sperm can open the door for generation of IVF based embryo; those might be transplanted in womb of live counterparts for propagation of population. Recently, iPSCs have been generated for snow leopard (Panthera uncia), native to mountain ranges of central Asia, which belongs to cat family; this breakthrough has raised the possibilities for cryopreservation of genetic material for future cloning and other assisted reproductive technology (ART) applications, for the conservation of cat species and biodiversity. Generation of leopard iPSCs has been achieved through retroviral-system based genomic integration of OCT4, SOX2, KLF4, cMYC, and NANOG. These iPSCs from snow leopard also open an avenue for further transformation of iPSCs into gametes [122]. The in vivo maturation of grafted tissue depends both on age and on hormonal status of donor tissue. These facts are equally applicable to accepting host. Ectopic xenografts of cryopreserved testis tissue from Indian spotted deer (Moschiola indica) to nude mice yielded generation of spermatocytes [123], suggesting that one-day procurement of functional sperm from premature tissue might become a general technique in wildlife conservation. In summary, tissue biopsies from dead or live animals can be used for generation of iPSCs and functional gametes; those can be used in assisted reproductive technology (ART) for wildlife conservation.

The spectacular progress in the field of stem cells research represents great scope of stem cells regenerative therapeutics. It can be estimated that by 2020 or so we will be able to produce wide array of tissue, organoid, and organs from adult stem cells. Inductions of pluripotency phenotypes in terminally differentiated adult cells have better therapeutic future than ESCs, due to least ethical constraints with adult cells. In the coming future, there might be new pharmaceutical compounds; those can activate tissue specific stem cells, promote stem cells to migrate to the side of tissue injury, and promote their differentiation to tissue specific cells. Except few countries, the ongoing financial and ethical hindrance on ESCs application in regenerative medicine have more chance for funding agencies to distribute funding for the least risky projects on UCSCs, BMSCs, and TSPSCs from biopsies. The existing stem cells therapeutics advancements are more experimental and high in cost; due to that application on broad scale is not feasible in current scenario. In the near future, the advancements of medical science presume using stem cells to treat cancer, muscles damage, autoimmune disease, and spinal cord injuries among a number of impairments and diseases. It is expected that stem cells therapies will bring considerable benefits to the patients suffering from wide range of injuries and disease. There is high optimism for use of BMSCs, TSPSCs, and iPSCs for treatment of various diseases to overcome the contradictions associated with ESCs. For advancement of translational application of stem cells, there is a need of clinical trials, which needs funding rejoinder from both public and private organizations. The critical evaluation of regulatory guidelines at each phase of clinical trial is a must to comprehend the success and efficacy in time frame.

Dr. Anuradha Reddy from Centre for Cellular and Molecular Biology Hyderabad and Mrs. Sarita Kumari from Department of Yoga Science, BU, Bhopal, India, are acknowledged for their critical suggestions and comments on paper.

There are no competing interests associated with this paper.

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Stem Cells Applications in Regenerative Medicine and ...

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Regenerative & Sports Medicine | Dr. Rand McClain

Newswise The American Medical Society for Sports Medicine (AMSSM) has released a position statement on Principles for the Responsible Use of Regenerative Medicine in Sports Medicine.

This position statement provides sports medicine physicians with information on regenerative medicine terminology, a brief review of the basic science and clinical studies, regulatory considerations, and best practices for introducing the orthobiologic classification of regenerative therapies into their clinical practice.

The document is being published in the Clinical Journal of Sport Medicine, with accompanying editorial highlights published in the British Journal of Sports Medicine. Both are freely accessible on their respective websites.

Sports medicine physicians would benefit from decision-making guidance about whether to introduce orthobiologics into their practice and how to do it responsibly, said Dr. Jonathan Finnoff, the Chief Medical Officer of the United States Olympic and Paralympic Committee and the lead author of the statement. The information within this statement will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine and orthobiologics in their practice.

In 2019, the AMSSM Board of Directors established a Regenerative Medicine Task Force, with a subgroup charged to develop a regenerative medicine position statement. The Task Force brought together a writing group that included sports medicine physicians and scientists who are recognized leaders in bioethics, research, and regenerative medicine clinical applications to produce this statement.

The field of regenerative medicine, and the sub-classification of orthobiologics, involves a variety of therapies and techniques focused on the repair or replacement of damaged or diseased tissue to restore function. Despite these novel therapies being very attractive to sports medicine physicians and patients alike, this is a complex and controversial topic.

Common orthobiologics that are employed in research and medical practice are being combined under the umbrella of stem cell therapy in a manner that is confusing to both patients and the public, said Dr. Shane Shapiro, one of the lead authors of the statement. The need for scientifically validated treatments for non-healing orthopedic and sports conditions has increased interest in orthobiologics and other regenerative therapies to address existing treatment gaps.

The document contains brief discussions of the basic science, proposed therapeutic mechanisms of action, and clinical evidence related to regenerative medicine products, including uses for platelet-rich plasma and other cellular therapies. Additionally, the statement features sections regarding regulatory considerations and an in-depth portion on introducing regenerative medicine into clinical practice.

Ultimately, this AMSSM position statement on regenerative medicine advocates for the advancement of orthobiologic science, patient safety and education towards the responsible translation of regenerative therapies, said Dr. Kenneth Mautner, co-lead author of the position statement and an AMSSM Board member.

About the AMSSM: AMSSM is a multi-disciplinary organization of sports medicine physicians dedicated to education, research, advocacy and the care of athletes of all ages. The majority of AMSSM members are primary care physicians with fellowship training and added qualification in sports medicine who then combine their practice of sports medicine with their primary specialty. AMSSM includes members who specialize solely in non-surgical sports medicine and serve as team physicians at the youth level, NCAA, NFL, MLB, NBA, WNBA, MLS and NHL, as well as with Olympic and Paralympic teams. By nature of their training and experience, sports medicine physicians are ideally suited to provide comprehensive medical care for athletes, sports teams or active individuals who are simply looking to maintain a healthy lifestyle. http://www.amssm.org

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AMSSM Releases Position Statement on Regenerative Medicine in Sports Medicine - Newswise

-Achieved target enrollment in CTX001 clinical trials for beta thalassemia (TDT) and sickle cell disease (SCD); regulatory submissions planned for late 2022-

-Reported positive results from the ongoing Phase 1 CARBON clinical trial evaluating the safety and efficacy of CTX110 for CD19+ B-cell malignancies; enrollment continues, with potential registrational trial incorporating consolidation dosing expected to initiate in Q1 2022-

-Implementing consolidation dosing protocols for CTX120 and CTX130 clinical trials; enrollment continues, with top-line data expected to report in 1H 2022-

-Regenerative medicine and in vivo programs continue to progress and remain on track-

ZUG, Switzerland and CAMBRIDGE, Mass., Nov. 03, 2021 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today reported financial results for the third quarter ended September 30, 2021.

The third quarter marked significant progress across our portfolio, said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. With our partner Vertex, we achieved target enrollment for the CTX001 clinical trials in patients with beta thalassemia and sickle cell disease, which can support regulatory submissions in late 2022. Additionally, we demonstrated proof of concept for our allogeneic CAR-T platform with positive data from our CARBON trial of CTX110, which showed that immediately available off-the-shelf cell therapies can offer efficacy similar to autologous CAR-T with a differentiated safety profile for patients with large B-cell lymphomas. Based on these encouraging results, we plan to expand the CARBON trial into a potentially registrational trial in the first quarter of 2022. Furthermore, we hope to bring these transformative allogeneic CAR-T therapies to patients in outpatient and community oncology settings, enabling broad access."

Story continues

Recent Highlights and Outlook

Third Quarter 2021 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $2,477.4 million as of September 30, 2021, compared to $2,589.4 million as of June 30, 2021. The decrease in cash of $112.0 million was primarily driven by cash used in operating activities to support ongoing research and development of the Companys clinical and pre-clinical programs.

Revenue: Total collaboration revenue was $0.3 million for the third quarter of 2021, compared to $0.1 million for the third quarter of 2020. Collaboration revenue primarily consisted of revenue recognized in connection with our collaboration agreements with Vertex.

R&D Expenses: R&D expenses were $105.3 million for the third quarter of 2021, compared to $71.0 million for the third quarter of 2020. The increase in expense was driven by development activities supporting the advancement of the hemoglobinopathies program and wholly-owned immuno-oncology programs, as well as increased headcount and supporting facilities related expenses.

G&A Expenses: General and administrative expenses were $24.4 million for the third quarter of 2021, compared to $21.5 million for the third quarter of 2020. The increase in general and administrative expenses for the year was primarily driven by headcount-related expense.

Net Loss: Net loss was $127.2 million for the third quarter of 2021, compared to a net loss of $92.4 million for the third quarter of 2020.

About CTX001CTX001 is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD, in which a patients hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate or eliminate transfusion requirements for patients with TDT and reduce or eliminate painful and debilitating sickle crises for patients with SCD. Earlier results from these ongoing trials were published as a Brief Report in The New England Journal of Medicine in January of 2021.

Based on progress in this program to date, CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for both TDT and SCD. CTX001 has also been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both TDT and SCD.

Among gene-editing approaches being investigated/evaluated for TDT and SCD, CTX001 is the furthest advanced in clinical development.

About the CRISPR-Vertex CollaborationVertex and CRISPR Therapeutics entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 represents the first potential treatment to emerge from the joint research program. Under a recently amended collaboration agreement, Vertex will lead global development, manufacturing and commercialization of CTX001 and split program costs and profits worldwide 60/40 with CRISPR Therapeutics.

About CLIMB-111The ongoing Phase 1/2 open-label trial, CLIMB-Thal-111, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About CLIMB-121The ongoing Phase 1/2 open-label trial, CLIMB-SCD-121, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About CLIMB-131This is a long-term, open-label trial to evaluate the safety and efficacy of CTX001 in patients who received CTX001 in CLIMB-111 or CLIMB-121. The trial is designed to follow participants for up to 15 years after CTX001 infusion.

About CTX110CTX110, a wholly owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting cluster of differentiation 19, or CD19. CTX110 is being investigated in the ongoing CARBON trial.

About CARBONThe ongoing Phase 1 single-arm, multi-center, open label clinical trial, CARBON, is designed to assess the safety and efficacy of several dose levels of CTX110 for the treatment of relapsed or refractory B-cell malignancies.

About CTX120CTX120, a wholly-owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting B-cell maturation antigen, or BCMA. CTX120 is being investigated in an ongoing Phase 1 single-arm, multi-center, open-label clinical trial designed to assess the safety and efficacy of several dose levels of CTX120 for the treatment of relapsed or refractory multiple myeloma. CTX120 has been granted Orphan Drug designation from the FDA.

About CTX130CTX130, a wholly-owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting cluster of differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX130 is being developed for the treatment of both solid tumors, such as renal cell carcinoma, and T-cell and B-cell hematologic malignancies. CTX130 is being investigated in two ongoing independent Phase 1, single-arm, multi-center, open-label clinical trials that are designed to assess the safety and efficacy of several dose levels of CTX130 for the treatment of relapsed or refractory renal cell carcinoma and various subtypes of lymphoma, respectively.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic collaborations with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

CRISPR THERAPEUTICS word mark and design logo, CTX001, CTX110, CTX120, and CTX130 are trademarks and registered trademarks of CRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.

CRISPR Therapeutics Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Kulkarni in this press release, as well as statements regarding CRISPR Therapeutics expectations about any or all of the following: (i) the safety, efficacy, data and clinical progress of CRISPR Therapeutics various clinical programs, including CTX001, CTX110, CTX120 and CTX130; (ii) the status of clinical trials and preclinical studies (including, without limitation, the expected timing of data releases and development, as well as initiation and completion of clinical trials) and development timelines for CRISPR Therapeutics product candidates; (iii) expectations regarding the data that has been presented from our various clinical trials (including our CARBON trial) as well as data that will be generated by ongoing and planned clinical trials, and the ability to use that data for the design and initiation of further clinical trials or to support regulatory filings; (iv) the actual or potential benefits of regulatory designations; (v) the potential benefits of CRISPR Therapeutics collaborations and strategic partnerships; (vi) the intellectual property coverage and positions of CRISPR Therapeutics, its licensors and third parties as well as the status and potential outcome of proceedings involving any such intellectual property; (vii) the sufficiency of CRISPR Therapeutics cash resources; and (viii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies including as compared to other therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients not to be indicative of final trial results; the potential that clinical trial results may not be favorable; that one or more of CRISPR Therapeutics internal or external product candidate programs will not proceed as planned for technical, scientific or commercial reasons; that future competitive or other market factors may adversely affect the commercial potential for CRISPR Therapeutics product candidates; uncertainties inherent in the initiation and completion of preclinical studies for CRISPR Therapeutics product candidates (including, without limitation, availability and timing of results and whether such results will be predictive of future results of the future trials); uncertainties about regulatory approvals to conduct trials or to market products; the potential impacts due to the coronavirus pandemic such as (x) delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; (y) the timing and progress of clinical trials, preclinical studies and other research and development activities; and (z) the overall impact of the coronavirus pandemic on its business, financial condition and results of operations; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, quarterly report on Form 10-Q, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com

Media Contact:Rachel Eides+1-617-315-4493rachel.eides@crisprtx.com

CRISPR Therapeutics AGCondensed Consolidated Statements of Operations(Unaudited, In thousands except share data and per share data)

Three Months Ended September 30,

Nine Months Ended September 30,

2021

2020

2021

2020

Revenue:

Collaboration revenue

$

329

$

148

$

900,733

$

349

Grant revenue

495

1,331

Total revenue

$

824

$

148

$

902,064

$

349

Operating expenses:

Research and development

105,321

71,008

304,163

184,581

General and administrative

24,352

21,539

78,675

62,442

Total operating expenses

129,673

92,547

382,838

247,023

(Loss) income from operations

(128,849

)

(92,399

)

519,226

(246,674

)

Total other income, net

1,101

160

3,806

5,804

Net (loss) income before income taxes

(127,748

)

(92,239

)

523,032

(240,870

)

Benefit (provision) for income taxes

595

Continued here:
CRISPR Therapeutics Provides Business Update and Reports Third Quarter 2021 Financial Results - Yahoo Finance

Item 1.01 Entry into a Material Definitive Agreement.

On October 29, 2021, the Company entered into an Exchange Agreement (the"Exchange Agreement") with shareholders who were issued shares under (i) variousconsulting and employment agreements during 2021 (the "Service Providers"), and(ii) those shareholders who were issued shares of common stock pursuant to theCompany's Management and Consultants Performance Stock Plan (the "MCP Plan")(each person who received shares pursuant to the MCP Plan is referred to as an"MCP Plan Holder").

The Service Providers who executed the Exchange Agreement were issued a total of30,300,000 shares under their respective consulting or employment agreements(the "Service Provider Shares"), and the MCP Plan Holders who executed theExchange Agreement received a total of 49,500,000 shares under the MCP Plan, foran aggregate of 79,800,000 shares of common stock. As of the effective date ofthe Agreement, the Service Providers and MCP Plan Holders who executed theExchange Agreement agreed to exchange their respective Service Provider Sharesor the shares issued under the MCP Plan for newly issued shares pursuant to theCompany's newly formed 2021 Equity Incentive Plan (the "EIP"), on a 1:1 basis,resulting in the issuance of 79,800,000 shares of common stock under the EIP(the "Exchange Shares").

The Exchange Agreement contains certain customary representations, warranties,and covenants for transactions of this type.

The description of the Exchange Agreement does not purport to be complete and isqualified in its entirety by reference to the full text of the form of ExchangeAgreement which is attached as Exhibit 10.1 to this Current Report on Form8-K and is incorporated herein by reference.

Item 3.02 Unregistered Sales of Equity Securities.

The disclosure set forth above in Item 1.01 of this Current Report on Form 8-Kwith respect to the issuances of the Exchange Sharers pursuant to the ExchangeAgreement is incorporated by reference into this Item 3.02.

The Exchange Shares were issued in reliance on the exemption from registrationrequirements thereof provided by Section 4(a)(2) of the Securities Act.

Item 9.01 Financial Statements and Exhibits.

* Schedules, exhibits and similar attachments have been omitted pursuant to Item601(a)(5) of Regulation S-K. The Company hereby undertakes to furnish copies ofsuch omitted materials supplementally upon request by the U.S. Securities andExchange Commission.

1

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ORGANICELL REGENERATIVE MEDICINE, INC. : Entry into a Material Definitive Agreement, Unregistered Sale of Equity Securities, Financial Statements and...

ALBANY, N.Y., Nov. 3, 2021 /PRNewswire/ -- Advancements in blood thawing devices have pivoted on the changing requirements of fresh frozen plasma (FFP) in transfusion practices and thawing procedures in cryopreservation. Plasma thawers to maintain the integrity of FFPs are growing in applications in laboratories, blood banks, and hospital settings. New procedures and technologies have been introduced in the blood thawing system market, which prevent potential risks of contamination. Particularly, the adoption of dry bathing systems for preventing transfusion-associated bacterial sepsis in treating blood disorders and cancer is gaining momentum.

The use of FDA-approved, CE-marked, and ISO certified plasma thawers are gaining popularity in umbilical cord blood processing and cell-based therapies, thereby enriching the prospects of regenerative medicine. The need for new device designs and software for temperature controllers occupies a key role in improving the existing cryopreservation protocols, which has opened up a lucrative avenue for players, notes the study on the blood thawing systems market.

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Dry plasma thawing products are gaining preference over traditional water baths or wet plasma thawers, as they help increase the success of transfusion of adult stem cells. Asia Pacific is a highly lucrative market, where the players have gained opportunities from rising on-demand cell thawing to successfully deliver cell-based therapies to target population. The global valuation of the blood thawing system market is projected to reach US$ 400 Mn by 2030, at a CAGR of 7.7% during the forecast period.

Key Findings of Blood Thawing System Market Study

GMP-compliant Equipment Improve Safety and Effectiveness of Thawing Processes: End users have become increasingly aware about Good Manufacturing Practice (GMP), manufacturer's instructions, and other guidelines for preparing FFPs for use in various applications of transfusion medicine. Most prominently, the risk of transfusion-associated bacterial sepsis has led to constant technological advancements in the blood thawing equipment to ensure the efficacy of the thawing method. GMP-ready cryochain hardware and software are gaining traction in umbilical cord blood processing, finds a TMR study on the blood thawing system market.

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The success of cryopreservation is dependent on appropriate execution of thawing procedures. Indeed, advances made in the protocols for on-demand thawing in regenerative medicine have bolstered the prospects of the blood thawing system market.

Regulatory Approval of Next-generation Thawing Devices Extends Horizon: The need for eliminating continuous blood products manufacturing is a key underpinning for adopting reliable thawing processes. In this light, thawing equipment for rapid, reliable thawing of FFP is garnering attention of clinicians for use in patients in emergency setting as well as for meeting the demand in planned hospitalizations.

Next-gen plasma thawing devices promise low turnaround time, are of portable designs, and ensure high throughput. The use of such devices is expected to rise in various applications in exchange transfusions, stem cell transfusions, and crystalloid infusion solutions.

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Blood Thawing System Market: Key Drivers

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Blood Thawing System Market: Regional Dynamics

Blood Thawing System Market: Key Players

Some of the key players in the blood thawing system market are Sartorius AG, Thermo Fisher Scientific, Inc., Cytiva (GE Healthcare), Cardinal Health, KW Scientific Apparatus Srl, Boekel Scientific, Barkey GmbH & Co. KG, Helmer Scientific Inc., and Fremon Scientific Inc.

Global Blood Thawing System Market: Segmentation

Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated with Latest Healthcare Industry Research Reportsby Transparency Market Research:

Blood Purification Equipment Market: Increasing knowledge and understanding of pathophysiology and hematology due to additional research and development coupled with noteworthy progress in bio separation techniques are some of the other factors contributing to the overall growth of the global blood purification equipment market

Autoimmune Disease Diagnostics Market: Increasing awareness and knowledge about autoimmune diseases among patients and care-givers would significantly contribute to the growth of the autoimmune disease diagnostics market. Rising awareness among people and increasing government initiatives are the major factors driving the autoimmune disease diagnostics market

Capillary and Venous Blood Sampling Devices Market: Manufacturers in the capillary and venous blood sampling devices market are increasing their focus to develop COVID-19 rapid test kits that are suitable for qualitative detection of the novel coronavirus using finger-prick samples. Companies are increasing efforts to innovate in small volume blood collection devices that are being made available for retail pharmacies.

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Blood Thawing System Market to Witness Massive Revenue Streams from Growing Demand for Rapid Dry Plasma Thawing Products for FFPs in Blood Banks,...

Conference Call and Webcast Scheduled for 9:15 a.m. Eastern Time

BRISBANE, Calif., November 04, 2021--(BUSINESS WIRE)--Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, today reported third quarter financial results and provided business and clinical highlights.

"We are delighted to share clinical data and business updates across several programs demonstrating that Sangamo has three important assets progressing toward late-stage development. Our gene therapy portfolio is advancing with accumulating safety and efficacy data in our Fabry and hemophilia A programs, and preliminary proof-of-concept data demonstrate the clinical potential of our zinc finger genome engineering technology in sickle cell disease. These data readouts show the progression of our first-generation genomic medicine pipeline and potentially pave the way for new treatments. Our next generation programs focus on genome regulation and allogeneic CAR-Treg cell therapy, where we have a robust preclinical pipeline in neurological and autoimmune diseases. We are energized by this momentum and look forward to continued execution of our corporate strategy," said Sandy Macrae, Chief Executive Officer of Sangamo.

Recent Clinical and Business Highlights

Fabry Disease First four patients dosed exhibited above normal -Gal A activity; Phase 3 planning initiated

Earlier today, we announced preliminary clinical data from the first four patients treated in our Phase 1/2 STAAR study evaluating isaralgagene civaparvovec, or ST-920, our wholly owned Fabry disease gene therapy product candidate. Data as of the September 17, 2021 cutoff date from the four patients in the first two dose cohorts showed that isaralgagene civaparvovec was generally well tolerated. All four patients exhibited above normal alpha-galactosidase A (-Gal A) activity, which was maintained for up to one year for the first patient treated and through 14 weeks for the most recently treated patient. Activity of 2-fold to 15-fold above mean normal was observed at last measurement as of the cutoff date. Withdrawal from enzyme replacement therapy (ERT) has taken place for one patient and is planned for the other patient on ERT, based on the stability of their -Gal A activity following treatment.

The fifth patient in the STAAR study, who is the first patient in the third cohort (3e13vg/kg), was dosed after the cutoff date. The sixth patient is currently in screening also for the third dose cohort. We expect to provide updated data throughout 2022 and present these results at a medical meeting.

Based on the STAAR study results to date, we have initiated planning for a Phase 3 Fabry disease clinical trial.

Sickle Cell Disease Preliminary-proof-of-concept data will be presented at ASH as clinical program advances

Story continues

Preliminary proof-of-concept results from the Phase 1/2 PRECIZN-1 study investigating SAR445136, formerly BIVV003, an investigational zinc finger nuclease gene edited cell therapy, in patients with severe sickle cell disease (SCD) will be presented at the 63rd Annual Meeting of the American Society of Hematology (ASH) on December 12, 2021. Results as of the June 25, 2021 cutoff date show that all four treated patients did not require blood transfusions post engraftment and had no adverse or serious adverse events related to SAR445136 through 65 weeks of follow-up for the longest treated patient. The four treated patients all experienced increases in total hemoglobin, fetal hemoglobin and percent F cells.

We and Sanofi continue to advance the sickle cell disease program. We recently obtained manufacturing requirements guidance from FDA in preparation for further potential clinical studies. Separately, we and Sanofi made the business decision to cease development of the beta thalassemia indication in order to focus resources on the sickle cell disease program. ST-400 for beta thalassemia was developed with the support of a grant from the California Institute for Regenerative Medicine (CIRM).

Hemophilia A Four patients at highest dose experienced mean FVIII activity of 30.9% at week 104

Updated follow-up results from the Phase 1/2 Alta study of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A will be presented at ASH on December 12, 2021. For the four patients in the highest dose 3e13vg/kg cohort who have reached 104 weeks of follow-up as of the May 19, 2021 cutoff date, mean Factor VIII (FVIII) activity was 30.9% at week 104 as measured by chromogenic assay. In this cohort, the annualized bleeding rate was zero for the first year after treatment and 0.9 throughout total duration of follow-up. Giroctocogene fitelparvovec was generally well tolerated.

We and Pfizer also announced that some of the patients treated in the Phase 3 AFFINE trial of giroctocogene fitelparvovec experienced FVIII activity greater than 150% following treatment. None of these patients have experienced thrombotic events and some have been treated with direct oral anticoagulants to reduce thrombotic risk. Pfizer voluntarily paused screening and dosing of additional patients in the trial to implement a protocol amendment intending to provide guidance regarding the management of patients with FVIII levels that exceed 150%. On November 3, 2021, Pfizer was informed that the FDA has put this trial on clinical hold. The next step is to share the proposed protocol amendment with health authorities and respond to the clinical hold, after which the Companies will be able to provide updated timing for the trial.

Renal Transplant First patient enrolled, expect two patients to be dosed by mid-2022

The first patient has been enrolled in our Phase 1/2 STEADFAST study evaluating TX200, our wholly owned autologous HLA-A2 CAR Treg cell therapy product candidate treating patients receiving an HLA-A2 mismatched kidney from a living donor. We expect the first two patients in this study to be dosed by the middle of 2022 following kidney transplantation. We continue to open study sites and screen patients.

Research, Manufacturing, and Corporate Updates

Biogen announced type 1 myotonic dystrophy (DM1) as the previously undisclosed neuromuscular preclinical target in our collaboration.

We recently completed and brought online our in-house cell therapy manufacturing facility in our Brisbane, California headquarters and remain on track to complete our in-house cell therapy manufacturing facility in Valbonne, France by year-end.

We appointed D. Mark McClung as Chief Operating Officer, an important organizational step to support the multiple advancing wholly owned and partnered programs.

Third Quarter 2021 Financial Results

Consolidated net loss attributable to Sangamo for the third quarter ended September 30, 2021 was $47.7 million, or $0.33 per share, compared to a net loss attributable to Sangamo of $1.6 million, or $0.01 per share, for the same period in 2020.

Revenues

Revenues for the third quarter ended September 30, 2021, were $28.6 million, compared to $57.8 million for the same period in 2020, a decrease of $29.2 million.

The reduction in revenue was primarily due to a $39.3 million decrease related to our giroctocogene fitelparvovec and C9ORF72 collaboration agreements with Pfizer, resulting from the completion of our activities in 2020, and a $2.3 million decrease related to our collaboration agreement with Sanofi. These decreases were partially offset by higher revenues of $11.5 million and $1.3 million related to our collaboration agreements with Novartis and Biogen, respectively.

GAAP and Non-GAAP operating expenses

Three Months EndedSeptember 30,

Nine Months EndedSeptember 30,

(In millions)

2021

2020

2021

2020

Research and development

$

62.5

$

45.3

$

179.0

$

128.3

General and administrative

14.5

16.2

47.1

50.2

Total operating expenses

77.0

61.5

226.1

178.5

Stock-based compensation expense

(7.9

)

(6.7

)

(24.9

)

(19.1

)

Non-GAAP operating expenses

$

69.1

$

54.8

$

201.2

$

159.4

Total operating expenses on a GAAP basis for the third quarter ended September 30, 2021 were $77.0 million compared to $61.5 million for the same period in 2020. Non-GAAP operating expenses, which exclude stock-based compensation expense, for the third quarter ended September 30, 2021 were $69.1 million compared to $54.8 million for the same period in 2020.

The increase in total operating expenses on a GAAP basis was primarily driven by our higher clinical and manufacturing supply expenses along with our increased headcount to support the advancement of our clinical trials and our ongoing collaborations.

Cash, cash equivalents and marketable securities

Cash, cash equivalents and marketable securities as of September 30, 2021 were $519.0 million compared to $692.0 million as of December 31, 2020.

Revised Financial Guidance for 2021

We are revising our full-year operating expense guidance initially provided on February 24, 2021 and reiterated most recently on August 5, 2021 as follows:

(in millions)

Initially Provided February 24, 2021;Reiterated May 4, 2021and August 5, 2021

Updated on November 4, 2021

Estimated GAAP Operating Expenses

$285 to $305

$300 to $310

Estimated Non-GAAP Operating Expenses

$255 to $275*

$265 to $275**

*excludes estimated stock-based compensation of $30 million

**excludes estimated stock-based compensation of $35 million

Conference Call

Sangamo will host a conference call today, November 4, 2021, at 9:15 a.m. Eastern Time, which will be open to the public. The call and live Q&A will be webcast.

The conference call dial-in numbers are (877) 377-7553 for domestic callers and (678) 894-3968 for international callers. The conference ID number for the call is 5178059. Participants may access the live webcast via a link on the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations. Call replay will be available for one week following the conference call. The conference call replay numbers for domestic and international callers are (855) 859-2056 and (404) 537-3406, respectively. The conference ID number for the replay is 5178059.

About Sangamo Therapeutics

Sangamo Therapeutics is a clinical-stage biopharmaceutical company with a robust genomic medicines pipeline. Using ground-breaking science, including our proprietary zinc finger genome engineering technology and manufacturing expertise, Sangamo aims to create new genomic medicines for patients suffering from diseases for which existing treatment options are inadequate or currently dont exist. For more information about Sangamo, visit http://www.sangamo.com.

Forward-Looking Statements

This press release contains forward-looking statements regarding our current expectations. These forward-looking statements include, without limitation, statements relating to the therapeutic and commercial potential of our product candidates, the anticipated plans and timelines of Sangamo and our collaborators for screening, enrolling and dosing patients in and conducting our ongoing and potential future clinical trials and presenting clinical data from our clinical trials, the anticipated advancement of our product candidates to late-stage development including potential future Phase 3 trials, anticipated implementation of a protocol amendment for the Phase 3 AFFINE clinical trial of giroctocogene fitelparvovec and the resumption of the dosing of additional patients in the trial; our revised 2021 financial guidance related to GAAP and non-GAAP total operating expenses and stock-based compensation; our continued execution of our corporate strategy; the anticipated completion of our in-house cell therapy manufacturing facility in Valbonne, France; and other statements that are not historical fact. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties related to the effects of the evolving COVID-19 pandemic and the impacts of the pandemic on the global business environment, healthcare systems and business and operations of Sangamo and our collaborators, including the initiation and operation of clinical trials; the research and development process, including the enrollment, operation and results of clinical trials and the presentation of clinical data; the uncertain timing and unpredictable nature of clinical trials and clinical trial results, including the risk that any protocol amendment for the Phase 3 AFFINE trial of giroctocogene fitelparvovec may not be accepted by the relevant review bodies in a timely manner, or at all, or that the FDA may not lift its clinical hold on the Phase 3 AFFINE trial in a timely manner, or at all, each of which could further delay or preclude further patient dosing in the trial as well as the risks that therapeutic effects observed in clinical trial results will not be durable in patients and that final clinical trial data will not validate the safety and efficacy of our product candidates; reliance on results of early clinical trials, which results are not necessarily predictive of future clinical trial results; our limited experience manufacturing biopharmaceutical products, including the risks that we may be unable to maintain compliant manufacturing facilities, build additional facilities and manufacture our product candidates as intended; and our ability to achieve expected future financial performance.

There can be no assurance that we and our collaborators will be able to develop commercially viable products. Actual results may differ materially from those projected in these forward-looking statements due to the risks and uncertainties described above and other risks and uncertainties that exist in the operations and business environments of Sangamo and our collaborators. These risks and uncertainties are described more fully in our Securities and Exchange Commission filings and reports, including in our Annual Report on Form 10-K for the year ended December 31, 2020 as supplemented by our Quarterly Report on Form 10-Q for the quarter ended September 30, 2021. Forward-looking statements contained in this announcement are made as of this date, and we undertake no duty to update such information except as required under applicable law.

Non-GAAP Financial Measure

To supplement our financial results and guidance presented in accordance with GAAP, we present non-GAAP total operating expenses, which exclude stock-based compensation expense from GAAP total operating expenses. We believe that this non-GAAP financial measure, when considered together with our financial information prepared in accordance with GAAP, can enhance investors and analysts ability to meaningfully compare our results from period to period and to our forward-looking guidance, and to identify operating trends in our business. We have excluded stock-based compensation expense because it is a non-cash expense that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. This non-GAAP financial measure is in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. We encourage investors to carefully consider our results under GAAP, as well as our supplemental non-GAAP financial information, to more fully understand our business.

SELECTED CONSOLIDATED FINANCIAL DATA

(unaudited; in thousands, except per share data)

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Sangamo Therapeutics Reports Recent Business and Clinical Highlights and Third Quarter 2021 Financial Results - Yahoo Finance

NASHVILLE, Tenn., Nov. 4, 2021 /PRNewswire/ --Cryoport, Inc. (NASDAQ: CYRX) ("Cryoport" or the "Company"),a global leader in temperature-controlled supply chain solutions for the life sciences industry,today announced financial results for the three- and nine-month periods ended September 30,2021.

Jerrell Shelton, CEO of Cryoport, commented, "We delivered an outstanding third quarter and nine months of the year for the Company with strength across the board in all areas of our business. During the third quarter, our total revenue grew to a record $56.7 million driven by 38% organic growth year-over-year from Cryoport Systems and CRYOGENE and continuing strong revenue performance by MVE Biological Solutions and CRYOPDP. Our robust performance was driven by superlative execution by our global teams across all our business units. Our markets are strong and growing. Demand for MVE Biological Solutions' products remained at record highs, Cryoport Systems added 38 new customers during the quarter, and we successfully expanded the footprints for both CRYOPDP and CRYOGENE.

"Our Biopharma/Pharma revenue increased 371% year over year in the third quarter of 2021 or 41%, organically. But the story does not end there, we now support a record 582 clinical trials, compared with 561 at the end of the second quarter of 2021 and 517 at the end of the third quarter of 2020. We also support eight commercial therapies in regenerative medicine, including Novartis' KYMRIAH, Gilead/Kite's YESCARTAand TECARTUS, bluebird bio's ZYNTEGLO andSKYSONA, Bristol Myers Squibb's BREYANZI and ABECMA and Orchard Therapeutics' LIBMELDY. Additionally, four of the approved therapies received extended or supplemental approvals in the third quarter.

"Our revenue by market for the three- and nine-months ended September 30, 2021, as compared to the same periods in 2020 was asfollows:

Cryoport, Inc. and Subsidiaries

Total revenues by market

(unaudited)

Three Months Ended September 30,

Nine Months Ended September 30,

(in thousands)

2021

2020

% Change

2021

2020

% Change

Biopharma/Pharma

$ 46,001

$ 9,760

371%

$ 133,878

$ 27,120

394%

Animal Health

8,261

223

3598%

25,655

664

3762%

Reproductive Medicine

2,431

1,189

105%

6,635

2,551

160%

Total revenues

$ 56,693

$ 11,172

407%

$ 166,168

$ 30,335

448%

"Our solutions are experiencing accelerating global demand as a record number of cell and gene therapies are slated for commercialization in the coming months and years."

Mr. Shelton concluded, "We continue to set the pace and the standard for supply chain solutions for the regenerative medicine industry which continues to be in its very early stages of development. To support our continued global growth, we have expanded into 33 facilities in 16 countries and have initiated further expansion within the fast-growing Asia-Pacific (APAC) and EMEA (Europe, Middle East, and Africa) regions.We believe our strong momentum will continue to build through the remainder of the year and beyond as we realize the large commercial revenue potential of our vast pipeline of clinical trials supported. Our performance is a testament to the power of our strategy and our team's commitment to Cryoport and its mission, and, with that, we expect significant worldwide opportunities ahead to continue building sustainable, long-term value for shareholders."

Biopharma/Pharma

Our total Biopharma/Pharma revenue increased by $36.2 million, or 371%, to $46.0 million for the third quarter of 2021 compared to $9.8 million for the third quarter of 2020, driven by strong revenue contributions from all business units. For the third quarter of 2021, Biopharma/Pharma revenue grew organically by $4.0 million, or 41%, to $13.8 million compared to third quarter in the prior year.

As of the end of the third quarter, we supportedanettotalof582 clinical trials, compared with 561 at the end of the second quarter 2021 and 517 in third quarter 2020. The number of trials by phase and region are as follows:

Cryoport Supported Clinical Trials by Phase

Clinical Trials

September 30,

2021

2020

2019

Phase 1

240

207

180

Phase 2

272

244

191

Phase 3

70

66

54

Total

582

517

425

Cryoport Supported Clinical Trials by Region

Clinical Trials

September 30,

2021

2020

2019

Americas

459

411

360

EMEA

92

83

55

APAC

31

23

10

Total

582

517

425

A total of nine (9) Cryoport supported Biologic License Applications (BLAs) or Marketing Authorization Applications (MAAs) were filed in the nine months ended September 30, 2021, based on internal information and forecasts from the Alliance for Regenerative Medicine, of which three (3) were filed during the third quarter of 2021. Looking forward, we anticipate up to another four (4) BLA and MAA submissions for Cryoport-supported products during the remainder of 2021 and, at this time, an additional twenty-one (21) filings in 2022. Additionally, a total of four (4) Cryoport supported therapies received extended or supplemental approvals in the third quarter.

Animal Health

Our revenue from the Animal Health market increased by $8.0 million, or 3,598%, to $8.3 million for thethird quarter ended September 30, 2021,ascomparedtothesameperiodin2020 andwas primarily driven byouracquisitionofMVE Biological Solutions,whichhasastrongandlongstanding presenceinthismarket. Third quarter revenue grew organically by 31% over the prior year demonstrating successful execution of our engagement strategy within the animal health space.

Reproductive Medicine

Reproductive Medicine revenue more than doubled to $2.4 million for the third quarter of 2021 compared to $1.2 million for the third quarter of 2020, an increase of $1.2 million, or 105%. We see continuing strong demand for our CryoStork solutionprovided by Cryoport Systems driven by fertility clinic networks that are looking for global standardization on our best-in-class solution. MVE Biological Solutions also contributed revenue to our Reproductive Medicine market through its portfolio of cryogenic shipper and freezersolutions. We plan to continue to add agreements with new fertility clinics to our network globally during the remainder of 2021 and beyond to drive increased adoption of our services as well as expand our support efforts within this space to EMEA and APAC.

Financial Highlights

Note: All reconciliations of GAAP to adjusted (non-GAAP) figures above are detailed in the reconciliation tables included later in the press release.

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Cryoport Reports Record Third Quarter and Nine Months Revenue for 2021 - PRNewswire

TOKYO & MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--The SanBio Group (SanBio Co., Ltd. of Tokyo, Japan , SanBio, Inc. of Mountain View, California, US, and SanBio Asia Pte. Ltd. of Singapore) (TOKYO:4592), hereby announce that data comparing outcome measures for persons with traumatic brain injury (TBI) living with chronic motor deficits was published in Expert Review of Neurotherapeutics.

Success in clinical trials in chronic TBI is challenging to define and measure; therefore, this publication is an important advancement for the field of research as it relates to the assessment of persons with motor deficits resulting from a TBI, said Michael A. McCrea, Co-Director, Center For Neurotrauma Research; Professor, Department Of Neurosurgery, Medical College Of Wisconsin, Milwaukee, USA; and lead author for the publication. This study supports the use of Disability Rating Scale (DRS) and Fugl-Meyer Motor Scale (FMMS) in the evaluation of long-term functional outcomes and motor impairment in future clinical trials of persons with chronic motor deficits secondary to TBI.

While acute TBI is widely assessed using Extended Glasgow Outcome Scale (GOS-E), this scale is less well-defined for persons who have chronic, or long-term, motor deficits as a result of their injury. The publication, entitled, Determining minimally clinically important differences (MCIDs) for outcome measures in patients with chronic motor deficits secondary to traumatic brain injury, determined MCIDs for DRS and FMMS. MCID is defined as the smallest change on a measure that is reliably associated with a meaningful change in a patient's clinical status, function, or quality of life.

Establishing MCIDs for the DRS and FMMS in chronic TBI provides improved precision for assessing long-term functional outcomes and motor impairment, respectively, as compared to the widely used GOS-E Scale, which is most appropriate for use in acute TBI. The findings of this study support the use of DRS and Fugl-Meyer Scales in the evaluation of clinical outcomes, and define the amplitude of clinically meaningful improvement for future chronic TBI clinical trials.

At SanBio, we are passionate about improving the lives of persons living with long-term motor deficits as a result of a TBI or stroke. This publication will help to overcome one of the most challenging areas of clinical research: determining the minimal improvement that would be clinically meaningful in patients with chronic motor deficit. We would like to extend our gratitude to the physicians and rehabilitation specialists who supported this important work, added, Bijan Nejadnik, M.D., Corporate Officer, Chief Medical Officer and Head of Research.

This retrospective analysis is from SanBios 1-year, double-blind, randomized, surgical sham-controlled, Phase 2 STEM cell therapy for TRAumatic brain injury (STEMTRA) trial (NCT02416492), in which persons with chronic motor deficits secondary to TBI (n=61) underwent intracerebral stereotactic implantation of SB623 or sham surgery. MCIDs for DRS and FMMS were triangulated with anchor-based, distribution-based, and Delphi panel estimates. The published Delphi panel results are available here. The MCIDs for DRS and FMMS were: 1) 1.5 points for the Disability Rating Scale; 2) 6.2 points for the Fugl-Meyer Upper Extremity Subscale; 3) 3.2 points for the Fugl-Meyer Lower Extremity Subscale; and 4) 8.4 points for the Fugl-Meyer Motor Scale in persons with chronic motor deficits secondary to TBI.

The full publication can be accessed here.

About the STEM cell therapy for TRAumatic brain injury (STEMTRA) Trial

STEMTRA was a 12-month, Phase 2, randomized, double-blind, surgical sham-controlled, global trial evaluating the efficacy and safety of SB623 compared to sham surgery in patients with stable chronic neurological motor deficits secondary to TBI (https://clinicaltrials.gov identifier: NCT02416492). In this study, SB623 cells were implanted directly around the site of brain injury. The primary endpoint was mean change from baseline in FMMS score at six months to measure changes in motor impairment.

To be eligible for this trial, patients (ages 18-75) must have been at least 12 months post-TBI and had a Glasgow Outcome Scale extended (GOS-E) score of 3-6 (e.g., moderate or severe disability). The STEMTRA trial treated 61 patients from 27 sites in the U.S., Japan and Ukraine.

In this study, SB623 met its primary endpoint, with patients treated with SB623 achieving an average 8.3-point improvement from baseline in the FMMS, versus 2.3-points in the control group, at 6 months (p=0.040). No new safety signals were identified, and the most commonly reported adverse event was headaches. The Group, based on the study results, aims to apply for manufacture and marketing approval for SB623 as a regenerative medicine product by utilizing Japans conditional and time-limited approval system for regenerative medicine products.

About Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. The estimated global incidence of acute TBI during 2016 was 27 million cases, and the estimated global prevalence of chronic impairment secondary to TBI was 55.5 million cases. Overall, TBI and long-term motor deficits secondary to TBI significantly impair persons self-care, employability, and quality of life, and are major burdens on healthcare systems worldwide. In the United States, approximately 43% of surviving hospitalized persons with TBI experience long-term motor deficits, with 5.3 million people estimated to live with long-term motor deficits secondary to TBI.

About SB623

SB623 is a proprietary, cell-based investigational product made from allogeneic modified and cultured adult bone marrow-derived mesenchymal stem cells (MSCs) that undergo temporary genetic modification. Implantation of SB623 cells into injured nerve tissue in the brain is expected to trigger the brains natural regenerative ability to recover lost motor functions. SanBio is preparing to file a Biologics License Application with the Pharmaceuticals and Medical Devices Agency in Japan for SB623 for the treatment of chronic motor deficits resulting from TBI with STEMTRA results.

About SanBio Group (SanBio Co., Ltd., SanBio, Inc. and SanBio Asia Pte. Ltd.)

SanBio Group is engaged in the regenerative cell medicine business, spanning research, development, manufacture, and sales of regenerative cell medicines. The Companys propriety regenerative cell medicine product, SB623, is currently being investigated for the treatment of several conditions including chronic neurological motor deficit resulting from traumatic brain injury and stroke. The Company is headquartered in Tokyo, Japan, Mountain View, California, US, and SanBio Asia Pte. Ltd. of Singapore), and additional information about SanBio Group is available at https://sanbio.com/en/

Sources:Alves, et al, Why Does Brain Trauma Research Fail? World Neurosurg. (2019) 130:115-121.Selassie AW, et al. Incidence of long-term disability following traumatic brain injury hospitalization, U.S., 2003. J Head Trauma Rehabil 2008;23:123-31.James SL, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:56-87.Walker WC & Pickett TC. Motor impairment after severe traumatic brain injury: a longitudinal multicenter study. J Rehabil Res Dev 2007;44:975-82.

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SanBio Announces Publication Comparing Outcome Measures for Persons With Chronic Traumatic Brain Injury in Expert Review of Neurotherapeutics -...

SEAL BEACH, Calif. & SAN DIEGO--(BUSINESS WIRE)--Dendreon Pharmaceuticals, a commercial-stage biopharmaceutical company and pioneer in the development of cellular immunotherapy, and Shoreline Biosciences, a biotechnology company developing allogeneic off-the-shelf, standardized, and targeted natural killer (NK) and macrophage cellular immunotherapies derived from induced pluripotent stem cells (iPSC) for cancer, today announced an alliance to advance the future of iPSC-derived cellular therapies.

The alliance leverages Dendreons extensive manufacturing, process development and end-to-end logistics expertise for the advancement of Shorelines pipeline of iPSC-derived cellular therapies. Dendreon is providing scalable cGMP manufacturing support for certain programs through clinical development and launch, enabling Shoreline to rapidly advance multiple products in parallel.

With more than a decade of proven expertise in cell therapy manufacturing and an established supply chain and logistics infrastructure, Dendreon is well positioned to support Shoreline in manufacturing from Phase I clinical trials through commercialization, said Maria Cho, Vice President of Business Development and Corporate Strategy. We are thrilled to partner with Shoreline to enable the future of cell therapy and change the way serious diseases are treated.

We are excited to partner with Dendreon, a leader in cell therapy, to manufacture cost-efficient, highly-scalable product candidates, said Mohammad El-Kalay, Ph.D., Senior VP & Head of CMC for Shoreline. Through our partnership with Dendreon, we are accelerating the commercialization of our next generation NK cell and macrophage products to bring scalable, allogeneic, off the shelf therapies to more patients in need.

About Dendreon

Dendreon is a commercial-stage biopharmaceutical company and end-to-end provider of manufacturing services for the cell therapy market. Dendreons flagship product, PROVENGE (sipuleucel-T), was the first FDA-approved immunotherapy made from a patients own immune cells and has been prescribed to over 40,000 men in the U.S. since 2010. Dendreon is headquartered in Seal Beach, Calif. For more information about Dendreons contract manufacturing services division, please visit https://www.dendreon.com/Partner-With-Us.

About Shorelines iPSC NK cell technology

Shoreline has developed a proprietary platform focused on iPSC-derived natural killer (NK) cells and macrophages that are optimized with precise and rational genetic reprogramming. The Shoreline NK cell and macrophage-based cell therapies are designed to provide an effective and efficient means for targeting and killing tumors as well as repairing tissue homeostasis. Shorelines approach, based on the advantage of its iPSC cell engineering and expansion, is being used to create a streamlined, affordable, and scalable manufacturing process that can deliver cell therapy treatments to patients in a more cost-effective, time-saving manner. Shorelines technology is at the forefront of regenerative medicine and is being used to develop potential therapies to treat a wide range of oncology indications.

About Shoreline Biosciences

Shoreline is dedicated to creating next-generation cellular immunotherapies for cancer that overcome the current limitations of first-generation cell therapy products. Shoreline is building a pipeline of natural killer (NK) cell and macrophage-cell therapy candidates derived from its deep expertise in iPSC differentiation methods and genetic reprogramming of disease relevant pathways. Shoreline has strategic partnerships with Kite, a Gilead Company, and BeiGene, a global biotechnology company, and is supported by high-quality institutional investors. Shoreline Biosciences is headquartered in San Diego, CA.

For more information, please visit https://shorelinebio.com/ and engage with us on LinkedIn.

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Dendreon Pharmaceuticals and Shoreline Biosciences Announce CMC and Manufacturing Alliance to Advance the Future of iPSC Cellular Therapy - Business...

Findings led by experts in Seattle, San Francisco and Cincinnati suggest that some severe cases of heart failure have root causes surprisingly similar to neurodegenerative diseases like Alzheimers, Huntingtons and ALS.

CINCINNATI, Nov. 3, 2021 /PRNewswire/ -- One of the leading reasons why children and adults need heart transplants is a condition called dilated cardiomyopathy (DCM).

Model of mutant RBM20 differential splicing and P-body impacts in dilated cardiomyopathy. Proposed model for the impact of wild-type and mutant RBM20 on nuclear regulation of splicing based on RNA-Seq and eCLIP data as compared to cytoplasmic role of mutant RBM20 on P-body formation and 3UTR association with mRNAs implicated in granule formation.

Some cases of heart failure have root causes surprisingly similar to diseases like Alzheimers, Huntingtons and ALS.

Over time, sometimes quite rapidly, the heart's thick strong muscle tissue becomes thin and weak, causing the left ventricle to swell like a balloon. This makes the heart less able to squeeze efficiently, which can lead to blood clots, irregular heartbeats, and sometimes sudden death when the malfunctioning heart simply stops beating. The origins of cardiomyopathy are diverse, including viral infections, autoimmune diseases, toxic drug exposures, and dozens of gene mutations.

Now, a multi-disciplinary team of clinicians and researchers has deciphered the function of a specific genetic mutation that causes cardiomyopathy. Their findings, published Nov. 3, 2021, in Nature Communications, were made possible by growing gene-edited human heart tissue from induced pluripotent stem cells and measuring the activity, location and binding of this mutant protein.

The team was led by co-corresponding authors Charles Murry, MD, PhD, a regenerative medicine expert at the University of Washington; Bruce Conklin, MD, a genetic engineering expert with the Gladstone Institutes in California, and Nathan Salomonis, PhD, a computational genomics expert at Cincinnati Children's.

"We hope this study will lead to broader insights that could lead to improved heart failure therapies," Conklin says.

Cutting-edge experiments expose more of the heart's inner workings

Over the last several decades, the research community has made many discoveries that have led to improved medications and medical devices that can dramatically extend life by slowing down the progression of heart failure. However, we still lack proven cures.

Story continues

This study reveals a new mechanism of cardiomyopathy initiation by the RNA binding motif protein 20 (RBM20). This protein helps control RNA splicing in the heart, the process by which RNAs are sliced and diced to give rise to different proteins in different tissues. Normally, RBM20 splices RNAs to make proteins that enable the heart to adapt to stress and contract regularly throughout a person's entire life. But a class of mutations in RBM20 result in severe cardiomyopathy in adulthood.

"We and others had previously studied RBM20's function during heart development, but we had little to no clue of why it stops working in disease. We needed to step up our game if our research was to have a clinical impact," says Alessandro Bertero, PhD, who contributed to the work while at the University of Washington and now leads an Armenise-Harvard Laboratory at the University of Turin in Italy.

Discovering this protein's role was especially complex because knocking out this gene in animal models does not mimic the damaging effects seen in people. Instead, the work required editing the genome of healthy cells and engineering human heart tissue from these cells in a lab dish. Only by producing heart tissue similar to that found in humans could the authors understand the contractile defects and molecular mechanisms underlying this gene's function in a controlled manner.

"That was exactly what we intended when we started this project by genome-editing induced pluripotent stem cells," says co-leading author Yuichiro Miyaoka, PhD, of the Tokyo Metropolitan Institute of Medical Science.

First, the team observed that the engineered muscle tissue carrying the mutant form of RBM20 did not function like tissue engineered with normal RBM20 or lacking the protein all together. The mutated muscle fibers contracted with significantly less force and upstroke velocity, much like a heart affected by cardiomyopathy.

Then, at the single-cell level, the team detected another important clue. Normally, RBM20 is located exclusively within the cell nucleus. However, the mutated form localizes almost entirely out of the nucleus, in the cell's cytoplasm.

This, by itself, did not mean muchuntil the cell was exposed to heavy stress. When that occurred, the mutant protein was detected within tiny "stress granules" made of protein and RNA that cells rapidly produce as a reaction to stress. In contrast, RBM20 in healthy cells remained within the nucleus and distinct from stress granules. This suggests there are additional cellular mechanisms, along with changes in splice-activity, leading to RBM20 cardiomyopathy.

"When the RNA binding landscape of mutant RBM20 was revealed by a technology called enhanced CLIP, it mimicked the binding of other splicing factors that have been implicated in neurodegenerative diseases. These factors, when mutated, also change their activity from RNA splicing to RNA aggregation outside the nucleus," says co-author Gene Yeo, PhD, MBA, a member of the Department of Cellular and Molecular Medicine at the University of California San Diego.

"Over time, such aggregates play havoc with other cell functions, ultimately leading to the tissue-weakening of heart muscle during cardiomyopathy," Salomonis says.

"It is intriguing to note the parallels between our observations with RBM20 and recent findings in neuro-degeneration," the paper states. "Indeed, recent work has hypothesized cytoplasmic RBM20 may be similar to the cytoplasmic RNP granules associated with neurodegeneration (Schneider et al., 2020), such as TAU for Alzheimer s disease, Huntingtin for Huntington s disease, and FUS for amyotrophic lateral sclerosis (ALS)."

Next steps

Co-authors for this study also included scientists from the University of Cincinnati Department of Electrical Engineering and Computer Science, Sana Biotechnology, and the University of California San Francisco.

The co-authors say the 3D heart tissue model they've developed has the potential to be used to test new drugs to block the formation of cytoplasmic granules as a possible treatment for cardiomyopathy, even those without RBM20 mutations.

"RBM20 has been a frustrating protein to study, as animal models don't fully recapitulate human disease pathology," says lead author Aidan Fenix, PhD. "It's exciting to now have an in vitro human cell model of RBM20 cardiomyopathy that shows the major clinical feature of dilated cardiomyopathy--reduced contractile force. We hope these models will speed the discovery of therapies to treat RBM20 dilated cardiomyopathy."

About this study

This work was supported by grants from the National Heart, Lung, and Blood Institute (U01 HL099997, P01 HL089707, R01 HL130533, F32 HL156361-01, HL149734, R01 HL128362, R01 HL128368, R01 HL141570, R01 HL146868); the National Institute of Diabetes and Digestive and Kidney (U54DK107979-05S1); the National Science Foundation (NSF CMMI-1661730); a JSPS Grant-in-Aid for Young Scientists, and grants from NOVARTIS, the Mochida Memorial Foundation, SENSHIN Medical Research Foundation, Naito Foundation, Uehara Memorial Foundation, a Gladstone-CIRM Fellowship, and the A*STAR International Fellowship.

Cision

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SOURCE Cincinnati Children's Hospital Medical Center

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Heart Tissue in a Dish Reveals New Links Between Neurodegeneration and Heart Disease - Yahoo Finance

Supply chain woes are a headache for multiple industries, and the tech sector is no different amid semiconductor and component shortages and logistics disasters. The one exception may be 3D printing companies, which may actually benefit from supply chain challenges.

Stratasys' third-quarter earnings report hinted at an inflection point for 3D printing as supply chain issues are forcing manufacturers to rip up playbooks that have worked for decades. Offshore manufacturing doesn't look as good as it used to. Shipping costs are killing companies' margins, so you'll need more manufacturing closer to the customer. And inventory forecasting is a nightmare due to hoarding.

3D printing can alleviate a lot of these issues--as long as vendors can get enough inventory to make their own systems. Yoav Zeif, CEO of Stratasys, explained the supply chain challenges and opportunities well on the company's conference call.

We are one of those privileged industries there are not only suffering from the supply chain challenges, but also enjoying it long term because this is what brings to life the essence and the power of additive manufacturing. You want no more offshoring. You want to have digital inventory. You want to produce near the customer, and we see it every day in the level of engagement we have with the largest OEMs. We see that the world of manufacturing is going to change and be much more digitalized than what we see now.

Stratasys won't be the only one that may benefit from a shift from traditional supply chain practices to additive manufacturing.

Desktop Metal said it opened a new in-house manufacturing facility that will triple assembly space for its Production System platform. The upshot is that Desktop Metal is seeing pent-up demand for its Production System P-50 metal 3D printing platform.

3D Systems is also betting that additive manufacturing will see a demanding pop as enterprises look to make supply chains more flexible. 3D Systems has industrial use cases but has staked out healthcare and regenerative medicine as growth markets.

Lilach Payorski, CFO of Stratasys, said the third-quarter revenue growth of 24.3% was a sign of "the inflection point we are experiencing." "There was also strong performance from our manufacturing business, in particular, improvement from automotive and industrials in Europe," she said. Healthcare remains Stratasys' fastest growing business.

Stratasys reported revenue of $159 million with a net loss of $18.1 million, or 28 cents a share. Non-GAAP earnings were a penny a share. During the quarter, Stratasys landed a $20 million contract with the US Navy.

While in the long run, Stratasys can benefit from supply chain turmoil, Payorski said the company also has short-term issues like every other enterprise. She said:

We are carefully monitoring the ongoing macro issues of high global logistic costs and inflationary pricing of raw materials, which have pressured margins. Our top priority is to deliver our product in a timely manner. To help ensure this, we have increased production levels to offset sea and air delays in our planning process. We continue to evaluate a wide area of shipping options to ensure we can deliver goods with a minimal business impact.

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3D printing vendors poised to benefit long term from supply chain disruptions - ZDNet

UPDATE: U.S. regulators on Wednesday signed off on extending COVID-19 boosters to Americans who got the Moderna or Johnson & Johnson vaccine and said anyone eligible for an extra dose can get a brand different from the one they received initially. Latest update here.

_________________________________________________________________________

With both the Moderna and Johnson & Johnson vaccines nearing authorization for their COVID booster shots, what still needs to happen and what can you expect?

Here's what we know so far.

A panel of U.S. health advisers on Friday endorsed booster doses of Johnson & Johnsons single-shot COVID-19 vaccine. On Thursday, the same panel unanimously recommended a half-dose booster of the similar Moderna vaccine for certain groups.

The panel's vote marked the first step in a review process that also includes sign-off from the leadership of both the Food and Drug Administration and the Centers for Disease Control and Prevention.

Federal regulators are also expected to authorize the mixing and matching ofCOVID-19 booster dosesthis week and experts have said that announcement from the FDA is likely to come along with authorization for boosters of the Moderna and Johnson & Johnson shots.

The FDA will use its advisers recommendations in deciding whether to authorize the additional boosters. The agency isnt bound by the panel's vote but its ultimate decision could help expand the nations booster campaign.

If it approves, theres still another hurdle: A panel convened by the Centers for Disease Control and Prevention will need to offer more specifics on who should get one.

The CDC's advisory panel is expected to meet Thursday to discuss booster dose data. Once the panel makes its recommendation, a decision from the CDC is expected to follow soon after.

Illinois' health department said it is already anticipating the CDC will authorize the shots for both vaccines.

The FDA panel voted unanimously to recommend a Moderna booster shot for seniors, as well as younger adults with other health problems, jobs or living situations that put them at increased risk from COVID-19. The doses would be given to those who received their second dose at least six months ago.

But there's no evidence that it's time to open booster doses of either the Moderna or Pfizer vaccine to everybody, the panel stressed despite initial Biden administration plans to eventually do that.

Meanwhile, the panel backed boosters for anyone who received the J&J vaccine, which is authorized for people 18 and older, marking a shift from what the group recommended for both Pfizer and Moderna.

J&J has asked the FDA for flexibility with its booster, arguing the extra dose adds important protection as early as two months after initial vaccination -- but that it might work better if people wait until six months later.

The FDAs advisory panel voted unanimously that a booster should be offered without setting a firm time. The advisers cited growing worry that recipients of J&Js vaccination seem to be less protected than people who got two-dose Pfizer or Moderna options and that most got that single dose many months ago.

The push for boosters kicked off last month after the Food and Drug Administration authorized third doses of the Pfizer vaccine for seniors and younger adults with health problems, jobs or living conditions that place them at higher risk from the coronavirus. Though some who are immunocompromised can also get extra doses of the Pfizer and Moderna vaccines.

Here's a complete breakdown of who is eligible so far,according to the CDC:

What counts as a qualifying underlying health condition? Here's a list from the CDC:

In addition to the Pfizer authorization, officials have also cleared booster doses of both the Pfizer and Moderna vaccines for people with weakened immune systems.

According to the CDC, immunocompromised groups include people who have:

The agency notes that "people should talk to their healthcare provider about their medical condition, and whether getting an additional dose is appropriate for them."

Federal regulators are expected to authorize the mixing and matching ofCOVID-19 booster shotsthis week, but who should do it and when?

Mixing and matching refers to giving a booster dose of a vaccine that's different from the vaccine type that was used for the initial vaccination series.

The FDA, however, is expected to say that, especially for the mRNA vaccines from Pfizer and Moderna that have proved most effective against the virus, maintaining consistency in the vaccine course was still preferable. The agency was still finalizing guidance for the single-shot J&J vaccine.

Already, guidance from the Centers for Disease Control and Prevention has advised that mixing and matching booster shots for immunocompromised individuals, particularly those who received mRNA vaccines, was allowed in some situations.

"For people who received either Pfizer-BioNTech or Modernas COVID-19 vaccine series, a third dose of the same mRNA vaccine should be used. A person should not receive more than three mRNA vaccine doses," the CDC's website states. "If the mRNA vaccine product given for the first two doses is not available or is unknown, either mRNA COVID-19 vaccine product may be administered."

TheNational Institutes of Health study, which was released Wednesday and has yet to be peer reviewed, found that people who received the Johnson & Johnson vaccine produced stronger antibody levels after receiving a booster shot made by Moderna or Pfizer, compared to a booster from Johnson & Johnson. Those who were originally vaccinated with the Pfizer or Moderna vaccines and received either company's booster shot produced comparably strong immune responses, the researchers observed.

The findings were presented on Friday to the FDA's advisory committee. The panel met and recommended the authorization of a booster shot of Moderna and Johnson & Johnson.

The advisers didn't vote on whether that should be recommended but told the government to allow flexibility with boosters, saying there were no safety red flags even if it's not yet clear just how much difference, if any, mixing and matching may make in long-term protection.

In the real world all these kind of combinations are already happening so I think its a matter of some urgency for the FDA to help sort out what is admittedly a complicated and challenging scenario, said Dr. Ofer Levy of Boston Children's Hospital.

As for the dose, initial Moderna vaccination consists of two 100-microgram shots. But Moderna says a single 50-microgram shot should be enough for a booster.

The FDA panel wrestled with whether Moderna presented enough evidence backing its low-dose booster.

As the delta variant surged in July and August, a Moderna study found people who were more recently vaccinated had a 36% lower rate of breakthrough infections compared with those vaccinated longer ago.

Another study of 344 people found a six-month booster shot restored virus-fighting antibodies to levels thought to be protective and that included large jumps in antibodies able to target the delta variant. But that was a small study, and only about half of those people got the exact series of doses that would be offered under a Moderna booster campaign.

The data itself is not strong but it is certainly going in the direction that is supportive of this vote, said Dr. Patrick Moore of the University of Pittsburgh.

And several advisers worried that boosting with a lower dose might cost people some of the potential benefit of a full-strength third shot.

That may actually have a tremendous impact on the durability, Kurilla said.

Moderna said it chose the lower-dose booster because it triggered fewer uncomfortable shot reactions such as fever and achiness but also leaves more vaccine available for the global supply.

Now we have twice as much vaccine to go around, Dr. Robert Murphy,executive director of the Institute for Global Health at Northwestern University Feinberg School of Medicine, said in a statement. Thats a big thing. By recommending half a dose, you just doubled the amount of vaccine available. And theoretically there could be fewer side effects with a lower dose.

As breakthrough infections are reported, experts say certain at-risk groups in particular show the need for boosters.

We know that advanced age is a significant factor in COVID-19 breakthrough hospitalizations and deaths, but a booster dose can help provide continued protection, Illinois Department of Public Health Director Dr. Ngozi Ezike said Tuesday. While COVID-19 vaccines continue to be effective in reducing the risk of severe disease, hospitalization, and death, scientists and medical experts continue to watch for signs of waning immunity, how well the vaccines protect against variants, and how that data differs across age groups and risk factors.Booster doses recommended for those 65 years and older, and for long-term care residents, can combat waning immunity and help protect those at higher risk of severe illness.

Notably, Colin Powell, the first African American to serve as chairman of the Joint Chiefs of Staff and secretary of state, who passed away Monday,died from COVID-19 complications, even though he had been fully vaccinated against the coronavirus.

Powell, 84, was immunocompromised, and in the last few years, he had been treated for multiple myeloma, according to a longtime aide.

Following Powell's passing, doctors at Northwestern Medicine issued a news release in which they explained the 84-year-old's death shows the importance of booster shots.

Im afraid people will say the vaccine didnt help him," Murphy said. "But the mortality rate for vaccinated people is 11 times less than unvaccinated. People still die from the disease, especially if you are 84 and have underlying health risks."

The former secretary of state also underwent prostate cancer treatment in 2003. In announcing his death on social media, Powell's family did not address whether he had any underlying illnesses.

According to the Centers for Disease Control, patients who are older and/or immunocrompised are more vulnerable to contracting COVID with serious complications and death, even if they've been fully vaccinated.

But incidence of death from breakthrough cases still remains eight to 10 times less than unvaccinated persons with the same demographics, according to Northwestern doctors.

Dr. Khalilah Gates, associate professor of medicine in pulmonary and critical care at the Northwestern University Feinberg School of Medicine, said Powell's death enforces what doctors have been encouraging: continued vaccinations in older age groups and booster shots.

"For all of the Colin Powells amongst us, in our families, in our communities, we cannot afford to become lax. Weve come so far since March 2020, but we still have some ways to go together," the doctor said.

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Moderna, J&J COVID Booster Shots Near Authorization. Here's What to Know - NBC Chicago