Engineered cartilage and osteoarthritis – Boston Children’s Answers – Boston Children’s Discoveries

About one in seven adults live with degenerative joint disease, also known as osteoarthritis (OA). In recent years, as anterior cruciate ligament (ACL) injury and other joint injuries have become more common among adolescent athletes, a growing number of 20- and 30-somethings have joined the ranks of aging baby boomers living with chronic OA pain.

Key takeaways

Treatments for degenerative joint disease are limited, largely because the cartilage that protects the joints doesnt regenerate after birth. Without a way to stimulate regrowth of damaged cartilage, most treatments focus on managing symptoms. And with few curative treatment options, OA remains one of the leading causes of pain and disability in the United States.

Boston Childrens researcher April Craft, PhD, and her team want to change that. Their approach: grow cartilage in the lab that could be used to replace damaged articular tissues in patients joints.

The team first set out to understand how cartilage and joint tissues develop naturally and how stem cells differentiate into cartilage cells, or chondrocytes. The next step was to replicate that process in the lab, putting cells through the same stages of development.

In a study published this year in BMJ, members of the Craft Lab described their approach for generating cartilage from induced pluripotent stem cells (iPSC). Derived from patients own cells, iPSCs can give rise to virtually any type of cell in the body, including chondrocytes. The team generated cartilage-like tissues from two patients with progressive pseudorheumatoid arthropathy of childhood (PPAC), a genetic condition that causes severe premature joint degeneration.

We chose to study PPAC because joint degeneration in this condition progresses rapidly toward a state that is indistinguishable from end-stage OA, says Craft. Our iPSC model of PPAC cartilage will help us learn about this devastating disease. Their findings may possibly apply more broadly to OA from acute injuries or chronic overuse, as well as provide the basis for future therapeutics development.

Using cartilage engineered in the Craft Lab, the team has successfully repaired damaged joint tissues in rats and is preparing to test the procedure in large animals.

Because joint-lining cartilage is avascular and the implanted chondrocytes will be encased by the cartilage tissue itself, there is a reduced likelihood of implant rejection. Because of this, Craft believes that someday off-the-shelf cartilage for human patients could be created using one cell line. If so, live cartilage tissues could be produced, stored, and delivered to surgical teams as needed to replace damaged cartilage.

In some ways, the procedure resembles the most advanced cell therapy for cartilage: autologous chondrocyte implantation. In this two-procedure process, chondrocytes are harvested from one area of the body, expanded in number, and then implanted into the damaged area.

Off-the-shelf cartilage implants would allow patients to undergo just one surgical procedure rather than two. Replacing damaged cartilage with a piece of new cartilage that was generated ahead of time would omit the delay in manufacturing associated with autologous cartilage harvesting, reduce the rehabilitation time, and allow patients to return to their normal activities sooner after surgery.

The first humans to receive this novel implant would likely be patients who have pain and joint damage but havent yet progressed to severe degeneration. And eventually, it could be tried in others, such as athletes with joint damage.

This could have a profound impact on people as they age as well as athletes experiencing joint pain, says Craft.

Learn more about the Craft Lab and the Orthopedic Department.

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Engineered cartilage and osteoarthritis - Boston Children's Answers - Boston Children's Discoveries

BlueRock takes up option on iPSC cell therapy candidate OpCT-001 – The Pharma Letter

German pharma major Bayers (BAYN: DE) independently operated company BlueRock Therapeutics today revealed it has exercised its option to exclusively license OpCT-001 under a 2021 deal with FUJIFILM Cellular Dynamics and Opsis Therapeutics.

OpCT-001 is an induced pluripotent stem cell (iPSC) derived cell therapy candidate for the treatment of primary photoreceptor diseases and is the lead cell therapy candidate being developed under the strategic

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BlueRock takes up option on iPSC cell therapy candidate OpCT-001 - The Pharma Letter

The Enormous Potential of Induced Pluripotent Stem Cells (iPSCs) in Biomedical Research and Health Care – Medriva

In the realm of biomedical research and health care, one of the most promising advancements in recent years involves induced pluripotent stem cells (iPSCs). These cells, which can be reprogrammed to behave like embryonic stem cells, have vast potential for understanding and treating a broad range of diseases, including diabetes, cancer, and neurological disorders. Theyre also being used to develop new drugs and could pave the way for personalized medicine.

iPSCs are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state. This means they can potentially transform into any cell type in the body, making them a valuable resource for regenerative medicine and disease modeling. For example, they can be used to create patient-specific cell lines, which can then be used to study the mechanisms of disease at a cellular level, or to test potential treatments.

One of the significant advantages of iPSCs is their use in studying genetic diseases. By creating iPSCs from the cells of patients with specific genetic conditions, researchers can observe how these diseases develop and progress at a cellular level. This can provide invaluable insights into the underlying mechanisms of these conditions and could lead to the development of new, more effective treatments.

Moreover, iPSCs are playing a crucial role in drug discovery. They offer a more accurate and efficient way to test potential new drugs. Traditionally, new drugs are tested in animal models before being trialed in humans. But iPSCs provide a way to test these drugs on human cells, potentially speeding up the process and reducing reliance on animal testing.

Beyond disease study and drug development, iPSCs hold immense promise in the realm of regenerative medicine. They offer the potential to grow patient-specific tissues and organs for transplantation. This could revolutionize treatment for a variety of conditions, including heart disease, diabetes, and neurological disorders.

Furthermore, iPSCs have the potential to usher in a new era of personalized medicine. By creating patient-specific cell lines, treatments can be tailored to the individual, increasing their effectiveness and reducing the risk of adverse effects.

Despite their enormous potential, the use of iPSCs is not without challenges and ethical considerations. Issues such as the risk of tumorigenesis, the efficiency of reprogramming, and the possibility of immune rejection must be addressed. Moreover, the ethical implications surrounding the use of human cells in research and clinical applications must also be carefully considered.

Nonetheless, as our understanding and techniques improve, iPSCs are set to play an increasingly significant role in biomedical research and health care. With their potential to revolutionize disease study, drug development, regenerative medicine, and personalized healthcare, they represent one of the most exciting areas of modern medicine.

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The Enormous Potential of Induced Pluripotent Stem Cells (iPSCs) in Biomedical Research and Health Care - Medriva

Stem cells used to successfully treat arthritis in gorilla at Budapest zoo – University of Sheffield News

Stem cell therapy has been used to treat osteoarthritis in a gorilla for the first time, by scientists at the University of Sheffield.

Scientists at the University of Sheffield have used mesenchymal stem cells to treat arthritis in a gorilla at Budapest Zoo

The use of stem cells for the treatment of arthritis and regeneration of the damaged cartilage has been successfully piloted in several animal species, such as dogs and horses, in recent years

Liesel the gorilla is believed to be the first primate in the world to benefit from this joint work

Stem cell therapy has been used to treat osteoarthritis in a gorilla for the first time, by scientists at the University of Sheffield.

Liesel, the elderly matriarch at the Budapest Zoo has been finding it difficult to walk on her left leg for some time now, suggesting that she may be suffering from arthritis.

An international team, led by Endre Ss, Chief Vet and Acting Director General at the Budapest Zoo and Professor Mark Wilkinson, an Orthopaedic Surgeon and leading international expert in the treatment of human arthritis from the University of Sheffield, carried out a comprehensive assessment of Liesels major joints and used mesenchymal stem cells to treat alterations in her left hip and knee joints.

Osteoarthritis is a progressive degenerative process of the joint. Once the cartilage is worn and damaged, the process is irreversible and current treatments focus on symptomatic control but not to treat the disease itself.

The use of stem cells for the treatment of arthritis and regeneration of the damaged cartilage has been successfully piloted in several animal species in recent years, such as dogs and horses and small-scale clinical trials in humans have also proven to be a promising treatment for this condition. Liesel is thought to be the first primate in the world to receive the treatment and successfully benefited from the work of the research team.

Following previous successful research trials on arthritis-affected dogs, Stem CellX - a company made up of ateam of international scientists working in the field of stem cells, regenerative medicine, and genetics - was established to develop new technologies for the formulation of stem cell-based products for arthritis treatment in animals.

Stem CellX founder and Professor of Cell Signalling at the University of Sheffield, Endre Kiss-Tth has collaborated with Professor Mark Wilkinson for a number of years to explore novel treatment options for human arthritis. They now jointly lead a preclinical programme to test Stem CellX technologies for the development of a similar stem cell treatment in human patients.

The company recently partnered with Budapest Zoo to provide this treatment for animals in need, as well as supplying zoos globally.

The mesenchymal stem cells used for the procedure on Liesel were isolated from a piece of fat tissue donated by N'yaounda, a young female gorilla who underwent a planned minor operation in 2022. A specialist team at Stem CellX then isolated, purified and cultured these cells at their R&D base in Hungary to formulate a cell suspension that could be kept deep-frozen until the treatment.

Professor Kiss-Tth and Professor Wilkinson are now jointly leading a preclinical programme to test Stem CellX technologies for the development of a similar stem cell treatment in human patients.

Professor Endre Kiss-Toth, from the University of Sheffield and Founder of Stem CellX said:It has been a great privilege to be part of this word-first collaboration and bring together Stem CellX expertise in stem cell technologies, with the internationally leading clinical skills and knowledge in osteoarthritis pathogenesis of the University of Sheffield to provide a novel treatment option for Liesel to improve her quality of life in her golden years.

We are now following her recovery closely, in the hope to see marked improvement in her movements and in the use of her osteoarthritis affected leg.

Professor Mark Wilkinson, from the University of Sheffield and Leader of Clinical Orthopaedic Team, said:I was delighted to be part of the team doing this ground-breaking work and having the opportunity to treat Liesels arthritis. We are currently developing a similar treatment for humans. This work is in its very early stages but hopefully will lead to a real solution for patients to the pain and suffering that arthritis causes.

Honorary Associate Professor, Endre Ss, Leader of the Zoo Team said:The advanced husbandry and veterinary practices in modern zoos result inincreased longevity in many species, including apes. Our task is to providethe best medical care and best quality of life for these animals, despite theirage-related conditions. Stem-cell therapy hopefully brings in a new era in thisfield as well.

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Stem cells used to successfully treat arthritis in gorilla at Budapest zoo - University of Sheffield News

Allogeneic Stem Cell Therapy Falls Short on Stroke Outcomes – Medpage Today

Bone marrow-derived allogeneic stem cell therapy shortly after ischemic stroke did not improve outcomes at 90 days, a phase II/III randomized clinical trial known as TREASURE found.

The rate of excellent outcomes -- a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score (BI) of 95 or greater -- did not differ significantly between treatment and placebo groups (11.5% vs 9.8%, P=0.90; adjusted risk difference 0.5%, 95% CI -7.3% to 8.3%), Toshiya Osanai, MD, of Hokkaido University in Sapporo, Japan, and colleagues reported in JAMA Neurology.

However, exploratory subgroup analyses in patients with mRS scores of 0-2 at day 90 who were treated with the investigational multipotent adult progenitor cell therapy (MultiStem) seemed to show better outcomes, especially for patients with ischemic core volumes of 50 mL or more, and those age 64 or younger.

"Although there were no significant differences in the primary endpoint (excellent outcome at 90 days), subgroup analysis suggested that it may be effective in certain patient groups, such as younger patients and those with larger infarct size," Osanai wrote in an email to MedPage Today.

Exploratory post hoc analyses also indicated proportions of patients with global stroke recovery and a BI of 95 or greater at day 365 were significantly higher in the cell therapy group. BI scores range from 0 to 100, with a score of 100 indicating total independence.

"We had thought that the main mechanism of cell therapy for acute stroke would be immunomodulating and would start working quickly," Osanai said. "On the other hand, contrary to expectations, the cell therapy group tended to show predominant symptom improvement at 365 days rather than 90 days. At present, we cannot clearly explain this mechanism."

Reperfusion therapies for stroke offer varied outcomes, with many patients receiving endovascular thrombectomy still experiencing disability 3 months after stroke. Cell therapy, an alternative of interest, has shown mixed results for other cardiovascular indications. And though some research has suggested improved outcomes for stroke with autologous cell therapy, these studies were limited by small sample sizes and time-consuming procedures for stem cell preparation and administration, Osanai and colleagues noted.

Researchers included 206 adults from academic and clinical centers in Japan who had acute ischemic stroke (baseline NIHSS score of 8-20), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis, and an mRS score of 0 or 1 before stroke onset. Patients with lacunar or brainstem infarction, a change in NIHSS score of 4 or greater during a minimum period of 6 hours between screening and randomization, and those who received combined reperfusion therapy were excluded.

Participants had a mean age of 76.5 and 54.4% were male. They received a single intravenous dose of allogeneic stem cell therapy or placebo for 30-60 minutes between 18 and 36 hours after stroke onset. Patient visits were scheduled at 7, 30, 90, and 365 days after randomization, with phone calls at day 60 and every 2 months after day 90.

Primary safety endpoints, including grade 3 or 4 infusion-related allergic reactions, did not differ between groups. Treatment-emergent adverse events occurred in 29.8% of the cell therapy group and 11.8% of the placebo group.

Limitations of the trial included patient heterogeneity. The authors acknowledged that subgroup and post hoc analyses did not include statistical multiplicity and results were exploratory with small sample sizes. In addition, patients treated with both tissue plasminogen activator and mechanical thrombectomy were excluded.

Sophie Putka is an enterprise and investigative writer for MedPage Today. Her work has appeared in the Wall Street Journal, Discover, Business Insider, Inverse, Cannabis Wire, and more. She joined MedPage Today in August of 2021. Follow

Disclosures

The study was funded by Healios K.K., and investigational products were provided by Athersys.

Osanai reported relationships with Healios K.K., and co-authors reported relationships with pharmaceutical companies and other entities.

Primary Source

JAMA Neurology

Source Reference: Houkin K, et al "Allogeneic stem cell therapy for acute ischemic stroke the phase 2/3 TREASURE randomized clinical trial" JAMA Neurol 2024; DOI: 10.1001/jamaneurol.2023.5200.

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Allogeneic Stem Cell Therapy Falls Short on Stroke Outcomes - Medpage Today

Could Treatments for HIV and Sickle Cell Open the Gene Therapy Floodgates? – BioSpace

Pictured: Illustration of gloved hands using tools to manipulate a DNA double helix/iStock, MicrovOne

In the early 1990s, Mike McCune and his colleagues thought theyd found a path to a one-time HIV treatment for babies: genetically modifying hematopoietic stem cells to suppress the virus and then transplanting them into the bone marrow. But the treatment never made it to clinical trials.

It was not considered to be a good business plan, he explained, because companies would make more money by selling these patients antiretroviral therapies for a lifetime than to deliver a one-time treatment.

Vertex Pharmaceuticals and CRISPR Therapeutics Casgevy, which involves a process much like McCunes HIV treatmentex vivo gene editing of blood stem cells for the treatment of sickle cell disease (SCD) followed by transplantation back into the patientdid make it to market, having been recently approved by the FDA as the first CRISPR-based therapy. But Casgevy is pricy: it costs a whopping $2.2 million dollars. Its competitor Lyfgenia, another ex vivo gene therapy for SCD approved at the same time, carries a sticker price of $3.1 million. The high cost may limit access even for patients in the U.S., and will likely be a far more formidable barrier in sub-Saharan Africa, where 79% of babies with SCD are born.

Now McCune and others are looking to bring gene therapy to the masses by developing treatments that involve treating cells in vivo, which could be far less costly than the ex vivo variety. Requiring only a single injection, the in vivo approach would use vectors to deliver DNA-changing machinery into cells. In the case of SCD, the target would be blood-making stem cells and the tweaks would induce them to make healthy hemoglobin, McCune explained; for HIV, viral DNA could be snipped inside infected cells to prevent viral replication and spread, as well as reinfection.

While an existing in vivo gene therapies for rare genetic diseases also have eye-popping sticker prices, McCune argued that over time, costs will fall.

McCune, now head of the Gates Foundations HIV Frontiers program, is helping to forge agreements between the philanthropy and multiple private companies with the aim of making gene therapy an accessible reality as a treatment for both HIV and SCD. And at least one biotech, Excision BioTherapeutics, is pursuing a similar approach to HIV treatment independently of Gates.

As McCune sees it, there will be both a market and payers for a one-shot HIV treatment, both in the U.S. and in sub-Saharan Africa. He points out that the healthcare system is currently paying tens of thousands of dollars annually for each HIV patient in the U.S., money that could be redirected to paying for a cure. And in sub-Saharan Africa, he added, the U.S. is spending about $7 billion each year on antiretroviral treatment for people with HIV under a program called PEPFARfunding that could likely cover the cost of a one-shot treatment instead.

Theres no comparable payer for an SCD treatment, he said. We have to work on that. And I think thats going to become really important because the inequities of healthcare, so poignantly highlighted during COVID, are going to become even more glaringly obvious now that there are multimillion-dollar treatments that are likely to remain inaccessible to many people with SCD.

Gates has partnered with companies including Guide Therapeutics, bluebird bio, GreenLight Biosciences, Intellia Therapeutics, CRISPR Therapeutics, Immunocore, BioNTech, Vir, Ensoma, Emmune, Addition and Novartis, as well as nonprofits and academic labs, to work on aspects of in vivo gene therapy. The foundation has also partnered with the National Institutes of Health, which committed to kicking in $100 million toward the effort.

Agreements with partners, McCune said, include a non-exclusive right for the Gates Foundation to make sure that the technologies are available to people living with HIV and SCD in low- and middle-income countries. Why would they give us those rights? he asked. Part of the answer is that the applications of this platform are diverse, outside of the realm of HIV and sickle [cell disease] and into the realm of the more remunerative diseases that companies seem to focus on in the context of gene therapy, including cancer. They would see this as a pathway for return on investment, which [could] be huge, McCune said.

Intellia, a former Gates grantee, is in the preclinical stages of developing an in vivo CRISPR treatment for SCD, company spokesperson Ian Karp wrote in an email to BioSpace. The benefit of a one-time treatment certainly has applicability to patients across the globe, he said. Additionally, our technology platform is modular, such that we do hope to leverage it across multiple indications / diseases. Oftentimes the only change we need to make from one investigational product to the next (particularly when targeting the same cell type and edit type) is in the targeting region of the guide RNA which serves to direct the CRISPR machinery to the gene of interest.

Similarly, Christine Silverstein, chief financial officer at Excision BioTherapeutics (which has not received Gates funding), said that the technology behind the companys candidate CRISPR HIV treatment, the Fast Tracked EBT-101, may be applied to other chronic viral infectious diseases including herpes and hepatitis B. In fact, our work in HIV is setting the foundation for advancements of Excisions pipeline which unites next-generation CRISPR nucleases with a novel, multiplexed gene editing approach to develop potentially curative therapies, she said in a statement.

But success is by no means assured. Despite the current excitement over CRISPR, hurdles to its therapeutic use remain, including not-insignificant safety concerns, and safety issues have also cropped up with other gene therapies. The Gates Foundation itself is hedging its bets, working in parallel to drive the development of a therapeutic vaccine for HIV.

Still, McCune is dreaming big. Even for conditions where effective treatments exist, these sorts of in vivo treatments might be something that takes pills off the shelves and sets the course for a different kind of medicine.

Shawna Williams is a senior editor at BioSpace. She can be reached at shawna.williams@biospace.com or on LinkedIn.

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Could Treatments for HIV and Sickle Cell Open the Gene Therapy Floodgates? - BioSpace

Embryo Patrol. Artificial Embryos Are Not Human Babies | by Karen Marie Shelton | ILLUMINATION-Curated | Jan, 2024 – Medium

Artificial Embryos Are Not Human Babies Didactic Model of Human Embryonic Development Wagner Souza Esilva Wikimedia

Artificial embryos are not human. Theyre simply a cluster of cells. To be legally human, they must meet the definition of an in vitro fertilized human ovum.

As of the end of 2023, artificial embryos couldnt be successfully implanted into mammals or humans. They couldnt lead to pregnancies, and there is no plan for that to happen in the future.

Synthetic embryos utilize stem cells groundbreakingly, sidestepping the need for sperm or eggs. Ongoing breakthroughs might eventually aid research into genetic disorders and improve babies health, including reducing the risk of problem pregnancies and miscarriages.

Artificial embryos are not related to in vitro fertilization (IVF), which can lead to a human pregnancy.

The term is misleading. These structures arent really synthetic, nor are they exactly embryos. But theyre similar. They are tiny balls of cells arising from a sperm fertilizing an egg but created from stem cells grown in the lab.

Synthetic human embryos, or SHEEFs (synthetic human entities with embryo-like features), are created from very early (actually pre-embryonic) zygotic cells called stem cells.

The stem cells are called pluripotent because they have the potential to develop into almost every cell of the body.

The lab-created embryos are not connected to a beating heart or a brain. They do include cells that would typically go on to form a version of a placenta, yolk sac, and embryo itself.

The model embryos, which resemble human versions, recreate the earliest stages of human development. They could provide a crucial window into genetic disorders and the underlying biological causes of recurrent miscarriage.

Robin Lovell-Badge, headent head of stem cell biology and developmental genetics at Francis Crick Institute in London, reported project advancements. She explained weve cultivated embryos to a specific stage just beyond what is equivalent to 14 days of development for a natural embryo.

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Embryo Patrol. Artificial Embryos Are Not Human Babies | by Karen Marie Shelton | ILLUMINATION-Curated | Jan, 2024 - Medium

Enhancing Stem Cell Tracking with Nanoparticle Imaging Agents – AZoNano

Sponsored by MerckJan 23 2024Reviewed by Emily Magee

Stem cell therapies show promise in tissue engineering, regenerative medicine, and their homing effect. They offer hope for treating numerous incurable diseases like Parkinsons disease, liver failure, ischemic heart disease, and cancer.

However, understanding the cell distribution, migration behaviors, and functionality post-engraftment remains challenging due to the absence of effective in vivo tracing methods. This lack impedes the clinical progress of stem cell therapies.

To overcome this hurdle, it is crucial to develop advanced imaging strategies that can label and track transplanted stem cells without disrupting their normal functions. These strategies are necessary to uncover therapeutic mechanisms and assess safety before clinical trials.

Imaging techniques suited for stem cells should prioritize non-toxicity, high resolution, longevity, and the dynamic provision of cell fate information. Over recent years, several bioimaging approaches have emerged.

One particularly promising tactic involves leveraging well-designed nanoparticles as contrast agents to monitor stem cells. These nanoparticles boast unique physicochemical properties and offer versatility and customizability.

However, existing imaging methods still fall short of meeting all the necessary in vivo stem cell tracking demands.

This article provides a concise examination of the four commonly utilized nanoparticle-based imaging techniques for the tracking of stem cells: magnetic resonance imaging (MRI), fluorescence imaging, ultrasound imaging (USI), and photoacoustic imaging (PAI) (Figure 1).

Emphasis is placed on the design of contrast nanoagents, the corresponding imaging mechanisms, and the specific challenges these nanoagents have addressed.

The objective is to illuminate potential pathways for future advancements in contrast agent development, aiming to create more sophisticated solutions for the in vivo tracking of transplanted stem cells.

Figure 1.Various contract nanoagents designed for magnetic resonance imaging, fluorescence imaging, ultrasound imaging, and photoacoustic imaging modalities in stem cell trackingin vivo.Image Credit:Merck

The preferred method for in vivo stem cell imaging is MRI, owing to its distinctive attributes such as unrestricted penetration depth, exceptional spatial (ranging from 40 to 100 m), and temporal (ranging from minutes to hours) resolution, and safe operational nature.1

MRI operates in two main categories: T1/T1* and T2/T2*-weighted MRI. These categories are determined by the relaxation time of the longitudinal (T1) and transverse (T2) components of the magnetization vector towards equilibrium below the applied magnetic field.

MRI contrast agents, such as gadolinium (III) chelates and superparamagnetic iron oxide nanoparticles (SIONPs), are introduced to heighten resolution and amplify signal intensity by influencing the relaxation times of nearby water protons.2

Gadolinium (III) chelates are efficient T1 contrast agents as they accelerate the longitudinal relaxation rate (T1), thereby enhancing positive contrast in T1-weighted MRI sequences.

SIONPs function as T2 contrast agents and have found widespread application in MRI-based cell tracking by producing negative contrast through the reduction of T2/T2* relaxation times.

The subsequent section reviews nanoparticle-based contrast agents that have demonstrated clinical or commercial validation for their utility in stem cell tracking applications.

Nanoparticle-based stem cell labeling agents necessitate specific criteria: colloidal stability, non-toxicity, strong magnetism, and efficient labeling. Achieving colloidal stability in aqueous solutions typically involves utilizing hydrophilic polymer coatings like chitosan, dextran, and PEG, among others.

A preclinical study by Margarita Gutova et al. demonstrated the transplantation of neural stem cells (NSCs) labeled with dextran-coated ferumoxytol (FDA-approved SIONPs) into patients with brain tumors.3 The distribution of NSCs was consistently monitored over 12 weeks at various intervals, followed by surveillance serial MRI scans.3

Enhanced labeling efficiency can be achieved by modifying particle surfaces to carry a positive charge or specific ligands.

For instance, compared to ferumoxytol, self-assembling ferumoxytol nano-complexes altered with heparin and protamine sulfatewhich reversed the original particle's negative chargeexhibited increased labeling efficiency and a threefold rise in T2 relaxivity.

This modification approach demonstrated in vivo MRI detection of a minimum of 1000 HPF-labeled cells implanted within rat brains.4

Clinically approved Gd-DTPA enclosed within cationic liposomes ensured highly efficient uptake of Gd and exceptional intracellular retention in mesenchymal stem cells.

The Gd-DTPA-liposomes complex contrast agent rendered 500000 labeled stem cells distinctly visible for a minimum of two weeks on a 3.0 T clinical scanner, effectively overcoming the relatively low MRI sensitivity of Gd-DTPA.5

Monitoring the migration and survival of stem cells is crucial for both therapeutic efficacy and safety evaluations.

For investigating stem cell migration, Lili Jiang et al. observed that T2*-weighted MRI successfully tracked the migration of implanted pluripotent stem cells labeled with SIONPs (from Merck KGaA, Darmstadt, Germany) from the injection site to the injured brain areas for more than four weeks.6

In assessing cell survival, Ashok J. Theruvath et al. observed significant changes in ferumoxytol-labeled apoptotic matrix-associated stem cell implants (MASIs), indicating a substantial loss of iron signals and an extended T2 relaxation time, which persisted up to two weeks post-implantation during a cartilage repair process.7

When coupled with histopathologic examination, a ferumoxytol-based contrast agent could serve as an indicator distinguishing between living and deceased stem cells.

The duration for tracking stem cells varies depending on specific tissues, organs, and diseases, spanning from several days to months. An effective strategy for in vivo stem cell tracking involves evaluating cell distribution, migration, and differentiation, as well as assessing the efficacy and safety of cell implantation.

Despite the rapid advancements in nanoparticle-based MRI for stem cell tracking, certain challenges persist. These include imaging the differentiation and functionality of stem cells, integrating MRI contrast agents with reporter genes, and combining MRI with other noninvasive imaging tools.

Fluorescence imaging, a traditional optical imaging method, is affordable and highly sensitive, but its effectiveness is limited by poor tissue penetration (<1 cm) in comparison to MRI technology.

One potential solution involves fine-tuning fluorophores or fluorescent proteins to be responsive within the near-infrared (NIR) range, enabling deeper tissue penetration. However, challenges like severe photo-bleaching and light scattering restrict tracking efficiency and duration.8

The evolution of fluorescent nanoparticles (NPs) has significantly enhanced the capability of fluorescent imaging for long-term stem cell tracing in vivo.

Quantum dots (QDs), a set of classic inorganic semiconductor NPs used for cell labeling,9 rely on the transition behaviors of excited electrons across various energy levels. These transitions can be adjusted by manipulating material components or compositions, enabling the realization of NIR emission.

For instance, CdSe/ZnS core/shell structures were developed specifically to label and track adipose tissue-derived stem cells (ASCs) in C57BL/6 mice models using NIR emission.10

Modifying the bandgap of materials significantly enhances the optical properties of QDs.11

Wang et al. coupled NIR-II fluorescence QDs of Ag2S with the traditional bioluminescence red firefly luciferase (RFLuc) to label human mesenchymal stem cells (hMSCs).

Using a wide spectrum spanning from 400 to 1700 nm, the researchers investigated the dynamic tracking of survival and osteogenic differentiation of the transplanted hMSCs in a mouse model with calvarial defects.12

Up-conversion nanoparticles (UCNPs) have also been employed to label and track mouse MSCs. UCNPs utilize the anti-Stokes process, absorbing multiple NIR photons to generate a single short-wavelength photon.13,14

Despite this, rare earth metal ions doped in UCNPs and heavy metal ions in QDs pose potential safety risks for tracing clinical stem cells. Aggregation-induced emission (AIE) fluorophores offer a secure method to track stem cells, boasting excellent photostability in comparison to inorganic NPs.15-18

AIE fluorophores remain non-emissive when dispersed but emit robust fluorescence when in an aggregated state due to limited intramolecular rotation, unlike aggregation caused by quenching (ACQ). This unique property makes Dots or AIE NPs present enduring and robust fluorescent signals.

For example, AIE Dots derived from tetraphenyl ethylene have demonstrated the ability to trace the journey of adipose-derived stem cells (ADSCs) over an extended period, outperforming green fluorescent proteins (FPs) and other bioluminescent molecules.18

It is also easy to adjust the AIE monomer for NIR or even NIR-II emission. The advancement of AIE Dots is an encouraging option for in vivo stem cell tracking, offering prolonged stability and reliability.

Due to its remarkable temporal and spatial resolution and substantial tissue penetration depth, ultrasound imaging stands as a potent method for noninvasive and long-term cell tracking in stem cell therapies.19

However, its effectiveness is hindered by the limited contrast between implanted cells and neighboring soft tissues. To address this, ultrasound contrast agents (UCAs), a type of echogenic material, are deployed in clinical settings to enhance contrast and amplify detection signals.20

Traditional UCAs are micro-sized gas-filled bubbles, made of a bioinert heavy gas enveloped by stabilizing shells like proteins, lipids, and biocompatible polymers.21 The potential of these microbubbles for tracking stem cells is curbed by their inadequate structural stability, big microscale size, and short half-life.

Recent research has directed its attention toward scaling down UCAs, leading to the development of nanoscale UCAs such as nanobubbles, silica nanoparticles, and nanotubes tailored for ultrasound imaging.22

Achieving stability in the shell structure is crucial for nanobubbles. Leon et al. described a highly stable nanobubble type by employing a bilayer shell design with varying elastic properties akin to bacterial cell envelopes.23

These ultrastable nanobubbles exhibit minimal signal loss under continuous ultrasound exposure in vitro and boast a prolonged lifespan when tested in vivo. However, due to their small size, nanobubbles might lack sufficient ability to efficiently scatter ultrasonic waves.

To address this, a "small to large" transformation approach has been proposed. This strategy involves nanoscale UCAs transforming into microbubbles upon exposure to ultrasound, thereby amplifying the resulting echo signals.24 Gas-generating nanoparticles exemplify this concept.25,26

Min et al. reported a carbonate copolymer nanoparticle featuring a distinctive gas-generating mechanism. These nanoparticles undergo hydrolysis, yielding microscale CO2 bubbles that effectively absorb ultrasonic energy.27

Silica nanoparticles and similar glass-based nanomaterials significantly boost ultrasound signals due to tissue irregularities caused by the rigid characteristics of these nanoparticles, creating high impedance differences at tissue interfaces.28

Chen et al. detailed an innovative exosome-like silica (ELS) nanoparticle with high ultrasound impedance mismatches designed specifically for stem cell labeling and tracking using ultrasound.29

The researchers found that the nanoparticles' discoid shape, coupled with a positive charge, facilitated cellular uptake, and inherently heightened echogenicity. Silica nanoparticles with varied structures, like hollow and mesoporous configurations, also exhibited substantial ultrasound contrast.30

These silica-based nanoparticles show promise as UCAs for real-time stem cell tracking through ultrasound imaging due to their relatively robust structural integrity, low toxicity, and adaptable size and structure.

Biosafety and precise imaging are crucial for tracking cells in vivo over extended periods. PAI emerges as a promising biomedical imaging technique, based on the principle of the photoacoustic effect.

When a pulsed laser is introduced, it generates heat. The intermittent heat results in expansion, which is identified by PAI as a mechanical wave. This imaging method couples the strong contrast of optical imaging with the deep tissue penetration capabilities of ultrasonic imaging, offering real-time and high-resolution data in vivo.

PAI contrast nano agents are extensively used in vivo for imaging stem cells due to their exceptional capacity for photothermal conversion and the nanoparticles' biocompatibility

Various PAI contrast nano agents have been developed to absorb light across a spectrum, stretching from visible light to the NIR II region. This aims to minimize light absorbance and scattering within tissues.

Tracking methods that solely provide physical information, such as the whereabouts of labeled stem cells, do not meet the demands of studying stem cell engraftment. There is a pressing need for new platforms that can indicate real-time cell function and viability, crucial for clinical applications.

By focusing on the design of contrast nanoagents, new studies of PAI-based stem cell tracking were outlined in the following aspects: shape, component, size, and surface modification, shedding light on the essential factors that require consideration in the design of PAI contrast agents (Table 1).

Gold nanoparticles stand out among the various PAI contrast agents due to their notable advantages, including outstanding photothermal conversion efficiency, stable imaging capabilities, and high biosafety. The inert feature of gold nanoparticles has little effect on cell function.32

The Suggs group employed gold nanospheres of different sizes (20 nm, 40 nm, and 60 nm) in vivo to label and monitor MSCs.33

This study demonstrated the possibility of loading gold nanoparticles into MSCs for imaging purposes while preserving cell functionality post-loading. The research showed that gold nanoparticles remained detectable within stem cells for up to fourteen days, highlighting the potential for long-term and noninvasive cell tracking via PAI.

Anisotropic gold nanoparticles exhibit superior photothermal conversion efficiency. Jokerst et al. highlighted that applying a silica coating notably boosted the uptake rate of gold nanorods into stem cells by up to five times, achieving a minimum detection limit of 100000 labeled cells in vivo.34

The intricate transplant microenvironment in vivo poses challenges. Ricles et al. utilized a dual gold nanoparticle system, comprising gold nanorods and gold nanospheres, to track transplanted stem cells and image infiltrated macrophages.35

These studies introduced a novel approach to differentiate delivered stem cells from infiltrating immune cells, offering insights into the mechanisms of injury healing. Researchers also combined PAI with other imaging techniques to enhance tracking accuracy.

Nam et al. merged PAI with ultrasound imaging to monitor MSCs labeled with citrate-stabilized gold nanospheres.36 This combined approach offered both morphological insights through ultrasound imaging and functional information via photoacoustic imaging, allowing for spatial visualization of labeled MSCs.

Qiao et al. employed magnetic resonance and PAI techniques to track iron oxide (IO)@Au core-shell structure-labeled MSCs for imaging brain tumors.

This system exhibited potential for mapping cell trajectories and visualizing stem cell migration toward brain tumors in real time.37 Additionally, nanoparticles with NIR absorption capabilities were developed for stem cell tracking via PAI due to the superior penetration depth of NIR light.

Kim et al. utilized Prussian blue nanoparticles with robust light absorption at 740 nm for tracking stem cells.38

In vivo, these nanoagents demonstrated detection limits of 200 cells/L, enabling monitoring for up to fourteen days post-injection, attributed to the excellent bio-stability and NIR-I detectability. Yin et al. developed a NIR-II organic semiconductor polymer specifically for stem cell tracking via PAI.39

The researchers observed a significant 40.6-fold and 21.7-fold enhancement in subcutaneous and brain imaging, respectively, primarily due to the deep tissue penetration of NIR-II light.

To monitor stem cell activity post-transplantation, Dhada et al. engineered a ROS-sensitive dye (R775c) coated onto gold nanorods.

The strategy leveraged the fact that stem cells release ROS to degrade dying cells in vivo, enabling the measurement of stem cell viability. Consequently, they could simultaneously visualize cell viability and location in vivo using PAI.40

Table 1.The design of nanoparticle-based contrast agents for PAI.Source:Merck

Table 2. Comparison of different imaging modalities. Source:Merck

Nano agents offer key advantages over organic molecules in PAI imaging, primarily in terms of photostability, water solubility, and biocompatibility.

The limitations of PAI hinge on the penetration depth and photothermal conversion efficiency of contrast nano agents. Therefore, future advancements in PAI imaging are likely to focus on developing nanomaterials with enhanced NIR-II responsiveness and improved biocompatibility.

Advancing stem cell-based therapies heavily relies on the progress of stem cell tracking techniques. Current imaging technologies present both strengths and limitations (Table 2).

Consequently, the choice of imaging modalities depends on specific tissue requirements and imaging depth.

A range of nanoparticles, including iron oxide nanoparticles, quantum dots, aggregative-induced emission nanoparticles, silica nanoparticles, and gold nanoparticles, have been employed for stem cell tracing due to their distinct physical-chemical properties. These properties enhance imaging signals upon irradiation.

By elaborately designing the structures and compositions, nanoparticles play a pivotal role in improving the performance of existing imaging modalities concerning imaging resolution, stability, and lifespan. However, tracking stem cells in vivo remains a significant challenge in the biomedical field.

The amplitude of the image signal typically correlates linearly with contrast nanoagent concentration, but as contrast agents within cells dilute through cell division, challenges arise. This fuels the necessity for a new generation of contrast agents that resist dilution or prompt cells to self-synthesize these agents, addressing this issue.

Additionally, apart from cell division, studies indicate that nanoparticle levels within cells achieve equilibrium via endocytosis and exocytosis, potentially leading to false positive detections in vivo.

Moreover, few contrast agents can capture a cell's live state and normal functional abilities, severely limiting the exploration of stem cell therapy mechanisms. Therefore, concerted efforts are crucial to design multifunctional contrast agents that address these concerns.

Lastly, the advancement of both imaging devices (the "hardware") and imaging contrast agents (the "software") is urgently needed. This development aims to enable precise, long-term, and dynamic tracking of transplanted stem cells, a critical aspect of the field.

This information has been sourced, reviewed, and adapted from materials provided by Merck.

For more information on this source, please visit Merck.

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Enhancing Stem Cell Tracking with Nanoparticle Imaging Agents - AZoNano

1st-of-its-kind therapy blocks immune attack after stem-cell transplant – Livescience.com

A new treatment may be able to prevent a common immune-related complication of lifesaving bone-marrow transplants, a midstage clinical trial shows.

In patients with blood cancer, high doses of chemotherapy or radiation therapy are used to kill the cancerous cells, but these treatments also damage the patients' healthy, blood-forming stem cells. To rectify this, doctors may perform a type of bone-marrow transplant known as an allogeneic hematopoietic stem cell transplant (HSCT), in which blood-forming stem cells from a healthy donor are transplanted into the cancer patient.

But there's a potential catch: Immune cells in the donor's tissue can sometimes attack the recipient's tissue, because the cells see it as foreign. A short-term form of this condition, called graft-versus-host disease (GVHD), affects around 40% of bone-marrow transplant patients, while different studies estimate that between 6% and 80% develop a chronic form of GVHD.

There are ways to reduce a patient's risk of this reaction, for example, by prescribing immune-suppressing drugs, but this reduces their ability to fight pathogens. There are also treatments that target a type of immune cell called T cells in the donor tissue. Although these therapies can be effective, they may come with an increased risk of cancer relapse or infection, the scientists behind the new trial wrote in a study published Jan. 4 in the journal Blood.

Related: Zika virus could potentially treat cancer, another early study hints

In contrast, the new treatment, called CD24Fc, derails the immune response at an earlier stage, by inhibiting the response of the cells responsible for activating T cells.

Specifically, the treatment prevents so-called antigen-presenting cells from activating donor T cells that would go on to attack the cancer patient's cells that have been damaged by radiation and chemotherapy before transplantation. These antigen-presenting cells can differentiate between the damaged host cells and pathogens, such as viruses, so CD24Fc only quietens the unwanted inflammation tied to GVHD and not other, helpful immune activity. As such, CD24Fc has also been trialed as a treatment for other conditions that are exacerbated by an off-the-rails immune response to tissue damage, such as severe COVID-19.

"The molecular targets of the intervention are new and original," Dr. Ivan Maillard, a professor of medicine at the University of Pennsylvania who was not involved in the research, told Live Science in an email. CD24Fc kicks in right as the body senses the tissue damage associated with the transplant procedure, rather than later on, he said.

The new trial included 26 patients with blood cancer who received three doses of CD24Fc in the month before they underwent an allogeneic HSCT. They also received the standard, post-transplant immunosuppressive treatment. Of these patients, only one developed moderate-to-severe GVHD within six months of their surgery.

The researchers cross-referenced the trial participants' data to that of 92 patients who underwent the same procedure but without CD24Fc. These patients' results were pulled from a database, and 68 of the patients, or 74%, developed GVHD within six months.

Related: 'Bionic breast' could restore sensation for cancer survivors

The trial's results are "impressive," Dr. Javier Bolaos Meade, a professor of oncology at Johns Hopkins Medicine who was not involved in the research, told Live Science in an email. However, after a year, the researchers found no significant difference in overall survival rates, risk of chronic GVHD, or relapse rates between the two groups, which was "disappointing," he said.

CD24Fc caused minimal side effects in most patients, the authors wrote in the paper. However, two of the 26 patients developed a rare-but-serious skin disorder called Stevens-Johnson syndrome, which is normally caused by an adverse immune reaction to certain medications.

"Whether this rare complication was related to administration of CD24Fc cannot be excluded and will require careful monitoring and evaluation in future trials," Dr. Paul Martin, a professor emeritus of clinical research at the Fred Hutchinson Cancer Center in Seattle who was not involved in the research, wrote in a commentary accompanying the study.

The authors highlighted several limitations of the study, including that it was small and that the conclusions about CD24Fc's effectiveness stem from comparisons to historic data, rather than to a typical control group you'd expect in a gold-standard trial. This may have skewed the reliability of the findings for several reasons; for instance, the trial patients and historic patients may have differed from each other in key ways that weren't flagged or accounted for.

Nevertheless, Bolaos Meade and Maillard anticipate that there will be more studies testing this approach to GVHD prevention, which could provide more robust data about its effectiveness.

This article is for informational purposes only and is not meant to offer medical advice.

Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to community@livescience.com with the subject line "Health Desk Q," and you may see your question answered on the website!

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1st-of-its-kind therapy blocks immune attack after stem-cell transplant - Livescience.com

Stem cell research project to launch into space – Fox Weather

Science experiments are launching to the space station on NASA's 20th Northrop Grumman mission.

A Mayo Clinic research project focusing on gravitys role in bone loss will be one of several experiments aboard a SpaceX Falcon 9 rocket when it lifts off from Cape Canaveral Space Force Station later this month.

The mission is known as NG-20 and is destined to deliver food, supplies and experiments to the International Space Station.

The stem cell experiment has been a long time in the planning and researchers say theyll be able to learn more about tissue repair and regeneration.

"Weve known for some time that astronauts lose bone density on long-duration space flights," Dr. Abba Zubair, a laboratory medicine and pathology specialist at the Mayo Clinic said in a statement. "We want to understand how this occurs so we can work on solutions that prevent bone loss not only in astronauts while theyre in space but also in patients here on Earth."

Northrop Grummans 20th operational cargo delivery flight

(Northrop Grumman / FOX Weather)

Zubair believes the experiment could have implications on clinical trials and travel to Mars.

"We will use what we learn from this project to advance our research on the road to clinical trials, with the ultimate goal of testing therapeutic agents that can prevent or treat bone loss that comes with osteoporosis, as well as bone loss that occurs in patients who are bedridden for long periods of time," Zubair stated.

2024 ROCKET LAUNCH SCHEDULE SHOWS CONTINUED STEADY PACE OF BLAST-OFFS

If weather or technical matters dont delay the launch, itll lift off from Floridas Space Coast on Jan. 29 with spacecraft named after NASA astronaut Dr. Patricia "Patty" Hilliard Robertson.

Robertson was killed during a private plane crash a year before she was set to arrive at the ISS in 2002.

"It is the companys tradition to name each Cygnus spacecraft in honor of an individual who has made substantial contributions to human spaceflight. Dr. Robertson was an accomplished medical doctor and avid acrobatic pilot prior to her NASA career," Northrop Grumman, the producer of the Cygnus spacecraft, stated.

Dr. Patricia "Patty" Hilliard Robertson

(NASA)

A crew of seven aboard the ISS will be tasked with unloading the Cygnus spacecraft a few days after launch.

The mission is Northrop Grummans 20th cargo flight to the ISS, which is expected to continue through 2026.

SEE THE OBJECT HUMANS LEFT BEHIND ON THE MOON

Other experiments aboard the NG-20 will involve testing a 3D metal printer, semiconductor manufacturing and a thermal protection system.

The Mayo Clinic stated a second space flight could launch by the end of the year, which would analyze bone formation and loss.

The combination of experiments is expected to help researchers study bones healing potential and lead to potential treatments that could be used in space and on Earth.

The International Space Station

(NASA)

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Stem cell research project to launch into space - Fox Weather