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Archive for the ‘Drug Development using MultiOrgan Chip’ Category

FDA Contemplates Changes in Trial Design, Drug Development and Use of AI in Clinical Trials

Curator: Stephen J. Williams, Ph.D.

Several pharma companies just told the FDA what AI in clinical trials should look like.

It is not what most people expect.
I went back through the RTCT comment letters from Novartis, Lilly, Bayer, Daiichi and others. Read together, they are the clearest signal yet on how AI will get adopted in drug development over the next few years.
Three things they make clear.
Adoption starts at the data layer, not the decision layer. Every letter drew the same line: AI supports qualified clinical judgment, it does not replace it. Daiichi was explicit that AI should not autonomously make dose escalation or safety decisions. But underneath that line, they want automation everywhere. Reconciliation, coding consistency, discrepancy detection, safety surveillance. That is where AI enters trials first, and it is where the near-term value is.
The bar is oversight, not sophistication. Lilly put it best: the FDA should select for the most mature oversight of AI, not the most mature AI. Across the letters, the requirements are validation, audit trails, data lineage, change control, human review that is evidenced rather than assumed. A brilliant model with weak governance does not clear this bar. A well governed one doing unglamorous work does.
The industry is already building the plumbing. Lilly and Bayer, independently, both proposed a DMF-style pathway letting AI vendors disclose model documentation directly to the FDA with sponsors referencing it.
Put those together and the future looks less like AI making trial decisions and more like AI making trial data trustworthy fast enough for humans to decide sooner.
The sponsors who lead this will not be the ones with the most sophisticated models. They will be the ones whose data operations were modernized and able to clean enough to move in real time.

 

FDA News Release

FDA Announces Major Steps to Implement Real-Time Clinical Trials

Agency unveils real-time trial proofs-of-concept and upcoming pilot program

For Immediate Release:

April 28, 2026

On May 27, 2026, the FDA posted a notice in the Federal Register extending the comment period for the Request for Information until June 29, 2026. 

The U.S. Food and Drug Administration today announced two major steps as part of an initiative to advance the implementation of real-time clinical trials (RTCT). First, the agency unveiled the successful initiation of two proof-of-concept clinical trials that will report endpoints and data signals to the agency in real time. Second, the agency released a Request for Information (RFI) regarding a proposed pilot program for RTCT that will launch this summer.  

Early-phase clinical trials are a bottleneck in drug development, often characterized by high uncertainty, limited patient populations, and inefficient decision-making processes. Data is typically reported from sites to sponsors, who analyze and subsequently submit data to the FDA. With improvements in AI and data science, sponsors and trial sites have the opportunity to conduct real-time trials in a way that enhances safety monitoring and radically increases efficiency.  

“For 60 years, we’ve been conducting clinical trials in the same way, where key data signals can take years to reach the FDA. The lag time can delay regulatory decisions unnecessarily and slow down the drug development timeline,” said FDA Commissioner Marty Makary, M.D., M.P.H. “We are boldly advancing a modern approach whereby FDA scientists can view safety signals and endpoints in real time as a trial progresses. This will help us accelerate promising therapies, and build toward our ultimate goal of running real-time, continuous trials across all phases of drug development.”  

The FDA is announcing the successful initiation of proof-of-concept RTCTs by AstraZeneca and Amgen. AstraZeneca is conducting a Phase 2 multi-site trial, TRAVERSE, in patients with treatment-naïve mantle cell lymphoma, with participation from The University of Texas MD Anderson Cancer Center and University of Pennsylvania. Amgen is conducting a Phase 1b trial, STREAM-SCLC, in patients with limited-stage small cell lung carcinoma and final site selection is in process. For each trial, the FDA met with the sponsor on the establishment of criteria for reporting signals in real time. The agency has since received and validated signals for AstraZeneca’s trial through Paradigm Health, thereby establishing the feasibility of the technical framework required for real-time signal sharing.

The FDA seeks to build on these proofs-of-concept with a broader pilot program. Today’s RFI seeks input on potential pilot program design and implementation, as well as evaluation metrics and success criteria.

“Real-time trials have been talked about for years. We demonstrated that it is not only possible, but also potentially transformative for the clinical trials ecosystem,” said Chief AI Officer Jeremy Walsh. “We have to consider our processes from the standpoint of a patient awaiting a potentially powerful treatment.”

Real-time clinical trials are an important step towards the agency’s goal of facilitating continuous trials. At present, most clinical development occurs in discrete phases. Because each defined phase of clinical development is run according to a protocol and typically as a separate study, there is generally a hiatus in the development program after one phase ends and the next begins. This slows the pace of product development. Because real-time trials allow the FDA to view key insights in real time, this hiatus could be eliminated or reduced to a minimum, enabling “continuous” trials.

The agency will accept comments on the RFI until May 29, 2026. The agency intends to disseminate final selection criteria in July and complete pilot selections in August. 

https://www.youtube.com/live/hPT6X4SKOjw?si=ZfLrn3NmYvyqFILm

 

https://www.ajmc.com/view/fda-will-require-only-1-study-to-approve-new-drugs-speeding-up-process

 

News|Articles|February 19, 2026

FDA Will Require Only 1 Study to Approve New Drugs, Speeding Up Process

Author(s)Julia Bonavitacola

Fact checked by: Christina Mattina

A commentary by FDA officials Vinay Prasad, MD, MPH, and Martin Makary, MD, MPH, details the new system for drug approvals in the US.

FDA Commissioner Martin Makary, MD, MPH, and his top deputy Vinay Prasad, MD, MPH, announced in a commentary published in The New England Journal of Medicine that the FDA will revamp its method of approving drugs for use in the US.1 The commentary announced that the agency’s historic reliance on 2 clinical trials will end, with only 1 pivotal trial needed for a drug to be approved for use nationwide.

“Going forward, the FDA’s default position is that 1 adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorization of novel products,” the FDA officials wrote in their commentary.

The FDA had previously worked under guidelines stating that “adequate and well-controlled investigations” were needed before a drug could be approved for widespread use, which were interpreted as generally requiring 2 clinical investigations.2 These guidelines had been in place since 1998, with only supplementary guidance published in 2019 and 2023. The newly announced shift marks the first substantial change in the methods of FDA approvals since the FDA obtained the authority to grant marketing authorizations.1

Makary and Prasad noted that these guidelines had been flexible in the past—specifically in oncology, where 1 study was often enough for a drug approval—but were confusing to drug manufacturers seeking to understand when only 1 trial would be acceptable. Moving forward, the default of using only 1 trial to grant a drug approval should clear up questions surrounding the necessary number of trials.

“The FDA’s historical reliance on 2 clinical trials rather than 1 was intended to provide credible causal evidence that a therapy could improve clinical outcomes with acceptable safety in a world where biologic understanding was more limited than it is today,” the FDA officials wrote. “Two trials should be seen as just 1 of many interlocking facets of clinical credibility, and in 2026 there are powerful alternative ways to feel assured that our products help people live longer or better than requiring manufacturers to test them yet again.”

This move is another step in Makary’s attempts to shorten FDA reviews, which started when he began his tenure last year.3 These include mandating the use of artificial intelligence for staffers and offering new medications a 1-month drug assessment if the FDA believes that the drug serves a national interest.

About 60% of first-of-a-kind drugs have been approved based on a single study in the past 5 years due to legislative initiatives that encouraged flexibility in reviewing drugs for conditions that were hard to treat. The drugs more likely to be affected by this new standard are for common diseases rather than those for rare diseases or cancers, which were already more often receiving approval based on a single trial.

This announcement comes a day after the FDA announced that it will now review Moderna’s seasonal mRNA flu vaccine application, which it had previously refused to look at due to perceived safety and efficacy concerns.4 The increased scrutiny of vaccines presents a contrast to the newly streamlined default standard for FDA approvals.

References

  1. Prasad V, Makary MA. One pivotal trial, the new default option for FDA approval—ending the two-trial dogma. N Engl J Med. 2026;394(8):815-817. doi:10.1056/NEJMsb2517623
  2. Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence. FDA. Updated November 30, 2023. Accessed February 19, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical
  3. Perrone M. FDA will drop two-study requirement for new drug approvals, aiming to speed access. AP News. Updated February 18, 2026. Accessed February 19, 2026. https://apnews.com/article/fda-drug-approval-studies-makary-prasad-a5aaa5501ae15f264bbd20d0dffa4dc4
  4. Steinzor P. FDA reverses course, will review Moderna’s mRNA flu vaccine. AJMC®. February 18, 2026. Accessed February 19, 2026. https://www.ajmc.com/view/fda-reverses-course-will-review-moderna-s-mrna-flu-vaccine

 

Pharm Stat. 2022 Aug 26;22(1):96–111. doi: 10.1002/pst.2262

Should the two‐trial paradigm still be the gold standard in drug assessment?

Stella Jinran Zhan 

1

, Cornelia Ursula Kunz 

2

, Nigel Stallard 

1,

  • Author information
  • Article notes
  • Copyright and License information

PMCID: PMC10087480  PMID: 36054079

Abstract

Two significant pivotal trials are usually required for a new drug approval by a regulatory agency. This standard requirement is known as the two‐trial paradigm. However, several authors have questioned why we need exactly two pivotal trials, what statistical error the regulators are trying to protect against, and potential alternative approaches. Therefore, it is important to investigate these questions to better understand the regulatory decision‐making in the assessment of drugs’ effectiveness. It is common that two identically designed trials are run solely to adhere to the two‐trial rule. Previous work showed that combining the data from the two trials into a single trial (one‐trial paradigm) would increase the power while ensuring the same level of type I error protection as the two‐trial paradigm. However, this is true only under a specific scenario and there is little investigation on the type I error protection over the whole null region. In this article, we compare the two paradigms by considering scenarios in which the two trials are conducted in identical or different populations as well as with equal or unequal size. With identical populations, the results show that a single trial provides better type I error protection and higher power. Conversely, with different populations, although the one‐trial rule is more powerful in some cases, it does not always protect against the type I error. Hence, there is the need for appropriate flexibility around the two‐trial paradigm and the appropriate approach should be chosen based on the questions we are interested in.

 

Szczepan Baran

Making preclinical evidence predict the clinic for 2- and 4-Legged Patients |  CSO, Instem | Co-Founder, Digital Preclinical Society | Co-Chair, VQN | President, 3Rs Collaborative

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For fifty years, preclinical safety ran on one rule: do the animal study, then justify the exception. Last week the #FDA‘s #OncologyCenterofExcellence released a draft guidance that quietly turns that rule around. Read the headlines and it is an animal-reduction story. One relevant species instead of two. A single three-month study instead of separate one- and three-month studies. A structured risk assessment in place of a study. And yet the reduction is not the point. The precondition is.


Each of those moves is permitted only when you already understand the product, the #targetbiology, and the #toxicity well enough to defend the omission. The study used to be the default. Now the knowledge is the default, and the study is what you add when the knowledge runs out. That is a higher bar, not a lower one. Dropping a study you cannot defend is easy. Defending the decision is the work.

Here is the part that should focus the mind. Across 7,565 drugs and five species, only one of 26 system organ classes showed strong cross-species concordance for both small molecules and biologics. Running the study was never the same as understanding the risk. I wrote this week’s Digital Record on what the guidance actually asks of sponsors, and why the teams that win the timeline treat their evidence as an asset, not an archive. If you lead nonclinical safety or translational science for an oncology biologic or a conjugate, read it as an evidence standard, then ask the harder question of your own programs: which study are you running out of habit, and could you defend dropping it on Monday. Know more. Run less. Defend both.


Issue #3 is free here: https://lnkd.in/eSYzkh_x

 

FDA Reports Meeting Year One Goals for Reducing Animal Drug Testing

June 8, 2026

On May 29, 2026, the Food and Drug Administration (FDA) released its latest guidance related to FDA’s intent to reduce unnecessary animal testing for nonclinical safety assessments, Oncology Pharmaceuticals: Streamlined Nonclinical Safety Studies for Biologics and Conjugated Products. The guidance is intended to help reduce unnecessary animal testing by incorporating an integrated knowledge-based risk assessment with a focus on three-month toxicology studies for certain oncology pharmaceuticals.

Sponsors may propose alternative approaches for a three-month general toxicology study for product classes not described in the guidance, provided such approaches are sufficient to address product safety. Such approaches for a three-month general toxicology study may include a non-sacrificial toxicology study, an alternative study design to reduce animal numbers, or a weight of evidence (WoE) risk assessment for products with well-understood targets to replace animal studies. These approaches could be supplemented with new approach methodologies (NAMs), as appropriate.

FDA’s recommendations cover general toxicology and WoE Assessment. For general toxicology, FDA stated that animal toxicology studies should use pharmacologically relevant species or WoE risk assessment in its absence. FDA stated that if pharmacological activity is similar to humans in both rodent and non-rodent species, then general toxicology may be conducted in a single rodent species and supplemented with WoE risk assessment as appropriate.

A WoE risk assessment may include multiple factors. The factors include nonclinical and clinical data generated with the investigational product (e.g., pharmacology, safety, and pharmacokinetics), a literature-based assessment of potential toxicities with the molecular target, toxicity findings in animals and humans associated with the same class of pharmaceuticals, and other data. The Center for Drug Evaluation and Research’s (CDER) oncology review divisions will determine when the WoE risk assessment is sufficient to address the safety risks based on the totality of evidence.

This guidance builds upon FDA’s initial Roadmap to Reducing Animal Testing in Preclinical Safety Studies (April 2025) to provide a strategic, stepwise approach using NAMs, such as organ-on-a-chip systems, computational modeling, and advanced in vitro assays (e.g., organoids and microphysiological systems). The principles come from a growing scientific recognition that animals are inadequate models of human health, i.e., over 90% of drugs that appear safe and effective in animals do not go on to receive approval in humans. In addition, the time and cost of long-term animal studies delay therapies reaching patients, e.g., developing a monoclonal antibody costs $600-750 million and may take up to nine years, with typical programs using 144 non-human primates at costs reaching $50,000 per animal.

FDA’s one-year progress report, Reducing Animal Testing in Nonclinical Studies Year One Progress and the Path Forward (April 2026) declared that the necessary foundations or goals had been met or exceeded, resulting in additional guidance. Some of those goals included:

  • On July 31, 2025, FDA made the Innovative Science and Technology Approaches for New Drugs pilot program permanent. The program employs the Drug Development Tool Qualification regulatory framework, providing a clear, predictable pathway for developers to gain formal FDA acceptance of NAMs.
  • In August 2025, FDA and the National Institutes of Health formalized a partnership in a Memorandum of Understanding to accelerate the standardization, qualification, and adoption of human-relevant alternative methods.
  • In October 2025, the CDER / Office of New Drugs Streamlined Nonclinical Studies and Acceptable New Approach Methodologies database went live, providing a searchable, regularly updated inventory of specific drug development contexts where streamlined nonclinical programs are acceptable.
  • In November 2025, FDA researchers from the National Center for Toxicological Research and CDER, collaborating with Emulate Inc. and the University of North Carolina at Chapel Hill, published challenges and solutions in measuring commonly used biomarkers for drug-induced liver injury in a liver-on-a-chip platform.
  • On December 2, 2025, FDA released draft guidance, Monoclonal Antibodies: Streamlined Nonclinical Safety Studies.
  • On December 8, 2025, FDA crossed a technological threshold by qualifying the AI-Based Histologic Measurement of NASH its first AI-based drug development tool for use in metabolic dysfunction-associated steatohepatitis clinical trials.
  • On March 18, 2026, FDA published a draft guidance document: General Considerations for the Use of New Approach Methodologies that established four core validation principles to transform the abstract question of “When is an alternative acceptable?” into concrete, actionable requirements. On the same date, FDA’s Level 2 update to “Pyrogen and Endotoxins Testing: Questions and Answers” guidance provided the flexibility for manufacturers to transition from Limulus Amoebocyte Lysate (LAL) reagents for bacterial endotoxin testing to transition from harvesting horseshoe crabs for production of LAL reagent to recombinant agents.

We will continue to monitor FDA’s continuing implantation of a framework to reduce animal testing in nonclinical studies.

This blog was drafted by Brian Malkin, a Spencer Fane attorney on the FDA Pharmaceutical and Biologics Market Team. For more information, visit spencerfane.com.

 

https://www.the-scientist.com/is-this-the-end-of-animal-testing-fda-announces-plans-to-phase-out-animals-in-drug-safety-studies-73031

 

F

or decades, preclinical testing in mice, rats, and nonhuman primates has been a crucial part of drug development, an important although not infallible way to ensure some measure of safety for human participants in clinical trials. In 2022, Congress passed the FDA Modernization Act 2.0, stating that the agency was no longer compelled by law to require animal testing.1 However, the act did not prohibit the FDA from requiring animal testing, and animal toxicity data remained an essential step in the path towards human trials.

But on April 10, the FDA announced plans to phase out these requirements, stating that they would be “reduced, refined, or potentially replaced” with New Approach Methodologies (NAMs). These methods include human-derived cell models, such as organoids and organ-on-a-chip systems, as well as in silico approaches such as pharmacokinetic modeling and toxicity-predicting machine learning algorithms. Within the year, certain monoclonal antibodies, which are most commonly used in the treatment of cancer and serious autoimmune disease, could be evaluated using a “primarily non-animal-based testing strategy.” According to the roadmap accompanying the FDA announcement, “In the long-term (3–5 years), FDA will aim to make animal studies the exception rather than the norm for pre-clinical safety/toxicity testing.”

This announcement has been met with both hopefulness and concern in the scientific community. On one hand, there is broad support for moving away from animal testing, which is ethically fraught, expensive, and not always predictive of human biological responses. On the other hand, scientists and pharmaceutical industry professionals have expressed that NAMs are not yet advanced enough to fully replace animal models.2,3 Moreover, there are concerns that dramatic reductions in budgets for scientific research and the firing of thousands of workers at the FDA and NIH will stall further development of NAMs and interfere with the functioning of the very systems that would be responsible for validating, standardizing, and monitoring the efficacy of these technologies.

Alex Rubinsteyn, a University of North Carolina at Chapel Hill researcher who uses machine learning approaches to inform the development of personalized cancer vaccines, supports reducing animal testing but is uncertain about how this will play out in practice in the current climate. “I think this could become a disaster,” he said. “But it could also potentially unlock a much faster rate of progress.”

Few would dispute the shortcomings of current animal testing pathways: About 90 percent of drugs that make it through preclinical trials never obtain FDA approval for use in humans, largely due to insufficient efficacy or safety.4 Joseph Wu, who studies patient-specific in vitro models of cardiovascular disease at Stanford University, said that this high failure rate is partly due to the inherent differences between human and rodent biology. Furthermore, he noted, “The heterogeneity that exists among humans cannot be captured by using a traditional mouse model.”

Additionally, despite attempts to streamline evaluations of drugs for currently untreatable diseases, “[Drug development] is still really slow and really expensive,” said Rubinsteyn. “And it’s unmatched to clinical realities for certain kinds of disease: There are sufficiently deadly diseases where you really would want to go much faster than you’re allowed to go.”

How Do In Vitro and In Silico Approaches Stack Up Against In Vivo?

Despite the inherent flaws in animal testing, many researchers say that NAMs are not yet advanced enough to fully replace traditional drug safety studies. For example, in a late 2024 report to the FDA Science Board, members of the NAMs subcommittee—convened in 2023 to provide recommendations on integrating NAMs into regulatory processes—wrote that, “Technical limitations to current NAMs exist…today, no assays fully capture the critical hazard endpoints for assessing all currently existing human or animal organ systems; therefore, NAMs cannot fully eliminate the use of integrated physiological systems such as in animal and human trials.”2

In a published response to the FDA announcement, the president of the National Association for Biomedical Research, Matthew Bailey, echoed these sentiments. “No AI model or simulation has yet demonstrated the ability to fully replicate all the unknowns about many full biological systems.”

Similarly, Rubinsteyn noted that while these models can be useful when the space is sufficiently constrained, in other situations, they are still no match for the complexity of biology. “The thing that I work on the most—personalized cancer vaccines—is totally plagued by machine learning models not capturing the relevant realm.”

“We could improve those models with cell lines, but ultimately, the cell lines will be different if we put them in the context of a living organism,” he continued. “[In vivo], the tumor cells will shift what they express. They have to deal with being in contact with other cells in the tissue. They’ll have to pull in vasculature, and they’ll have to deal with the immune environment. So, they’re going to shift how they behave.”

To address this problem, other research groups are building organ-on-a-chip systems as a closer approximation of how cells behave in living tissues. These models can have layers of cells supported by an extracellular matrix with a simplified vascular system, recapitulating some of the cell-cell interactions and mechanical forces present in a living organism.

Yu Shrike Zhang, a Harvard Medical School researcher who uses bioprinting, microfluidics, and other techniques to create improved organ-on-a-chip platforms, noted that these models are quite advanced for certain tissue types.5 “For the liver, the models are pretty precise in general,” Zhang said. “It’s been [studied] for a very long time, and people know exactly how it works.”

Indeed, a liver-on-a-chip model developed by the biotechnology company Emulate, Inc., was able to correctly identify drugs known to be toxic or nontoxic to the liver with a sensitivity of 87 percent and a specificity of 100 percent.6

Using organ-on-a-chip models, Zhang said, “In three to five years, I think we can probably get to a pretty high level in terms of testing [toxicity or biological responses] for individual organs.” Modeling interactions between different organs, however, is a more challenging task. Crosstalk between organ systems is complex and incompletely understood, and organs can be influenced, or influence each other, via changes in metabolism, blood circulation, immune function, endocrine signalling, or nervous system activity.7

Scaling is also a concern, according to Zhang. As size changes, different physical forces and properties increase or decrease in different ways. So, it is not yet entirely clear how to best model a 200-pound human body using organ-on-a-chip systems, some of which may be only a few cell layers thick.

“Things are quite complicated, both biologically and in terms of how these devices operate,” said Zhang. “Being able to really reproduce that organism-level interaction—I think that’s still something that will be really important to look into. Maybe that’s something that’s going to be mature in the next three to five years? I mean, no one knows. But I think that’s probably one of the major limitations right now.”

Refine, Reduce, Replace and the Promise of NAMS

Even scientists who are extremely enthusiastic about NAMs seem to view them as a tool to reduce, not completely replace animal testing. Wu, for example, has spent decades developing in vitro models using cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) to improve our understanding of cardiovascular disease. He has created an extensive biobank of human iPSCs, capturing genetic diversity in health and disease, and even founded a company, Greenstone Biosciences, which aims to accelerate the drug discovery process by combining in vitro and in silico approaches.

However, Wu said, “I’m a proponent of using all models. I’m not a proponent of saying that, ‘Oh, in the future, we should just get rid of mouse models.’” Instead, he said, applying these strategies prior to animal testing could greatly reduce the number of animals that would be needed for each experiment, enabling researchers to identify promising targets and screen for well-defined types of toxicity.

For example, Wu was part of a project led by fellow Stanford University cardiovascular biologist Mark Mercola, in which the team used iPSC-derived human cardiomyocytes and machine learning to classify existing drugs as low risk or intermediate/high risk for causing dangerous arrhythmias. Using area under the curve as a measure of the model’s accuracy—for which 0.5 indicates a random classifier and one is a perfect classifier—the model correctly identified risk with an area under the curve value of 0.95.8 In the future, a system like this one could help researchers spot potentially cardiotoxic compounds early in the drug development process. This has the potential to prevent the investment of time, money, and animal lives into investigating a drug that might treat one disease very well but be ultimately useless because of severe adverse effects.

Furthermore, unlike studies performed in strains of genetically identical mice, research with human cells can provide not only general safety predictions, but they also help identify which individuals might be most at risk for particular side effects and even suggest mechanisms for mitigating these effects.

For example, the chemotherapy drug doxorubicin can lead to heart failure in a subset of patients, but for many years, the mechanism of this cardiotoxicity was not known, and there was no way to predict which patients were at risk. In a study of eight breast cancer patients, Wu and his team showed that iPSC-derived cardiomyocytes from patients who experienced this side effect were more sensitive to doxorubicin toxicity than cells from patients who did not. 9 In the future, this could serve as a tool for screening patients prior to treatment. In a subsequent study, the researchers used a CRISPR-based approach to screen cardiomyocytes for genes that contributed to this vulnerability. One gene, which coded for the enzyme carbonic anhydrase 12, seemed to play a large role: When expression of this gene was inhibited in the cells, they were protected from doxorubicin toxicity.10 An antagonist of this enzyme, Indisulam, was also protective in heart cells. Only after all these experiments did the researchers test the drug in mice.

Continue reading below…

Since then, Wu and his team have used iPSC-derived cells, patient data, and AI to identify a candidate compound for the treatment of marijuana-induced vasculature inflammation, and two potential therapies for cardiac fibrosis.11–13 “These three papers all have mouse models, but they’re toward the end,” said Wu. “They’re only done for validation—the initial screen, initial validation, initial design, all that stuff is done [using] organoids, stem cells, and AI.”

The first candidate is currently in a Phase 1 clinical trial for the treatment of inflammation associated with heart failure, the second is in an open-label study for treating idiopathic pulmonary fibrosis. In the coming years, studies such as these will provide crucial data to answer the question of whether these newer drug development techniques can increase efficiency and reduce failure rates in clinical trials.

An Uncertain Future for Drug Development

Much work remains to be done, however, if animal testing is to be truly replaced in the next three to five years. In addition to the development of the NAMs technologies themselves, the FDA roadmap also calls for the creation of open-access toxicity information databases, developing strategies to validate NAMs, determining appropriate thresholds for eliminating animal testing, figuring out how to standardize these techniques so that they can be compared across many different laboratories, coordinating with other federal agencies, and monitoring how well all of this is working.

“Transitioning from animal-based testing to NAMs for safety will require careful planning, robust science, and collaboration,” the roadmap states.

But will this be possible in the chaos currently afflicting many government agencies and the dramatic changes to support for scientific research in the United States? The Trump administration has already terminated 1.8 billion dollars in National Institutes of Health (NIH) grants; the administration’s proposal for the upcoming year would slash the budget of the NIH by 40 percent.14,15

Some of these governmental budget cuts and funding freezes adversely impact the laboratories that have been instrumental in developing the very NAMs technologies the FDA is hoping to promote. For example, Harvard University bioengineer Donald Ingber, a pioneer in organ-chip research and scientific founder of Emulate, Inc., received stop-work orders on two major organ-on-a-chip projects in late April 2025.

Beyond the technologies themselves, planning and collaboration efforts may also be impacted by the major changes at these agencies. So far, 2025 has been marked by many cancelled or postponed scientific meetings at the FDA and NIH, as well as firings of thousands of workers, including many top-level officials and a large portion of communications roles, and the resignation of Peter Marks, director of Center for Biologics Evaluation and Research.

Rubinsteyn, for his part, worries about how reductions in animal testing requirements will play out in such an environment, raising concerns that insufficient oversight could create opportunities for unscrupulous companies to bring potentially unsafe drugs to market.

“I do think that this is, in principle, a positive direction for change,” he said. But depending on how these changes are implemented, “it could go quite wrong.”

Disclosure of conflicts of interest: Yu Shrike Zhang sits on the scientific advisory board and holds options with Xellar Biosystems.

Comparative Study 

Toxicol Sci

. 2015 Dec;148(2):355-67. doi: 10.1093/toxsci/kfv189. Epub 2015 Oct 5.

Correlation of In Vivo Versus In Vitro Benchmark Doses (BMDs) Derived From Micronucleus Test Data: A Proof of Concept Study

Lya G Soeteman-Hernández 1, Mick D Fellows 2, George E Johnson 3, Wout Slob 1

Affiliations Expand

Abstract

In this study, we explored the applicability of using in vitro micronucleus (MN) data from human lymphoblastoid TK6 cells to derive in vivo genotoxicity potency information. Nineteen chemicals covering a broad spectrum of genotoxic modes of action were tested in an in vitro MN test using TK6 cells using the same study protocol. Several of these chemicals were considered to need metabolic activation, and these were administered in the presence of S9. The Benchmark dose (BMD) approach was applied using the dose-response modeling program PROAST to estimate the genotoxic potency from the in vitro data. The resulting in vitro BMDs were compared with previously derived BMDs from in vivo MN and carcinogenicity studies. A proportional correlation was observed between the BMDs from the in vitro MN and the BMDs from the in vivo MN assays. Further, a clear correlation was found between the BMDs from in vitro MN and the associated BMDs for malignant tumors. Although these results are based on only 19 compounds, they show that genotoxicity potencies estimated from in vitro tests may result in useful information regarding in vivo genotoxic potency, as well as expected cancer potency. Extension of the number of compounds and further investigation of metabolic activation (S9) and of other toxicokinetic factors would be needed to validate our initial conclusions. However, this initial work suggests that this approach could be used for in vitro to in vivo extrapolations which would support the reduction of animals used in research (3Rs: replacement, reduction, and refinement).

Keywords: TK6 cells, benchmark dose 

https://www.drugdiscoverynews.com/why-toxicology-is-still-the-toughest-test-for-nam-adoption-17194

 

Toxicology remains the most challenging field for adopting new approach methodologies (NAMs) as it requires predicting systemic, long-term human health effects that are inherently complex to replicate outside a living organism. While NAMs offer human-relevant data, the industry faces significant hurdles in validating these methods to the same level of trust as traditional animal models.

DDN spoke with Justin Boyd, Product Manager at Sartorius, to explore how NAMs are being applied in practice across drug discovery and safety assessment, and what ultimately determines whether they transition from scientifically compelling tools into routine components of toxicology workflows.

You’ve spent much of your career building biologically relevant cellular models of disease. How does that emphasis on relevance shape how you think about NAMs in toxicology, compared with more traditional animal-based approaches?

I recently joined the vendor side of NAMs. For nearly two decades before that, as a drug hunter, I was less focused on building models and more on applying them. In that context, I thought of NAMs as fit-for-purpose tools to rapidly explore the effects of experimental drugs on the proximal human biology I care about.

Now, as Product Manager of a NAMs portfolio, I still strongly believe in that utility. The strengths of NAMs lie in: (1) conservation of human biology, (2) speed to data-driven decision-making, and (3) cost to execute study. That said, I don’t see NAMs as replacing the value of a whole organism — whether mouse, rat, or non-human primate. A preclinical toxicity study in animals provides a more comprehensive view of how a compound behaves in the context of an intact organism, including systemic interactions that are still not well captured in vitro.

However, NAMs create an opportunity to rank and/or differentiate compounds with higher molecular resolution while remaining “in human.” That kind of insight can meaningfully inform decisions about which compounds are worth advancing into more expensive and time-consuming animal studies.

Ultimately, I think of NAMs for toxicity as key complementary models for evaluating tissue-specific risk to drive decision to go into the animal models, leading to better stewardship of resources for drug discovery and animal welfare.

NAMs are often discussed as ethical or regulatory advances, but from your perspective, where do they most clearly outperform legacy toxicology methods scientifically?

With respect to performance, there are two clear areas where NAMs excel. First, NAMs can recapitulate aspects of human biology more faithfully than preclinical species. This becomes especially important when studying the proximal biology engaged by an experimental drug, where species differences can significantly limit interpretability.

Second, NAMs substantially reduce the time and cost required to reach a decision. From a project or program management perspective, the ability to make informed and confident stage-gate decisions is where the highest value lies. In this context, NAMs enable a more expedient and cost-effective approach to predicting toxicity in the pre-Investigational New Drug (IND) to IND space.

Although, it’s likely that animals will be used at this point, NAMs can and should be deployed to derisk the Good Laboratory Practice (GLP) toxicity studies in animals and potentially reduce the numbers of cohorts and time for treatments.

Many toxicology assays still rely on relatively reductionist systems. How close are we to NAMs that genuinely capture the complexity of chronic diseases like Alzheimer’s or Parkinson’s when it comes to assessing safety?

I think this is a tricky question, and I would start by noting that the complexity of Alzheimer’s (AD) and Parkinson’s disease (PD) pathobiology is part of what limits our ability to clearly distinguish mechanisms that cause disease from those that simply exacerbate progression. As such, “who, when, and how” these diseases are treated and the potential toxicity from treatment remain controversial.

In some cases, NAMs, particularly complex in vitro models with multiple cell types and structures, can recapitulate complex non-cell autonomous biology, such as the impact of inflammation on neuronal health. Moreover, computation-based NAM tools can help predict the trajectory of biology and stratify at-risk populations for toxicity outcomes.

So, when asking how close we are to NAMs that genuinely capture the complexity of chronic diseases like AD and PD, I would say they are, in many ways, as close to recapitulating that complexity as our current understanding allows us to define it.

Drug-induced nephrotoxicity remains a major clinical challenge. From your experience working with human kidney microtissues, why has traditional animal toxicology struggled to predict renal risk in humans?

It sounds cliché, but animals are not humans. In the case of the kidney, there are two key drivers of translational gaps.

First, the expression of key kidney genes and their protein products — particularly those governing transport and metabolism — differs significantly between preclinical species and humans. Second, baseline renal metabolism itself varies across species, further compounding these differences.

Given that the primary function of the kidney is to clear waste, toxins, and excess fluids from the blood, these species-specific differences directly impact our ability to predict nephrotoxicity using traditional animal models.

You’ve worked extensively with 3D human epithelial tissue models. What does moving from 2D cultures to 3D systems fundamentally change in how we understand toxicity mechanisms?

The difference between traditional 2D cultures and 3D systems, in the context of toxicity, is relatively straightforward. By recapitulating tissue structure, 3D models allow us to move beyond simply asking whether a compound is toxic, to understanding where that toxicity occurs and to what extent.

Understanding the relationship between exposure (where a polarized, functional cell sees a compound) and response is uniquely addressed in our systems compared to 2D. This is particularly important in epithelial tissues, where basolateral versus apical exposure can lead to very different toxicity outcomes. In skin, intestine, and lung, for example, cells may be exposed either from the basolateral side via systemic circulation or from the apical side through local administration or environmental contact. That distinction is fundamentally lost in 2D systems.

Do you see NAMs primarily as screening tools, or are they mature enough to inform dose selection, risk stratification, and IND-enabling decisions?

I believe NAMs have always been able to inform dose selection, risk stratification, and IND-enabling decisions. In fact, screening may not be the best deployment of NAMs due to scalability challenges and cost. The appropriateness of a NAM’s utility is dependent upon the limitations of the human biology you can explore within the NAM and the modality of the therapeutic. If the NAM contains the biology that you are targeting and the therapeutic modality is compatible with the model, then the NAM should be appropriate for dose selection, risk stratification and IND decisions.

One advantage you’ve previously highlighted is integrating human tissue models with live-cell analysis. Why is temporal resolution — seeing toxicity unfold in real time — so important?

There is both a practical and a biologically relevant dimension to the importance of temporal resolution in toxicity responses. From a practical standpoint, when developing any assay, identifying the time point at which the signal is maximal is essential for ensuring robustness and is a key part of assay optimization. In the context of toxicity, being able to observe the behavior and toxicity signals over time will enable you to identify the most appropriate time of incubation for maximal signal response.

Biologically, however, toxicity is not a single event — it manifests in different ways depending on mechanism. If you use tool compounds that induce toxicity through different mechanisms, knowing the kinetics of the toxicity response can help resolve whether your assay can distinguish direct and indirect mechanisms leading to toxicity.

In that sense, time to toxicity signal can be as informative as the signal itself, particularly when evaluating unknown compounds. In the context of advanced cell models for toxicity, often the exposure times can be prolonged (days to weeks) to predict clinical outcome.

NAMs can be scientifically compelling but still fail to gain traction. From a product and commercialization standpoint, what determines whether a NAM actually gets embedded into routine toxicology workflows?

This is the $100+ million question. Adoption of any platform is influenced by a range of factors — cost, fit-for-purpose utility, biological relevance, format, and ease of use among them. In practice, different players in the field tend to emphasize the aspects they value most, often based on their own balance of biological relevance versus scalability.

At the moment, traction tends to emerge organically through a “let’s try it and see if it works” approach. This is not unique to NAMs. However, toxicology is a particularly high-bar area, where established gold standards inherently challenge any new model system more than exploratory or discovery settings do. That makes sense: Toxicology groups are ultimately responsible for generating a weight of evidence that supports progression to the clinic.

In that context, NAMs introduce both opportunity and friction. While they offer potentially better predictive insight, they also require additional effort to validate against established approaches — often more effort than is required to continue using what is already accepted. Because of this, I would argue that regulators are the key gatekeepers of NAM adoption in toxicology. Ultimately, they define what is essential versus optional in the data package required to advance into the clinic. In my view, the biggest lever for accelerating adoption is therefore not customer preference, but regulatory acceptance.

What is the incentive to explore better models of toxicology if existing ones are “good enough” to reach regulatory endpoints? We could discuss the ethics and scientific rationale around choosing better, more predictive models. But if NAMs remain encouraged rather than required, it is difficult to expect meaningful acceleration in their uptake. I really hope that regulators recognize that there’s a big difference between accepting NAMs and requiring them. Making NAMs essential for toxicity studies for IND filing would catalyze their adoption far more effectively than incremental product refinement alone.

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About the Author

  • Bree Foster, PhD

  • Bree Foster is a science writer at Drug Discovery News with over 2 years of experience at Technology Networks, Drug Discovery News, and other scientific marketing agencies. She holds a PhD in comparative and functional genomics from the University of Liverpool and enjoys crafting compelling stories for science.

he 90% myth

Posted: by Chris Magee on 9/06/25

More on these Topics:

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Why do 90% of new drugs fail?

If you’ve read anything on animal testing, you’ll have read something to the effect that ‘more than 90% of drugs tested in animals fail in humans’. Is that some damning indictment of animal models? Absolutely not. Let’s unpack this a bit.

Note: The 90% statistic refers to regulatory safety testing. Other sorts of animal use, like discovering decapod sentience through ‘curiosity-driven’ basic research, will be discussed in another article since the applications are so broad and the application of the research so complex that percentages are usually meaningless. 

Tl;DR:

The drug attrition rate, which isn’t 90%, isn’t due to the use of animals and there’s no such thing as a drug that’s developed and tested using only animals before heading to human trials.

Let’s start at the beginning.

 

How drugs get licensed

In drug trials, all drugs intended for humans are tested on humans: they are tested and refined through three stages of clinical trial before being licensed for public use. Phase 1 of human testing looks primarily at safety, whereas phases 2 and 3 are for safety and then efficacy. Each stage uses more human volunteers than the last and the later stages might include those with a particular medical condition. There is also a post-licensing stage 4, where new treatments are introduced to the wider population, for instance into the clinic by specialist doctors.  

Image: Sanford Health 

Adverse reactions noted after a drug is licensed are fed back to the medicine’s regulator, the Medicines and Healthcare Devices Regulatory Authority (MHRA), which might do things like update the safety information in the booklet that comes with the medicines. Lots of medicines have their safety advice updated as the medicine is used in a greater number of patients.  

This is because drugs are licensed on the grounds of what they do in general, e.g. shrink a tumour or lower blood sugar. However, to what extent they work in an individual will vary greatly depending on dozens of factors from genetics to weight to hormones – even to the time of day. This is why there are specialist doctors for different diseases, as well as GPs, who take a patient-centric perspective on the medical tools available for that person (or animal). Hence, very few medicines are withdrawn – it’s usually a case of finessing the practice and guidance on using them safely and optimally and adapting their use for specific patients. 

 

Preclinical testing

Before drugs can go to human trials, they must pass a standard battery of safety tests using both animal and non-animal methods. These tests tend to be specified by bodies like the OECD (mainly for chemicals) and the International Conference on Harmonisation (mainly for pharmaceuticals), which can pool knowledge about how to use the best methods of safety testing, whatever these may be. 

Non-animal methods of drug testing can perform well but tend to be limited in scope to one organ system or one effect, whereas animal models tend to give a broader picture of how drugs will act in a whole living body and across a dozen organs at once. 

For some applications, non-animal methods are enough to conclude that drug development shouldn’t proceed, and the compound is therefore eliminated before hitting either the human or animal testing stages.  

With those drugs that do proceed, animals are very good at ‘predicting’ if a drug will be ‘safe’ in the first human trials.  

There are different statistical tools that can be used to determine this safety. Bayesian modelling (figure 1 below) can find ‘true positives’ (PPVs) and ‘true negatives’ (NPV) i.e. a percentage certainty that something will be safe in stage 1 human trials. Likelihood ratios (figure 2) offer a probability of safety. 

Bayesian modelling, NPV safety prediction
Organ category  Dog to human   Mouse to human  
Pulmonary  96%  95% 
Biochemical  95%  93% 
Renal  95%  96% 
Ophthalmology  94%  96% 
Haematology  93%  92% 
Cutaneous  91%  82% 
Musculoskeletal  91%  92% 
Cardiovascular  91%  75% 
Nervous system  90%  93% 
Liver  88%  89% 
Gastrointestinal  76%  69%

Figure 1: IQ Consortium translational database 

Likelihood ratios
Pre-test probability  Pre-test odds  Post-test odds  Post-test probability 
10%  0.11  3.16  76% 
20%  0.25  7.11  88% 
30%  0.43  12.18  92% 
40%  0.67  18.95  95% 
50%  1.00  28.43  97% 
60%  1.50  42.65  98% 
70%  2.33  66.34  99% 
80%  4.00  113.72  99% 
90%  9.00  255.87  100% 

Figure 2: Data from https://pubmed.ncbi.nlm.nih.gov/24329742/  

Different species of animal do more or less well at translating to humans depending on the target organs, the type of thing being tested and the size of its molecules. These species differences are well-known, as is the fact that you can increase your certainty that something will be safe or not if a rodent and a non-rodent species both yield similar results. 

Thus, the normal testing regime uses species like rats, plus a non-rodent species, usually a dog or primate. Around three-quarters of tests involve suffering in the mildest category, such as a blood test, with a quarter in the moderate category and very few in severe. This is because most of the information about the possible dangers of a new drug comes from a post-mortem of the animal that reveals changes to the internal organs and tissues, rather than observing whether a live animal gets sick or not. 

The fact that animals are good predictors of safety in humans is important because 40% of potential new drugs are ultimately removed due to failing these pre-human tests. This means that 40% of possible new drugs would have killed or seriously injured humans in phase 1 trials without the pre-human tests (which would be about 900 people a year in the UK).  

 

Preclinical results shape the human trial

But this is not the whole picture. The preclinical tests of all descriptions, including effects seen in animals, human cells, tissue samples and more, help to inform the design of human clinical trials in the first place. For instance, one or several of the tests might hint at potential issues with the liver, so extra measures can be taken to minimise that risk during the human trial. 

All drugs have potential side effects, and their use is always a balance of risk vs potential benefit for the individual patient. All of this means that a large number of drugs proceed to human trials as ‘safe enough to try’ but with a question mark over whether their risks will be manageable or not.  

An example of this management is paracetamol, which works better as a painkiller if taken regularly every 4-6 hours to allow it to build up in the tissues and bloodstream. However, we all know not to take a day’s dose all at once. 

 

So, what of the 90%? 

Drugs ‘fail’ at every stage of development and for several reasons. For every 100 possible drugs that even get to the animal testing stage, some 5,000 other compounds have already been eliminated. Drugs continue to be removed all the way through human testing too, in ever smaller numbers as we zero in on something that’s going to work. 

Percentages thus become less and less helpful for understanding what is happening. Having eliminated 5,000 candidates, for instance, we can be left with 10. If three of those 10 fails, then that’s 30%, which sounds massive, but it’s only 0.06% of the huge pile of 5,000 possible drugs we started with. 

In the same way, the 90% statistic is easy to misunderstand. 

As we’ve seen, 40% of possible drugs are removed as dangerous by the pre-human safety tests that are mainly in animals. The 90% that ‘fail’, then, is 90% of the 60% that pass preclinical trials. Also, by ‘failure’ it means to have failed for the purpose intended – many drugs can later be repurposed even if they fail in their intended application. 

What all this means is, for every 100 potential new drugs at the start of the process, 6 will become drugs in the pharmacy, 40 will be removed by preclinical tests and 54 will be removed for other reasons. 

Exactly what those reasons are is the critical point. 

Of those 54: 

  • C40-50% (26 drugs) will not be effective at the safe dose (something the animal test isn’t looking for); 
  • C25-30% (15 drugs) suspected or known toxicities cannot be managed; 
  • C10-15% (8 drugs) don’t absorb into the body or get to their target organ properly; and 
  • c10% (5 drugs) fail due to a lack of commercial need or misplaced strategic planning. 

In this way, lots of drugs fail to make it to the chemists’ shelves, but this has very little to do with the efficacy of the animal model as a safety screen for stage 1 clinical trials. Animals do that job very well.

What is exciting about new approaches – whether they use animals or not – is that they may be able to chip away at the other reasons for failure (more on this later).

 

Different targets have different success rates

One other complication is that ‘failure’ rates are not uniform.

Currently, translation from preclinical findings to clinical success varies a lot depending on the disease area. Eye treatments are about 35% successful, vaccines are about 40%. The most complex diseases of the most complex organs have, as you’d expect, a much higher failure rate which skews the averages and gives you this slightly bogus 90% figure by some methods of counting. However, there is no evidence that implicates animal models as the major reason for failure. In fact, researchers who found a c95% drug attrition rate also found that 86% of positive results in animals translated into positive results in humans.

This accords perfectly with the IQ Consortium translation database, of animal to human translation, recreated as a table in figure 1 above, which also averages out at 86%  

 

So, where do NAMs fit in?

The term ‘New Approach Methodologies‘ refers to the subset of non-animal technologies concerned with regulatory testing – i.e. the tests required by governments. Non-animal technologies have been in development and used in drug testing since the early 1970s, being applied alongside animal models to try to design better drugs, better clinical trials and spot potentially dangerous compounds. They have a more limited range of applications than a whole-body system, but can nevertheless be a quick, cheap and useful way of spotting red flags or pointing to a way forward. They are a standard part of the toolkit for drug testing, with their use accelerating exponentially in the past 20 years as technology improves. We have ever-better non-animal tests, which are still limited but can tell us enough in some cases to guide a decision on what compounds to try to turn into medicines. 

 

Organs on chips

Some of these techniques are relatively new approaches like organ-on-a-chip technologies. First conceived in the late 1990s, the first successful chip was developed in 2010. These devices, roughly the size of an AA battery, are made from a flexible, translucent polymer. Inside are tiny tubes, each less than a millimetre in diameter, lined with living cells taken from a particular human or animal organ. 

These can spot toxicities ranging from liver issues with new drugs to the effects on animals of industrial chemicals. They can be used early to avoid animal use and some emerging technologies could prevent up to 10% of drugs that would ultimately fail from entering animal trials in the first place. In a study completed in late 2022, for instance, liver chips identified compounds that were deemed safe enough to try by animal models, but would ultimately harm humans in wider testing, with 87% accuracy.  

That doesn’t mean it can spot 87% of drug toxicities, but 87% of those that would have failed later and specifically for liver-related safety reasons. Given that 40% of compounds are removed prior to human testing, 30% later fail due to unmanageable toxicity and 30% of those do so due to effects on the liver, using this test routinely would help to reduce the number of drugs that later failed human trials for unmanageable toxicity by around a third, or 4-5 drugs for every 100 entering testing. 

However, if also used early in the drug testing process they might also spot toxicities that would previously have needed an animal to detect, and this might be enough to halt testing. Liver toxicity is the reason for 14% of failures during preclinical tests so this would amount to a further 5 compounds per 100 that would not progress to the animal stage. As you can see from liver chip vendor Emulate’s own graphic, their chip reduces animal use, and is applied before animal trials. There would still, by their model, be an 82% failure rate and, of course, most drugs don’t fail for liver-related reasons.

Source: https://emulatebio.com/toxicology/

The UK authorises around 35 new drugs for use each year, yet for every drug approved another 9 fail, which would be around 315 trials, some 10% of which could be halted before hitting the animal or human stage, potentially preventing thousands of research animals from being born. This would undoubtedly save pharma companies money since human trials get more expensive the more they progress – from $ 25 million in Phase 1 to $ 54 million in Phase 3. 

The UK’s national centre for Refining, Reducing or Replacing animal use has a project to replace ‘second species’ animals like dogs and primates with computer models that have passed its proof-of-principle stage and are well into development, albeit with another three years of development left to run.

Even if this doesn’t work, it will tell us what we need to do to get it to work. As Jonas Salk, who used primates to create a polio vaccine, once said “There is no such thing as a failed experiment because learning what doesn’t work is a necessary step to learning what does.”  

 

New targets

Animal numbers will inevitably continue their steady march, with an occasional lurch, downward in terms of numbers, but it’s important to understand how all this fits together. Whilst it’s very easy to predict the future in general terms – clean energy, personalised medicine, healthier food – actually getting there is a bit of a slog. 

The other big reason for drug failure beyond the liver, for instance, is Torsades de Pointes. French for “twisting of the points” it’s a dangerous heart arrhythmia that’s the reason for a very similar proportion of preclinical and clinical failures as liver problems. It makes heart chips the next big target for validation, with sincere hopes that they can be made to work as well as liver chips. 

However, this is the low-hanging fruit on offer in terms of organ chips, with diminishing returns as the targets get harder, and the target systems get more complicated. A test for the heart or a kidney is one thing, a test for the Central Nervous System is quite another. In addition, heart arrhythmia and liver issues are the biggest single areas of failure for safety reasons, but the remaining 40% of reasons affect many other organs, each of which will need its own new animal or non-animal testing strategy. 

 

Where next? 

There is no one approach, then, that will create a revolution. We need new approaches, and we need new improvements to old approaches. My latest laptop, for instance, isn’t conceptually different from the first laptop I owned but it’s a lot lighter and faster due to hundreds of innovations across all of its components. Improvements to clinical outcomes will come from organ chips, big data and AI, but also from higher standards of scientific rigour, new animal models, more powerful technology and the synergies that arise from using it all together. 

Happily, there are very few regulatory barriers to adopting new non-animal technologies, the ethical framework for using new animal models is well-understood and nobody is opposed to using non-animal methods over animals. In addition, whatever the costs of failure during clinical trials, the cost of preclinical R&D and discovery clocks in at $403 million, making it easily the most expensive single stage in the drug development process. Hence, the greatest savings in cost or animal use associated with improvements in technology may have nothing to do with the requirements of the regulator and can be implemented as soon as new technologies mature. 

We do need to accelerate the validation of new animal and non-animal methods now that they’re emerging with rapidly increasing frequency. The OECD, the international association for sharing solutions to common problems, is the curator of scientific guidelines for the testing of chemicals. It makes the point that resources should be made available to test the reproducibility and reliability of new methods developed by single labs so that, if they work, they can be applied more widely, and more quickly. Inherent to their thinking is a bias against animal use. 

We also need to make sure that politicians aren’t distracted by ideological sideshows or lured towards counterproductive policy directions, like deadlines that amount to deregulation of harmful industries. whose products are only harmful when metabolised in a whole body. There are concrete measures that governments, or prospective governments, could be proposing but politicians of all stripes need to understand where to apply funding and focus to have a positive impact on man, animals and the environment. 

https://www.understandinganimalresearch.org.uk/news/the-90-myth

 

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Use of 3D Bioprinting for Development of Toxicity Prediction Models

Curator: Stephen J. Williams, PhD

SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019

The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”

Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.

A synopsis of the schedule and related works from the speakers is given below:

 

8:40 AM–9:20 AM Overview and Challenges of Bioprinting
Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM Putting 3D Bioprinting to the Use of Tissue Model Fabrication
Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM Break
10:20 AM–11:00 AM Uses of Bioprinted Liver Tissue in Drug Development
Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening
Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD

Sharon Presnell, Ph.D. President, Amnion Foundation

Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.

A few of her relevant publications:

Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis

Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner.  This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:

Please click here for Web based and PDF version of interview

Some highlights of the interview include

  • Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
  • Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
  • Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems”  however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
  • Additional challenges include the scalability of such systems and making such system accessible in a larger way
  1. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology

Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of BioprintingHeliyonBMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.

Some relevant references from Dr. Zhang

Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.

Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.

 

Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies.

Wu H, Lei P, Liu G, Shrike Zhang Y, Yang J, Zhang L, Xie J, Niu W, Liu H, Ruan J, Hu Y, Zhang C.

Sci Rep. 2017 Mar 23;7(1):359. doi: 10.1038/s41598-017-00506-z.

 

 

A liver-on-a-chip platform with bioprinted hepatic spheroids.

Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.

Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.

 

Marc Ferrer, National Center for Advancing Translational Sciences, NIH

Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.

At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.

Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.

 

Some relevant references for Dr. Ferrer

Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function.

Derr K, Zou J, Luo K, Song MJ, Sittampalam GS, Zhou C, Michael S, Ferrer M, Derr P.

Tissue Eng Part C Methods. 2019 Apr 22. doi: 10.1089/ten.TEC.2018.0318. [Epub ahead of print]

 

Determination of the Elasticity Modulus of 3D-Printed Octet-Truss Structures for Use in Porous Prosthesis Implants.

Bagheri A, Buj-Corral I, Ferrer M, Pastor MM, Roure F.

Materials (Basel). 2018 Nov 29;11(12). pii: E2420. doi: 10.3390/ma11122420.

 

Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.

Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.

SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.

 

A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models.

Boutin ME, Voss TC, Titus SA, Cruz-Gutierrez K, Michael S, Ferrer M.

Sci Rep. 2018 Jul 24;8(1):11135. doi: 10.1038/s41598-018-29169-0.

A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.

SLAS Discov. 2017 Jun;22(5):494-506. doi: 10.1177/2472555216687082. Epub 2017 Jan 31.

 

Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

Lal-Nag M, McGee L, Titus SA, Brimacombe K, Michael S, Sittampalam G, Ferrer M.

SLAS Discov. 2017 Jun;22(5):537-546. doi: 10.1177/2472555217698818. Epub 2017 Mar 15.

 

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions.

Fu J, Fernandez D, Ferrer M, Titus SA, Buehler E, Lal-Nag MA.

SLAS Discov. 2017 Jun;22(5):525-536. doi: 10.1177/2472555217696796. Epub 2017 Mar 9.

 

Other Articles on 3D Bioprinting on this Open Access Journal include:

Global Technology Conferences on 3D BioPrinting 2015 – 2016

3D Medical BioPrinting Technology Reporting by Irina Robu, PhD – a forthcoming Article in “Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices”

Bio-Inks and 3D BioPrinting

New Scaffold-Free 3D Bioprinting Method Available to Researchers

Gene Editing for Gene Therapies with 3D BioPrinting

 

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Pharmacotyping Pancreatic Cancer Patients in the Future: Two Approaches – ORGANOIDS by David Tuveson and Hans Clevers and/or MICRODOSING Devices by Robert Langer

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 4/5/2018

Featured video: Magical Bob

A fascination with magic leads Institute Professor Robert Langer to solve world problems using the marvels of chemical engineering.Watch Video

MIT News Office
March 27, 2018

http://news.mit.edu/2018/featured-video-magical-bob-langer-0327

 

This curation provides the resources for edification on Pharmacotyping Pancreatic Cancer Patients in the Future

 

  • Professor Hans Clevers at Clevers Group, Hubrecht University

https://www.hubrecht.eu/onderzoekers/clevers-group/

  • Prof. Robert Langer, MIT

http://web.mit.edu/langerlab/langer.html

Langer’s articles on Drug Delivery

https://scholar.google.com/scholar?q=Langer+on+Drug+Delivery&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ved=0ahUKEwixsd2w88TTAhVG4iYKHRaIAvEQgQMIJDAA

organoids, which I know you’re pretty involved in with Hans Clevers. What are your plans for organoids of pancreatic cancer?

Organoids are a really terrific model of a patient’s tumour that you generate from tissue that is either removed at the time of surgery or when they get a small needle biopsy. Culturing the tissue and observing an outgrowth of it is usually successful and when you have the cells, you can perform molecular diagnostics of any type. With a patient-derived organoid, you can sequence the exome and the RNA, and you can perform drug testing, which I call ‘pharmacotyping’, where you’re evaluating compounds that by themselves or in combination show potency against the cells. A major goal of our lab is to work towards being able to use organoids to choose therapies that will work for an individual patient – personalized medicine.

Organoids could be made moot by implantable microdevices for drug delivery into tumors, developed by Bob Langer. These devices are the size of a pencil lead and contain reservoirs that release microdoses of different drugs; the device can be injected into the tumor to deliver drugs, and can then be carefully dissected out and analyzed to gain insight into the sensitivity of cancer cells to different anticancer agents. Bob and I are kind of engaged in a friendly contest to see whether organoids or microdosing devices are going to come out on top. I suspect that both approaches will be important for pharmacotyping cancer patients in the future.

From the science side, we use organoids to discover things about pancreatic cancer. They’re great models, probably the best that I know of to rapidly discover new things about cancer because you can grow normal tissue as well as malignant tissue. So, from the same patient you can do a comparison easily to find out what’s different in the tumor. Organoids are crazy interesting, and when I see other people in the pancreatic cancer field I tell them, you should stop what you’re doing and work on these because it’s the faster way of studying this disease.

SOURCE

Other related articles on Pancreatic Cancer and Drug Delivery published in this Open Access Online Scientific Journal include the following:

 

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/26/pancreatic-cancer-articles-of-note-pharmaceuticalintelligence-com/

Keyword Search: “Pancreatic Cancer” – 275 Article Titles

https://pharmaceuticalintelligence.com/wp-admin/edit.php?s=Pancreatic+Cancer&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Drug Delivery: 542 Articles Titles

https://pharmaceuticalintelligence.com/wp-admin/edit.php?s=Drug+Delivery&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

Keyword Search: Personalized Medicine: 597 Article Titles

https://pharmaceuticalintelligence.com/wp-admin/edit.php?s=Personalized+Medicine&post_status=all&post_type=post&action=-1&m=0&cat=0&paged=1&action2=-1

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

 

 

VOLUME TWO WILL BE AVAILABLE ON AMAZON.COM ON MAY 1, 2017

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Topical Solution for Combination Oncology Drug Therapy: Patch that delivers Drug, Gene, and Light-based Therapy to Tumor, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Topical Solution for Combination Oncology Drug Therapy: Patch that delivers Drug, Gene, and Light-based Therapy to Tumor

Reporter: Aviva Lev-Ari, PhD, RN

 

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

Affiliations

  1. Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Harvard-MIT Division for Health Sciences and Technology, Cambridge, Massachusetts 02139, USA
    • João Conde,
    • Nuria Oliva,
    • Mariana Atilano,
    • Hyun Seok Song &
    • Natalie Artzi
  2. School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
    • João Conde
  3. Grup dEnginyeria de Materials, Institut Químic de Sarrià-Universitat Ramon Llull, Barcelona 08017, Spain
    • Mariana Atilano
  4. Division of Bioconvergence Analysis, Korea Basic Science Institute, Yuseong, Daejeon 169-148, Republic of Korea
    • Hyun Seok Song
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    • Natalie Artzi
  6. Department of Medicine, Biomedical Engineering Division, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    • Natalie Artzi

Contributions

J.C. and N.A. conceived the project and designed the experiments. J.C., N.O., H.S.S. and M.A. performed the experiments, collected and analysed the data. J.C. and N.A. co-wrote the manuscript. All authors discussed the results and reviewed the manuscript.

Nature Materials
15,
353–363
(2016)
doi:10.1038/nmat4497
Received
22 April 2015
Accepted
26 October 2015
Published online
07 December 2015

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

SOURCE

http://www.nature.com/nmat/journal/v15/n3/abs/nmat4497.html#author-information

 

 

Patch that delivers drug, gene, and light-based therapy to tumor sites shows promising results

In mice, device destroyed colorectal tumors and prevented remission after surgery.

Helen Knight | MIT News Office
July 25, 2016

Approximately one in 20 people will develop colorectal cancer in their lifetime, making it the third-most prevalent form of the disease in the U.S. In Europe, it is the second-most common form of cancer.

The most widely used first line of treatment is surgery, but this can result in incomplete removal of the tumor. Cancer cells can be left behind, potentially leading to recurrence and increased risk of metastasis. Indeed, while many patients remain cancer-free for months or even years after surgery, tumors are known to recur in up to 50 percent of cases.

Conventional therapies used to prevent tumors recurring after surgery do not sufficiently differentiate between healthy and cancerous cells, leading to serious side effects.

In a paper published today in the journal Nature Materials, researchers at MIT describe an adhesive patch that can stick to the tumor site, either before or after surgery, to deliver a triple-combination of drug, gene, and photo (light-based) therapy.

Releasing this triple combination therapy locally, at the tumor site, may increase the efficacy of the treatment, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research.

The general approach to cancer treatment today is the use of systemic, or whole-body, therapies such as chemotherapy drugs. But the lack of specificity of anticancer drugs means they produce undesired side effects when systemically administered.

What’s more, only a small portion of the drug reaches the tumor site itself, meaning the primary tumor is not treated as effectively as it should be.

Indeed, recent research in mice has found that only 0.7 percent of nanoparticles administered systemically actually found their way to the target tumor.

“This means that we are treating both the source of the cancer — the tumor — and the metastases resulting from that source, in a suboptimal manner,” Artzi says. “That is what prompted us to think a little bit differently, to look at how we can leverage advancements in materials science, and in particular nanotechnology, to treat the primary tumor in a local and sustained manner.”

The researchers have developed a triple-therapy hydrogel patch, which can be used to treat tumors locally. This is particularly effective as it can treat not only the tumor itself but any cells left at the site after surgery, preventing the cancer from recurring or metastasizing in the future.

Firstly, the patch contains gold nanorods, which heat up when near-infrared radiation is applied to the local area. This is used to thermally ablate, or destroy, the tumor.

These nanorods are also equipped with a chemotherapy drug, which is released when they are heated, to target the tumor and its surrounding cells.

Finally, gold nanospheres that do not heat up in response to the near-infrared radiation are used to deliver RNA, or gene therapy to the site, in order to silence an important oncogene in colorectal cancer. Oncogenes are genes that can cause healthy cells to transform into tumor cells.

The researchers envision that a clinician could remove the tumor, and then apply the patch to the inner surface of the colon, to ensure that no cells that are likely to cause cancer recurrence remain at the site. As the patch degrades, it will gradually release the various therapies.

The patch can also serve as a neoadjuvant, a therapy designed to shrink tumors prior to their resection, Artzi says.

When the researchers tested the treatment in mice, they found that in 40 percent of cases where the patch was not applied after tumor removal, the cancer returned.

But when the patch was applied after surgery, the treatment resulted in complete remission.

Indeed, even when the tumor was not removed, the triple-combination therapy alone was enough to destroy it.

The technology is an extraordinary and unprecedented synergy of three concurrent modalities of treatment, according to Mauro Ferrari, president and CEO of the Houston Methodist Research Institute, who was not involved in the research.

“What is particularly intriguing is that by delivering the treatment locally, multimodal therapy may be better than systemic therapy, at least in certain clinical situations,” Ferrari says.

Unlike existing colorectal cancer surgery, this treatment can also be applied in a minimally invasive manner. In the next phase of their work, the researchers hope to move to experiments in larger models, in order to use colonoscopy equipment not only for cancer diagnosis but also to inject the patch to the site of a tumor, when detected.

“This administration modality would enable, at least in early-stage cancer patients, the avoidance of open field surgery and colon resection,” Artzi says. “Local application of the triple therapy could thus improve patients’ quality of life and therapeutic outcome.”

Artzi is joined on the paper by João Conde, Nuria Oliva, and Yi Zhang, of IMES. Conde is also at Queen Mary University in London.

SOURCE

http://news.mit.edu/2016/patch-delivers-drug-gene-light-based-therapy-tumor-0725

Other related articles published in thie Open Access Online Scientific Journal include the following:

The Development of siRNA-Based Therapies for Cancer

Author: Ziv Raviv, PhD

https://pharmaceuticalintelligence.com/2013/05/09/the-development-of-sirna-based-therapies-for-cancer/

 

Targeted Liposome Based Delivery System to Present HLA Class I Antigens to Tumor Cells: Two papers

Reporter: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2016/07/20/targeted-liposome-based-delivery-system-to-present-hla-class-i-antigens-to-tumor-cells-two-papers/

 

Blast Crisis in Myeloid Leukemia and the Activation of a microRNA-editing Enzyme called ADAR1

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/06/10/blast-crisis-in-myeloid-leukemia-and-the-activation-of-a-microrna-editing-enzyme-called-adar1/

 

First challenge to make use of the new NCI Cloud Pilots – Somatic Mutation Challenge – RNA: Best algorithms for detecting all of the abnormal RNA molecules in a cancer cell

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/17/first-challenge-to-make-use-of-the-new-nci-cloud-pilots-somatic-mutation-challenge-rna-best-algorithms-for-detecting-all-of-the-abnormal-rna-molecules-in-a-cancer-cell/

 

miRNA Therapeutic Promise

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/01/mirna-therapeutic-promise/

Read Full Post »

What could replace animal testing – ‘Human-on-a-chip’ from Lawrence Livermore National Laboratory

The iCHIP research, Moya said, could have implications for creating new drugs to fight cancer, vaccines or evaluating the efficacy of countermeasures against biowarfare agents.

Lab scientist Heather Enright is leading research into the peripheral nervous system (PNS), which connects the brain to the limbs and organs. The PNS device has arrays of microelectrodes embedded on glass, where primary human dorsal root ganglion (DRG) neurons are seeded. Chemical stimuli such as capsaicin (to study pain response) then flow through a microfluidic cap to stimulate the cells on the platform.

The microelectrodes record electrical signals from the cells, allowing researchers to determine how the cells are responding to the stimuli non-invasively. Microscopic images can be acquired at the same time to monitor changes in intracellular ion concentrations, such as calcium. This platform is the first to demonstrate that long-term culture and chemical interrogation of primary human DRG neurons on microelectrode arrays is possible, presenting researchers with an advantage over current techniques.

Read full article at the SOURCE

 

http://universityofcalifornia.edu/news/human-chip-could-replace-animal-testing

Read Full Post »

Printing Cancer Tumors in 3D for Identification of Response to Drugs – Teleconference by Prof. Satchi-Fainaro, TAU, Medical School, 4/5/2016 noon EST

Reporter: Aviva Lev-Ari, PhD, RN

NY-Satchi-Fainaro-Teleconference_r1

 

 

 

 

Read Full Post »

Curbing Cancer Cell Growth & Metastasis-on-a-Chip’ Models Cancer’s Spread, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Curbing Cancer Cell Growth & Metastasis-on-a-Chip’ Models Cancer’s Spread

Curator: Larry H. Bernstein, MD, FCAP

 

New Approach to Curbing Cancer Cell Growth

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=189342

Using a new approach, scientists at The Scripps Research Institute (TSRI) and collaborating institutions have discovered a novel drug candidate that could be used to treat certain types of breast cancer, lung cancer and melanoma.

The new study focused on serine, one of the 20 amino acids (protein building blocks) found in nature. Many types of cancer require synthesis of serine to sustain rapid, constant and unregulated growth.

To find a drug candidate that interfered with this pathway, the team screened a large library of compounds from a variety of sources, searching for molecules that inhibited a specific enzyme known as 3-phosphoglycerate dehydrogenase (PHGDH), which is responsible for the first committed step in serine biosynthesis.

“In addition to discovering an inhibitor that targets cancer metabolism, we also now have a tool to help answer interesting questions about serine metabolism,” said Luke L. Lairson, assistant professor of chemistry at TSRI and principal investigator of cell biology at the California Institute for Biomedical Research (CALIBR).

Lairson was senior author of the study, published recently in the Proceedings of the National Academy of Sciences (PNAS), with Lewis Cantley of Weill Cornell Medical College and Costas Lyssiotis of the University of Michigan.

Addicted to Serine

Serine is necessary for nucleotide, protein and lipid biosynthesis in all cells. Cells use two main routes for acquiring serine: through import from the extracellular environment or through conversion of 3-phosphoglycerate (a glycolytic intermediate) by PHGDH.

“Since the late 1950s, it has been known that cancer cells use the process of aerobic glycolysis to generate metabolites needed for proliferative growth,” said Lairson.

This process can lead to an overproduction of serine. The genetic basis for this abundance had remained mysterious until recently, when it was demonstrated that some cancers acquire mutations that increased the expression of PHGDH; reducing PHGDH in these “serine-addicted” cancer cells also inhibited their growth.

The labs of Lewis C. Cantley at Weill Cornell Medical College (in work published in Nature Genetics) and David Sabatini at the Whitehead Institute (in work published in Nature) suggested PHGDH as a potential drug target for cancer types that overexpress the enzyme.

Lairson and colleagues hypothesized that a small molecule drug candidate that inhibited PHGDH could interfere with cancer metabolism and point the way to the development of an effective cancer therapeutic. Importantly, this drug candidate would be inactive against normal cells because they would be able to import enough serine to support ordinary growth.

As Easy as 1-2-800,000

Lairson, in collaboration with colleagues including Cantley, Lyssiotis, Edouard Mullarky of Weill Cornell and Harvard Medical School and Natasha Lucki of CALIBR, screened through a library of 800,000 small molecules using a high-throughput in vitro enzyme assay to detect inhibition of PHGDH. The group identified 408 candidates and further narrowed this list down based on cell-type specific anti-proliferative activity and by eliminating those inhibitors that broadly targeted other dehydrogenases.

With the successful identification of seven candidate inhibitors, the team sought to determine if these molecules could inhibit PHGDH in the complex cellular environment. To do so, the team used a mass spectrometry-based assay (test) to measure newly synthesized serine in a cell in the presence of the drug candidates.

One of the seven small molecules tested, named CBR-5884, was able to specifically inhibit serine synthesis by 30 percent, suggesting that the molecule specifically targeted PHGDH. The group went on to show that CBR-5884 was able to inhibit cell proliferation of breast cancer and melanoma cells lines that overexpress PHGDH.

As expected, CBR-5884 did not inhibit cancer cells that did not overexpress PHGDH, as they can import serine; however, when incubated in media lacking serine, the presence of CBR-5884 decreased growth in these cells.

The group anticipates much optimization work before this drug candidate can become an effective therapeutic. In pursuit of this goal, the researchers plan to take a medicinal chemistry approach to improve potency and metabolic stability.

 

How Cancer Stem Cells Thrive When Oxygen Is Scarce

(Image: Shutterstock)
image: Shutterstock

Working with human breast cancer cells and mice, scientists at The Johns Hopkins University say new experiments explain how certain cancer stem cells thrive in low oxygen conditions. Proliferation of such cells, which tend to resist chemotherapy and help tumors spread, are considered a major roadblock to successful cancer treatment.

The new research, suggesting that low-oxygen conditions spur growth through the same chain of biochemical events in both embryonic stem cells and breast cancer stem cells, could offer a path through that roadblock, the investigators say.

“There are still many questions left to answer but we now know that oxygen poor environments, like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells,” said Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. “That gives us a few more possible targets for drugs that diminish their threat in human cancer.”

A summary of the findings was published online March 21 in the Proceedings of the National Academy of Sciences.

“Aggressive cancers contain regions where the cancer cells are starved for oxygen and die off, yet patients with these tumors generally have the worst outcome. Our new findings tell us that low oxygen conditions actually encourage certain cancer stem cells to multiply through the same mechanism used by embryonic stem cells.”

All stem cells are immature cells known for their ability to multiply indefinitely and give rise to progenitor cells that mature into specific cell types that populate the body’s tissues during embryonic development. They also replenish tissues throughout the life of an organism. But stem cells found in tumors use those same attributes and twist them to maintain and enhance the survival of cancers.

Recent studies showed that low oxygen conditions increase levels of a family of proteins known as HIFs, or hypoxia-inducible factors, that turn on hundreds of genes, including one called NANOG that instructs cells to become stem cells.

Studies of embryonic stem cells revealed that NANOG protein levels can be lowered by a chemical process known as methylation, which involves putting a methyl group chemical tag on a protein’s messenger RNA (mRNA) precursor. Semenza said methylation leads to the destruction of NANOG’s mRNA so that no protein is made, which in turn causes the embryonic stem cells to abandon their stem cell state and mature into different cell types.

Zeroing in on NANOG, the scientists found that low oxygen conditions increased NANOG’s mRNA levels through the action of HIF proteins, which turned on the gene for ALKBH5, which decreased the methylation and subsequent destruction of NANOG’s mRNA. When they prevented the cells from making ALKBH5, NANOG levels and the number of cancer stem cells decreased. When the researchers manipulated the cell’s genetics to increase levels of ALKBH5 without exposing them to low oxygen, they found this also decreased methylation of NANOG mRNA and increased the numbers of breast cancer stem cells.

Finally, using live mice, the scientists injected 1,000 triple-negative breast cancer cells into their mammary fat pads, where the mouse version of breast cancer forms. Unaltered cells created tumors in all seven mice injected with such cells, but when cells missing ALKBH5 were used, they caused tumors in only 43 percent (six out of 14) of mice. “That confirmed for us that ALKBH5 helps preserve cancer stem cells and their tumor-forming abilities,” Semenza said.

How cancer stem cells thrive when oxygen is scarce    https://www.sciencedaily.com/releases/2016/03/160328100159.htm

The new research, suggesting that low-oxygen conditions spur growth through the same chain of biochemical events in both embryonic stem cells and breast cancer stem cells, could offer a path through that roadblock, the investigators say.

“There are still many questions left to answer but we now know that oxygen poor environments, like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells,” says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine and a member of the Johns Hopkins Kimmel Cancer Center.

Chuanzhao Zhang, Debangshu Samanta, Haiquan Lu, John W. Bullen, Huimin Zhang, Ivan Chen, Xiaoshun He, Gregg L. Semenza.
Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA.
Proceedings of the National Academy of Sciences, 2016; 201602883     DOI: 10.1073/pnas.1602883113

Significance

Pluripotency factors, such as NANOG, play a critical role in the maintenance and specification of cancer stem cells, which are required for primary tumor formation and metastasis. In this study, we report that exposure of breast cancer cells to hypoxia (i.e., reduced O2 availability), which is a critical feature of the tumor microenvironment, induces N6-methyladenosine (m6A) demethylation and stabilization of NANOG mRNA, thereby promoting the breast cancer stem cell (BCSC) phenotype. We show that inhibiting the expression of AlkB homolog 5 (ALKBH5), which demethylates m6A, or the hypoxia-inducible factors (HIFs) HIF-1α and HIF-2α, which activate ALKBH5 gene transcription in hypoxic breast cancer cells, is an effective strategy to decrease NANOG expression and target BCSCs in vivo.

N6-methyladenosine (m6A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m6A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxia-inducible factor (HIF)-1α- and HIF-2α–dependent expression of AlkB homolog 5 (ALKBH5), an m6A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m6A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF- and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O2, HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.

Specific Proteins Found to Jump Start Spread of Cancer Cells

http://www.genengnews.com/gen-news-highlights/specific-proteins-found-to-jump-start-spread-of-cancer-cells/81252417/

Metastatic breast cancer cells. [National Cancer Institute]
http://www.genengnews.com/Media/images/GENHighlight/thumb_Feb29_2016_NCI_MetastaticBreastCancerCells1797514764.jpg

Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center, with colleagues in Spain and Germany, have discovered how elevated levels of particular proteins in cancer cells trigger hyperactivity in other proteins, fueling the growth and spread of a variety of cancers. Their study (“Prognostic Impact of Modulators of G Proteins in Circulating Tumor Cells from Patients with Metastatic Colorectal Cancer”) is published in Scientific Reports.

Specifically, the international team, led by senior author Pradipta Ghosh, M.D., associate professor at the University of California San Diego School of Medicine, found that increased levels of expression of some members of a protein family called guanine nucleotide exchange factors (GEFs) triggered unsuspected hyperactivation of G proteins and subsequent progression or metastasis of cancer.

The discovery suggests GEFs offer a new and more precise indicator of disease state and prognosis. “We found that elevated expression of each GEF is associated with a shorter, progression-free survival in patients with metastatic colorectal cancer,” said Dr. Ghosh. “The GEFs fared better as prognostic markers than two well-known markers of cancer progression, and the clustering of all GEFs together improved the predictive accuracy of each individual family member.”

In recent years, circulating tumor cells (CTCs), which are shed from primary tumors into the bloodstream and act as seeds for new tumors taking root in other parts of the body, have become a prognostic and predictive biomarker. The presence of CTCs is used to monitor the efficacy of therapies and detect early signs of metastasis.

But counting CTCs in the bloodstream has limited utility, said Dr. Ghosh. “Enumeration alone does not capture the particular characteristics of CTCs that are actually tumorigenic and most likely to cause additional malignancies.”

Numerous efforts are underway to improve the value and precision of CTC analysis. According to Dr. Ghosh the new findings are a step in that direction. First, GEFs activate trimeric G proteins, and second, G protein signaling is involved in CTCs. G proteins are ubiquitous and essential molecular switches involved in transmitting external signals from stimuli into cells’ interiors. They have been a subject of heightened scientific interest for many years.

Dr. Ghosh and colleagues found that elevated expression of nonreceptor GEFs activates Gαi proteins, fueling CTCs and ultimately impacting the disease course and survival of cancer patients.

“Our work shows the prognostic impact of elevated expression of individual and clustered GEFs on survival and the benefit of transcriptome analysis of G protein regulatory proteins in cancer biology,” said Dr. Ghosh. “The next step will be to carry this technology into the clinic where it can be applied directly to deciphering a patient’s state of cancer and how best to treat.”

Metastasis-on-a-Chip’ Models Cancer’s Spread

http://www.mdtmag.com/news/2016/03/metastasis-chip-models-cancers-spread?et_cid=5200644&et_rid=461755519

In the journal Biotechnology Bioengineering, the team reports on its “metastasis-on-a-chip” system believed to be one of the first laboratory models of cancer spreading from one 3D tissue to another.

The current version of the system models a colorectal tumor spreading from the colon to the liver, the most common site of metastasis. Skardal said future versions could include additional organs, such as the lung and bone marrow, which are also potential sites of metastasis. The team also plans to model other types of cancer, such as the deadly brain tumor glioblastoma

To create the system, researchers encapsulated human intestine and colorectal cancer cells inside a biocompatible gel-like material to make a mini-organ. A mini-liver composed of human liver cells was made in the same way. These organoids were placed in a “chip” system made up of a set of micro-channels and chambers etched into the chip’s surface to mimic a simplified version of the body’s circulatory system. The tumor cells were tagged with fluorescent molecules so their activity could be viewed under a microscope.

To test whether the system could model metastasis, the researchers first used highly aggressive cancer cells in the colon organoid. Under the microscope, they saw the tumor grow in the colon organoid until the cells broke free, entered the circulatory system and then invaded the liver tissue, where another tumor formed and grew. When a less aggressive form of colon cancer was used in the system, the tumor did not metastasize, but continued to grow in the colon.

To test the system’s potential for screening drugs, the team introduced Marimastat, a drug used to inhibit metastasis in human patients, into the system and found that it significantly prevented the migration of metastatic cells over a 10-day period. Likewise, the team also tested 5-fluorouracil, a common colorectal cancer drug, which reduced the metabolic activity of the tumor cells.

“We are currently exploring whether other established anti-cancer drugs have the same effects in the system as they do in patients,” said Skardal. “If this link can be validated and expanded, we believe the system can be used to screen drug candidates for patients as a tool in personalized medicine. If we can create the same model systems, only with tumor cells from an actual patient, then we believe we can use this platform to determine the best therapy for any individual patient.”

The scientists are currently working to refine their system. They plan to use 3D printing to create organoids more similar in function to natural organs. And they aim to make the process of metastasis more realistic. When cancer spreads in the human body, the tumor cells must break through blood vessels to enter the blood steam and reach other organs. The scientists plan to add a barrier of endothelial cells, the cells that line blood vessels, to the model.

This concept of modeling the body’s processes on a miniature level is made possible because of advances in micro-tissue engineering and micro-fluidics technologies. It is similar to advances in the electronics industry made possible by miniaturizing electronics on a chip.

Scientists Synthesize Anti-Cancer Agent

A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University
A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University  http://www.dddmag.com/sites/dddmag.com/files/ddd1603_rice-anticancer.jpg

A team led by Rice University synthetic organic chemist K.C. Nicolaou has developed a new process for the synthesis of a series of potent anti-cancer agents originally found in bacteria.

The Nicolaou lab finds ways to replicate rare, naturally occurring compounds in larger amounts so they can be studied by biologists and clinicians as potential new medications. It also seeks to fine-tune the molecular structures of these compounds through analog design and synthesis to improve their disease-fighting properties and lessen their side effects.

Such is the case with their synthesis of trioxacarcins, reported this month in the Journal of the American Chemical Society.

“Not only does this synthesis render these valuable molecules readily available for biological investigation, but it also allows the previously unknown full structural elucidation of one of them,” Nicolaou said. “The newly developed synthetic technologies will allow us to construct variations for biological evaluation as part of a program to optimize their pharmacological profiles.”

At present, there are no drugs based on trioxacarcins, which damage DNA through a novel mechanism, Nicolaou said.

Trioxacarcins were discovered in the fermentation broth of the bacterial strain Streptomyces bottropensis. They disrupt the replication of cancer cells by binding and chemically modifying their genetic material.

“These molecules are endowed with powerful anti-tumor properties,” Nicolaou said. “They are not as potent as shishijimicin, which we also synthesized recently, but they are more powerful than taxol, the widely used anti-cancer drug. Our objective is to make it more powerful through fine-tuning its structure.”

He said his lab is working with a biotechnology partner to pair these cytotoxic compounds (called payloads) to cancer cell-targeting antibodies through chemical linkers. The process produces so-called antibody-drug conjugates as drugs to treat cancer patients. “It’s one of the latest frontiers in personalized targeting chemotherapies,” said Nicolaou, who earlier this year won the prestigious Wolf Prize in Chemistry.

Fluorescent Nanoparticle Tracks Cancer Treatment’s Effectiveness in Hours

Bevin Fletcher, Associate Editor    http://www.biosciencetechnology.com/news/2016/03/fluorescent-nanoparticle-tracks-cancer-treatments-effectiveness-hours

Using reporter nanoparticles loaded with either a chemotherapy or immunotherapy, researchers could distinguish between drug-sensitive and drug-resistant tumors in a pre-clinical model of prostate cancer. (Source: Brigham and Women's Hospital)

Using reporter nanoparticles loaded with either a chemotherapy or immunotherapy, researchers could distinguish between drug-sensitive and drug-resistant tumors in a pre-clinical model of prostate cancer. (Source: Brigham and Women’s Hospital)

Bioengineers at Brigham and Women’s Hospital have developed a new technique to help determine if chemotherapy is working in as few as eight hours after treatment. The new approach, which can also be used for monitoring the effectiveness of immunotherapy, has shown success in pre-clinical models.

The technology utilizes a nanoparticle, carrying anti-cancer drugs, that glows green when cancer cells begin dying. Researchers, using  the “reporter nanoparticles” that responds to a particular enzyme known as caspase, which is activated when cells die, were able to distinguish between a tumor that is drug-sensitive or drug-resistant much faster than conventional detection methods such as PET scans, CT and MRI.  The findings were published online March 28 in the Proceedings of the National Academy of Sciences.

“Using this approach, the cells light up the moment a cancer drug starts working,” co-corresponding author Shiladitya Sengupta, Ph.D., principal investigator in BWH’s Division of Bioengineering, said in a prepared statement.  “We can determine if a cancer therapy is effective within hours of treatment.  Our long-term goal is to find a way to monitor outcomes very early so that we don’t give a chemotherapy drug to patients who are not responding to it.”

Cancer killers send signal of success

Nanoparticles deliver drug, then give real-time feedback when tumor cells die   BY   SARAH SCHWARTZ

New lab-made nanoparticles deliver cancer drugs into tumors, then report their effects in real time by lighting up in response to proteins produced by dying cells. More light (right, green) indicates a tumor is responding to chemotherapy.

Tiny biochemical bundles carry chemotherapy drugs into tumors and light up when surrounding cancer cells start dying. Future iterations of these lab-made particles could allow doctors to monitor the effects of cancer treatment in real time, researchers report the week of March 28 in theProceedings of the National Academy of Sciences.

“This is the first system that allows you to read out whether your drug is working or not,” says study coauthor Shiladitya Sengupta, a bioengineer at Brigham and Women’s Hospital in Boston.

Each roughly 100-nanometer-wide particle consists of a drug and a fluorescent dye linked to a coiled molecular chain. Before the particles enter cells, the dye is tethered to a “quencher” molecule that prevents it from lighting up. When injected into the bloodstream of a mouse with cancer, the nanoparticles accumulate in tumor cells and release the drug, which activates a protein that tears a cancer cell apart. This cell-splitting protein not only kills the tumor cell, but also severs the link between the dye and the quencher, allowing the nanoparticles to glow under infrared light.

Reporter nanoparticle that monitors its anticancer efficacy in real time

Ashish Kulkarnia,b,1,Poornima Raoa,b,Siva Natarajana,b,Aaron Goldman, et al.
http://www.pnas.org/content/early/2016/03/28/1603455113.abstract

The ability to identify responders and nonresponders very early during chemotherapy by direct visualization of the activity of the anticancer treatment and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life. Current approaches to quantify response rely on imaging techniques that fail to detect very early responses. In the case of immunotherapy, the early anatomical readout is often discordant with the biological response. This study describes a self-reporting nanomedicine that not only delivers chemotherapy or immunotherapy to the tumor but also reports back on its efficacy in real time, thereby identifying responders and nonresponders early on

The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.

 

Cancer Treatment’s New Direction  
Genetic testing helps oncologists target tumors and tailor treatments
http://www.wsj.com/articles/cancer-treatments-new-direction-1459193085

Evan Johnson had battled a cold for weeks, endured occasional nosebleeds and felt so fatigued he struggled to finish his workouts at the gym. But it was the unexplained bruises and chest pain that ultimately sent the then 23-year-old senior at the University of North Dakota to the Mayo Clinic. There a genetic test revealed a particularly aggressive form of acute myeloid leukemia. That was two years ago.

The harrowing roller-coaster that followed for Mr. Johnson and his family highlights new directions oncologists are taking with genetic testing to find and attack cancer. Tumors can evolve to resist treatments, and doctors are beginning to turn such setbacks into possible advantages by identifying new targets to attack as the tumors change.

His course involved a failed stem cell transplant, a half-dozen different drug regimens, four relapses and life-threatening side effects related to his treatment.

Nine months in, his leukemia had evolved to develop a surprising new mutation. The change meant the cancer escaped one treatment, but the new anomaly provided doctors with a fresh target, one susceptible to drugs approved for other cancers. Doctors adjusted Mr. Johnson’s treatment accordingly, knocked out the disease and paved the way for a second, more successful stem cell transplant. He has now been free of leukemia for a year.

Now patients with advanced cancer who are treated at major centers can expect to have their tumors sequenced, in hopes of finding a match in a growing medicine chest of drugs that precisely target mutations that drive cancer’s growth. When they work, such matches can have a dramatic effect on tumors. But these “precision medicines” aren’t cures. They are often foiled when tumors evolve, pushing doctors to take the next step to identify new mutations in hopes of attacking them with an effective treatment.

Dr. Kasi and his Mayo colleagues—Naseema Gangat, a hematologist, and Shahrukh Hashmi, a transplant specialist—are among the authors of an account of Mr. Johnson’s case published in January in the journal Leukemia Research Reports.

Before qualifying for a transplant, a patient’s blasts need to be under 5%.

To get under 5%, he started on a standard chemotherapy regimen and almost immediately, things went south. His blast cells plummeted, but “the chemo just wiped out my immune system,”

Then as mysteriously as it began, a serious mycotic throat infection stopped. But Mr. Johnson couldn’t tolerate the chemo, and his blast cells were on the rise. A two-drug combination that included the liver cancer drug Nexavar, which targets the FLT3 mutation, knocked back the blast cells. But the stem cell transplant in May, which came from one of his brothers, failed to take, and he relapsed after 67 days, around late July.

He was put into a clinical trial of an experimental AML drug being developed by Astellas Pharma of Japan. He started to regain weight. In November 2014, doctors spotted the initial signs in blood tests that Mr. Johnson’s cancer was evolving to acquire a new mutation. By late January, he relapsed again , but there was a Philadelphia chromosome mutation,  a well-known genetic alteration associated with chronic myeloid leukemia. It also is a target of the blockbuster cancer drug Gleevec and several other medicines.

Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets

Naseema GangatMark R. LitzowMrinal M. PatnaikShahrukh K. HashmiNaseema Gangat

Highlights
•   The article reports on a case of AML that underwent clonal evolution.
•   We report on novel acquisition of the Philadelphia t(9;22) translocation in AML.
•   Next generation sequencing maybe helpful in these refractory/relapse cases.
•   Novel FLT3-inhibitor targeted therapies are another option in patients with AML.
•   Personalizing cancer treatment based on evolving targets is a viable option.

For acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215) to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉)

The development of kinase inhibitors for the treatment of leukemia has revolutionized the care of these patients. Since the introduction of imatinib for the treatment of chronic myeloid leukemia, multiple other tyrosine kinase inhibitors (TKIs) have become available[1]. Additionally, for acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors [2], [3], [4] and [5]. The article herein reports a unique case of AML that underwent clonal evolution while on a novel FLT3-inhibitor clinical trial.

Our work herein presents clinical and next generation sequencing data at the time of progression to illustrate these important concepts stemming from Darwinian evolution [6]. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process.

Our work focuses on a 23-year-old male who presented with 3 months history of fatigue and easy bruising, a white blood count of 22.0×109/L with 51% circulating blasts, hemoglobin 7.6 g/dL, and a platelet count of 43×109/L. A bone marrow biopsy confirmed a diagnosis of AML. Initial cytogenetic studies identified trisomy 8 in all the twenty metaphases examined. Mutational analysis revealed an internal tandem duplication of the FLT3 gene (FLT3-ITD).

He received standard induction chemotherapy (7+3) with cytarabine (ARA-C; 100 mg/m2for 7 days) and daunorubicin (DNM; 60 mg/m2 for 3 days). His induction chemotherapy was complicated by severe palatine and uvular necrosis of indeterminate etiology (possible mucormycosis).

Bone marrow biopsy at day 28 demonstrated persistent disease with 10% bone marrow blasts (Fig. 1). Due to his complicated clinical course and the presence of a FLT3-ITD, salvage therapy with 5-azacitidine (5-AZA) and sorafenib (SFN) was instituted. Table 1.
The highlighted therapies were employed in this particular case at various time points as shown in Fig. 1.

http://ars.els-cdn.com/content/image/1-s2.0-S221304891530025X-gr1.jpg

References

    • [1]
    • J.E. Cortes, D.W. Kim, J. Pinilla-Ibarz, et al.
    • A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias
    • New Engl. J. Med., 369 (19) (2013), pp. 1783–1796
    • [2]
    • F. Ravandi, M.L. Alattar, M.R. Grunwald, et al.
    • Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation
    • Blood, 121 (23) (2013), pp. 4655–4662
    • [3]
    • N.P. Shah, M. Talpaz, M.W. Deininger, et al.
    • Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study
    • Br. J. Haematol., 162 (4) (2013), pp. 548–552
    • [4]
    • Y. Alvarado, H.M. Kantarjian, R. Luthra, et al.
    • Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations
    • Cancer, 120 (14) (2014), pp. 2142–2149
    • [5]
    • C.C. Smith, C. Zhang, K.C. Lin, et al.
    • Characterizing and overriding the structural mechanism of the Quizartinib-Resistant FLT3 “Gatekeeper” F691L mutation with PLX3397
    • Cancer Discov. (2015)
    • [6]
    • M. Greaves, C.C. Maley
    • Clonal evolution in cancer
    • Nature, 481 (7381) (2012), pp. 306–313

 

 

 

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Medical MEMS, BioMEMS and Sensor Applications

Curator and Reporter: Aviva Lev-Ari, PhD, RN

 

Contents for Chapter 11

Medical MEMS, BioMEMS and Sensors Applications

Curators: Justin D. Pearlman, MD, PhD, FACC, LPBI Group, Danut Dragoi, PhD, LPBI Group and William H. Zurn, Alpha IP

FOR

Series E: Patient-centered Medicine

Volume 4:  Medical 3D BioPrinting – The Revolution in Medicine

Editors: Larry H Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/biomed-e-books/series-e-titles-in-the-strategic-plan-for-2014-1015/volume-four-medical-3d-bioprinting-the-revolution-in-medicine/

Work-in-Progress

ContactLens

Image Source

http://www.memsjournal.com/2010/05/medical-applications-herald-third-wave-of-mems.html

Image is courtesy of Google Images

 

WirelessPressure

Image Source

Stanford Engineering Team Invents Pressure Sensor That Uses Radio Waves | CytoFluidix

Image is courtesy of Google Images

 

Introduction by Dr. Pearlman

 

Chapter 1: Blood Glucose Sensors

1.1       MINIATURIZED GLUCOSE SENSOR – Google

  • Tiny wireless chip and miniaturized glucose sensor
  • Embedded between two layers of soft contact lens material
  • Accurate glucose monitoring for diabetics
  • Using bodily fluids, i.e. tears
  • Prototypes can generate one reading per second
  • Experimenting with LEDs
  • Early warning for the wearer

 

Chapter 2: Blood Chemistry Tests – up to 100 Samples

2.1       NON-INVASIVE BLOOD MONITOR- UCSD

  • Digital tattoo monitors blood below the skin
  • Tattoos are needle-less
    • Sensor-laden transdermal patch
  • Painless for the user Tiny sensors “ink”
  • Can read blood levels of:
    • Sodium, glucose, kidney function
  • Prototypes contain probes
  • Wireless, battery-powered chip
  • Continually test up to a hundred different samples

 

2.3       CELLPHONE-BASED RAPID-DIAGNOSTIC-TEST (RDT) READER – UCLA

  • Lateral flow immuno-chromatographic assays
  • Sense the presence of a target analyte in a sample
  • Device connects to the camera on a cell phone
  • Weighs only 65 grams

 

2.4       IMPLANTABLE BLOOD ANALYZER CHIP – EPFL

  • Implantable device for instantaneous blood analysis
  • Wireless data transmission to a doctor
  • Applications include monitoring general health
  • Tailor drug delivery to a patient’s unique needs
  • Includes five sensors and a radio transmitter
  • Powered via inductive coupling from a battery patch
  • Worn outside the body

 

Chapter 3: Motion Sensors for Head-Impact

3.1       HEAD-IMPACT MONITORING PATCH – STMicro & X2Biosystems

  • Wearable electronic contains MEMS motion sensors
  • Microcontroller, low-power radio transmitter, and power management circuitry
  • Cloud-based system combines athlete concussion history
  • Pre-season neurocognitive function, balance, and coordinate-performance data
  • Creates a baseline for comparison after a suspected injury event

 

Chapter 4: Drug Delivery & Drug Compliance Monitoring Systems

4.1       Smart Pill delivers Therapeutic Agent Load to target – ELECTRONIC PILL – Phillips

  • Electronic pill to treat gastrointestinal cancer
  • An ingestible pill is swallowed by the patient, finds its way to the tumor, dispenses the drugs and passes harmlessly from the body
  • Smart pill contains reservoir for drug supply, fluid pump for drug delivery, pH sensor (for navigation), thermometer, microprocessor, communication

 

4.2       Drug Compliance Monitoring Systems

4.2.1    INGESTIBLE BIOMEDICAL SENSOR – Proteus Digital Health

  • Biomedical sensor that monitors medication adherence
  • Embedded into a pill, the sensor is activated by stomach fluid
  • Transmits a signal through the body to a skin patch
  • Indicates whether a patient has ingested material

 

4.2.2    MICROPUMP DEVICES – Purdue University

  • Device based on skin contact actuation for drug delivery
  • Actuation mechanism only requires body heat
  • Induced actuation can result to a gradient of 100 Pa/oC
  • Sufficient to drive liquid drug through micro-needle arrays
  • Prototypes exhibit low fabrication costs, employment of biocompatible materials and battery-less operation Suitable for single- or multiple-use transdermal drug dispensers

 

4.2.3    IMPLANTABLE MEMS DRUG DELIVERY SYSTEM – MIT

  • Device can deliver a vasoconstrictor agent
  • On demand to injured soldiers to prevent hemorrhagic shock
  • Other applications include medical implants
  • For cancer detection and monitoring
  • Implant can provide physicians and patients
  • Real-time information on the efficacy of treatment

 

Chapter 5: Remove Monitoring of Food-related Diseases

5.1       LASER-DRIVEN, HANDHELD SPECTROMETER

  • For analyzing food scanned
  • Information to a cloud-based application
  • Examines the results Data is accumulated from many users
  • Used to develop warning algorithms
  • For Allergies, Bacteria

 

Chapter 6: Skin Protection and Photo-Sensitivity Management

6.1       WEARABLE-UVEXPOSURESENSOR – Gizmag

  • Wristband for monitoring UV exposure
  • Allows user to maximize vitamin D production
  • Reducing the risk of sun
  • Over-exposure and skin cancer
  • LED indicators light up as UV exposure accumulates
  • Flashes once the safe UV limit has been reached

 

6.2       WEARABLE SKIN SENSOR KTH – Chemistry 2011

  • Bio-patch for measuring and collecting vital information through the skin
  • Inexpensive, versatile and comfortable to wear
  • User Data being gathered depends on where it is placed on the body

 

Chapter 7: Ophthalmic Applications

7.1       INTRAOCULAR PRESSURE SENSOR – Sensimed & ST Microelectronics

  • Smart contact lens called Triggerfish
  • Contact lens can measure, monitor, and control
  • Intra-ocular pressure levels for patients
  • Catch early cases of glaucoma
  • MEMS strain gage pressure sensor
  • Mounted on a flexible substrate MEMS

 

7.2       MICRO-MIRRORS ENABLING HANDHELD OPHTHALMIC – OCT News

  • Swept source OCT model for retinal 3D imaging
  • Replaces bulky galvanometer scanners in a handheld OCT probe for primary care physicians
  • Ultrahigh-speed two-axis optical beam steering gimbal-less MEMS mirrors
  • MEMS Actuator with a 2.4 mm bonded mirror and an angular reach of +6°
  • Low power consumption of <100mW including the MEMS actuator driver Retinal 3D Imaging

 

Chapter 8: Hearing Assist Technologies

8.1       MEMS TECHNOLOGY FOR HEARING RESTORATION – University of Utah

  • Eliminates electronics outside the ear
  • Associated with reliability issues and social stigma
  • Accelerometer-based microphone
  • Successfully tested in cadaver ear canals
  • Prototype measures 2.5 x 6.2mm, weighs 25mg

 

Chapter 9: Lab-on-a-Chip

9.1       ORGAN-ON-A-CHIP – Johns Hopkins University

  • Silicon substrate for living human cells
  • Controlled environment
  • Emulate how cells function inside a living human body
  • Replace controversial and costly animal testing
  • Lab-on-a-chip: a cost effective end to animal testing

 

Chapter 10: Intra-Cranial Studies: Pressure Measurement, Monitoring and Adaptation

10.1:   CEREBRAL PRESSURE SENSOR – Fraunhofer Institute

  • Sensor to monitor cerebral pressure that can lead to dementia
  • Pressure changes in the brain can be measured and transmitted
  • Reading device outside the patient’s body
  • Operating at very low power, the sensor module
  • Powered wirelessly by the reading device

 

10.2    WIRELESS, IMPLANTABLE BRAIN SENSOR – National Institute of Biomedical Imaging and Bioengineering

  • Fully implantable within the brain
  • Allow natural studies of brain activity
  • Cord-free control of advanced prosthetics

Wireless charging Prototypes transmitted brain activity data

 

Chapter 11: Cardiac and Cardiovascular Monitoring System

11.1    IMPLANTABLE MICRO DEVICE FOR MONITORING AND TREATING ANEURISMS – Electronic Design

  • RF-addressed wireless pressure sensor are powered by inductive coupling
  • Do not need batteries MEMS pressure sensor
  • Wireless antenna are inserted near the heart
  • With a catheter, Blood-pressure readings
  • Are sent to a wireless scanner for monitoring Pressure changes
  • Deflect the transducer’s diaphragm
  • Change the LC circuit’s resonant

 

11.2    CUSTOM- FITTED, IMPLANTABLE DEVICE FOR TREATMENT AND PREDICTION OF CARDIAC DISORDERS – Washington University

  • Working prototypes were developed on inexpensive 3D printers
  • The 3D elastic membrane is made of a soft, flexible, silicon material
  • Precisely shaped to match the outer layer of the heart

 

Chapter 12: microfluidic chips

12.1    MICROFLUIDIC MEMS FOR DIABETES TREATMENT – Micronews

  • Watertight pump mounted on a disposable skin patch
  • Provides continuous insulin infusion
  • Controlled by a dedicated smart phone device
  • Incorporating a BGM (blood- glucose meter)

 

12.2    ACOUSTIC RECEIVER ANTENNA/SENSOR PDMS MEMBRANE – Purdue

POLY-DI-METHYL-SILOXANE (PDMS)

Polydimethylsiloxane called PDMS or dimethicone is a polymer widely used for the fabrication and prototyping of microfluidic chips.

It is a mineral-organic polymer (a structure containing carbon and silicon) of the siloxane family (word derived from silicon, oxygen and alkane). Apart from microfluidics, it is used as a food additive (E900), in shampoos, and as an anti-foaming agent in beverages or in lubricating oils.

For the fabrication of microfluidic devices, PDMS (liquid) mixed with a cross-linking agent is poured into a microstructured mold and heated to obtain a elastomeric replica of the mold (PDMS cross-linked).

 

Why Use PDMS for Microfluidic Device Fabrication?

 

PDMS was chosen to fabricate microfluidic chips primarily for those reasons:

Human alveolar epithelial and pulmonary microvascular endothelial cells cultured in a PDMS chip to mimick lung functions

  • It is transparent at optical frequencies (240 nM – 1100 nM), which facilitates the observation of contents in micro-channels visually or through a microscope.
  • It has a low autofluorescence [2]
  • It is considered as bio-compatible (with some restrictions).

The PDMS bonds tightly to glass or another PDMS layer with asimple plasma treatment. This allows the production of multilayers PDMS devices and enables to take advantage of technological possibilities offered by glass substrates, such as the use of metal deposition, oxide deposition or surface functionalisation.

PDMS, during cross-linking, can be coated with a controlled thickness on a substrate using a simple spincoat. This allows the fabrication of multilayer devices and the integration of micro valves.

It is deformable, which allows the integration of microfluidic valves using the deformation of PDMS micro-channels, the easy connection of leak-proof fluidic connections and its use to detect very low forces like biomechanics interactions from cells.

SOURCE

http://www.elveflow.com/microfluidic-tutorials/microfluidic-reviews-and-tutorials/the-poly-di-methyl-siloxane-pdms-and-microfluidics/

 

  • Ferrite RF radiation Acoustic wave Rectifier
  • Buried in PDMS Implantable miniature pressure sensor
  • Powered by an acoustically actuated cantilever
  • No battery required
  • Acoustic waves in the 200-500 hertz range
  • Cause cantilever to vibrate
  • Scavenging energy to power pressure sensor

 

Chapter 13: Peropheral Neuropathy Management

13.1    WIRELESS SHOE INSERT – Mobile Health News

  • WIRELESS SHOE INSERT – Mobile Health News
  • Help diabetics manage peripheral nerve damage
  • Insole collects data of where wearers
  • Putting pressure on their feet
  • Transmits wirelessly to a wristwatch-type display
  • Prevent amputations that often stem from diabetic foot ulcers

 

Chapter 14: Endoscopic Diagnostics Tools

14.1    ENDOSCOPE USING MEMS SCANNING MIRROR

  • For gastrointestinal and urological imaging
  • Alternative to biopsies in cancer detection
  • A laser beam pointed at the mirror is precisely deflected
  • Steered by the scanning mirror to reach a target

 

Chapter 15: MEMS guided Surgical Tools

15.1    MICROMACHINED SURGICAL TOOLS; SILICON MEMS TWEEZERS – ElectrolQ Used for minimally invasive surgical (MIS)

  • Procedures where diagnosis, monitoring, or treatment of diseases are performed
  • Performing with very small incisions MEMS
  • Based microsurgical tools is a key enabling technology for angioplasty, catheterization, endoscopy, laparoscopy, and neurosurgery

 

Summary by Dr. Pearlman

  • Multiple projects by Academia & Industry
  • Multiple MEMS devices for measuring body activities.
  • Many patch type devices attached to the skin
  • Devices attached to the eye
  • Smaller is better, lower footprint, lower power

 

 

 

 

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3-D Printed Liver

Curator: Larry H. Bernstein, MD, FCAP

 

 

3D-printing a new lifelike liver tissue for drug screening

Could let pharmaceutical companies quickly do pilot studies on new drugs
February 15, 2016    http://www.kurzweilai.net/3d-printing-a-new-lifelike-liver-tissue-for-drug-screening

Images of the 3D-printed parts of the biomimetic liver tissue: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right). (credit: Chen Laboratory, UC San Diego)

 

University of California, San Diego researchers have 3D-printed a tissue that closely mimics the human liver’s sophisticated structure and function. The new model could be used for patient-specific drug screening and disease modeling and could help pharmaceutical companies save time and money when developing new drugs, according to the researchers.

The liver plays a critical role in how the body metabolizes drugs and produces key proteins, so liver models are increasingly being developed in the lab as platforms for drug screening. However, so far, the models lack both the complex micro-architecture and diverse cell makeup of a real liver. For example, the liver receives a dual blood supply with different pressures and chemical constituents.

So the team employed a novel bioprinting technology that can rapidly produce complex 3D microstructures that mimic the sophisticated features found in biological tissues.

The liver tissue was printed in two steps.

  • The team printed a honeycomb pattern of 900-micrometer-sized hexagons, each containing liver cells derived from human induced pluripotent stem cells. An advantage of human induced pluripotent stem cells is that they are patient-specific, which makes them ideal materials for building patient-specific drug screening platforms. And since these cells are derived from a patient’s own skin cells, researchers don’t need to extract any cells from the liver to build liver tissue.
  • Then, endothelial and mesenchymal supporting cells were printed in the spaces between the stem-cell-containing hexagons.

The entire structure — a 3 × 3 millimeter square, 200 micrometers thick — takes just seconds to print. The researchers say this is a vast improvement over other methods to print liver models, which typically take hours. Their printed model was able to maintain essential functions over a longer time period than other liver models. It also expressed a relatively higher level of a key enzyme that’s considered to be involved in metabolizing many of the drugs administered to patients.

“It typically takes about 12 years and $1.8 billion to produce one FDA-approved drug,” said Shaochen Chen, NanoEngineering professor at the UC San Diego Jacobs School of Engineering. “That’s because over 90 percent of drugs don’t pass animal tests or human clinical trials. We’ve made a tool that pharmaceutical companies could use to do pilot studies on their new drugs, and they won’t have to wait until animal or human trials to test a drug’s safety and efficacy on patients. This would let them focus on the most promising drug candidates earlier on in the process.”

The work was published the week of Feb. 8 in the online early edition of Proceedings of the National Academy of Sciences.


Abstract of Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

Fernando

I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.

I agree with your observation that having the same DNA information doesn’t account for variability of cell function within an organ. The regulation of expression is in RNA translation, and that is subject to regulatory factors related to noncoding RNAs and to structural factors in protein folding. The result is that chronic diseases that are affected by the synthetic capabilities of the liver are still problematic – toxicology, diabetes, and the inflammatory response, and amino acid metabolism as well. Nevertheless, this is a very significant step for the testing of pharmaceuticals. When we look at the double circulation of the liver, hypoxia is less of an issue than for heart or skeletal muscle, or mesothelial tissues. I call your attention to the outstanding work by Nathan O. Kaplan on the transhydrogenases, and his stipulation that there are significant differences between organs that are anabolic and those that are catabolic in TPNH/DPNH, that has been ignored for over 40 years. Nothing is quite as simple as we would like.

Fernando commented on 3-D printed liver

3-D printed liver Larry H. Bernstein, MD, FCAP, Curator LPBI 3D-printing a new lifelike liver tissue for drug …

I wonder how equivalent are these hepatic cells derived from human induced pluripotent stem cells (hiPSCs) compared with the real hepatic cell populations.
All cells in our organism share the same DNA info, but every tissue is special for what genes are expressed and also because of the specific localization in our body (which would mean different surrounding environment for each tissue). I am not sure about how much of a step forward this is. Induced hepatic cells are known, but this 3-D print does not have liver shape or the different cell sub-types you would find in the liver.

 

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Human Factor Engineering: New Regulations Impact Drug Delivery, Device Design And Human Interaction

Curator: Stephen J. Williams, Ph.D.

Institute of Medicine report brought medical errors to the forefront of healthcare and the American public (Kohn, Corrigan, & Donaldson, 1999) and  estimated that between

44,000 and 98,000 Americans die each year as a result of medical errors

An obstetric nurse connects a bag of pain medication intended for an epidural catheter to the mother’s intravenous (IV) line, resulting in a fatal cardiac arrest. Newborns in a neonatal intensive care unit are given full-dose heparin instead of low-dose flushes, leading to threedeaths from intracranial bleeding. An elderly man experiences cardiac arrest while hospitalized, but when the code blue team arrives, they are unable to administer a potentially life-saving shock because the defibrillator pads and the defibrillator itself cannot be physically connected.

Human factors engineering is the discipline that attempts to identify and address these issues. It is the discipline that takes into account human strengths and limitations in the design of interactive systems that involve people, tools and technology, and work environments to ensure safety, effectiveness, and ease of use.

 

FDA says drug delivery devices need human factors validation testing

Several drug delivery devices are on a draft list of med tech that will be subject to a final guidance calling for the application of human factors and usability engineering to medical devices. The guidance calls called for validation testing of devices, to be collected through interviews, observation, knowledge testing, and in some cases, usability testing of a device under actual conditions of use. The drug delivery devices on the list include anesthesia machines, autoinjectors, dialysis systems, infusion pumps (including implanted ones), hemodialysis systems, insulin pumps and negative pressure wound therapy devices intended for home use. Studieshave consistently shown that patients struggle to properly use drug delivery devices such as autoinjectors, which are becoming increasingly prevalent due to the rise of self-administered injectable biologics. The trend toward home healthcare is another driver of usability issues on the patient side, while professionals sometimes struggle with unclear interfaces or instructions for use.

 

Humanfactors engineering, also called ergonomics, or human engineering, science dealing with the application of information on physical and psychological characteristics to the design of devices and systems for human use. ( for more detail see source@ Britannica.com)

The term human-factors engineering is used to designate equally a body of knowledge, a process, and a profession. As a body of knowledge, human-factors engineering is a collection of data and principles about human characteristics, capabilities, and limitations in relation to machines, jobs, and environments. As a process, it refers to the design of machines, machine systems, work methods, and environments to take into account the safety, comfort, and productiveness of human users and operators. As a profession, human-factors engineering includes a range of scientists and engineers from several disciplines that are concerned with individuals and small groups at work.

The terms human-factors engineering and human engineering are used interchangeably on the North American continent. In Europe, Japan, and most of the rest of the world the prevalent term is ergonomics, a word made up of the Greek words, ergon, meaning “work,” and nomos, meaning “law.” Despite minor differences in emphasis, the terms human-factors engineering and ergonomics may be considered synonymous. Human factors and human engineering were used in the 1920s and ’30s to refer to problems of human relations in industry, an older connotation that has gradually dropped out of use. Some small specialized groups prefer such labels as bioastronautics, biodynamics, bioengineering, and manned-systems technology; these represent special emphases whose differences are much smaller than the similarities in their aims and goals.

The data and principles of human-factors engineering are concerned with human performance, behaviour, and training in man-machine systems; the design and development of man-machine systems; and systems-related biological or medical research. Because of its broad scope, human-factors engineering draws upon parts of such social or physiological sciences as anatomy, anthropometry, applied physiology, environmental medicine, psychology, sociology, and toxicology, as well as parts of engineering, industrial design, and operations research.

source@ Britannica.com

The human-factors approach to design

Two general premises characterize the approach of the human-factors engineer in practical design work. The first is that the engineer must solve the problems of integrating humans into machine systems by rigorous scientific methods and not rely on logic, intuition, or common sense. In the past the typical engineer tended either to ignore the complex and unpredictable nature of human behaviour or to deal with it summarily with educated guesses. Human-factors engineers have tried to show that with appropriate techniques it is possible to identify man-machine mismatches and that it is usually possible to find workable solutions to these mismatches through the use of methods developed in the behavioral sciences.

The second important premise of the human-factors approach is that, typically, design decisions cannot be made without a great deal of trial and error. There are only a few thousand human-factors engineers out of the thousands of thousands of engineers in the world who are designing novel machines, machine systems, and environments much faster than behavioral scientists can accumulate data on how humans will respond to them. More problems, therefore, are created than there are ready answers for them, and the human-factors specialist is almost invariably forced to resort to trying things out with various degrees of rigour to find solutions. Thus, while human-factors engineering aims at substituting scientific method for guesswork, its specific techniques are usually empirical rather than theoretical.

HFgeneralpic

 

 

 

 

 

 

 

 

 

 

 

The Man-Machine Model: Human-factors engineers regard humans as an element in systems

The simple man-machine model provides a convenient way for organizing some of the major concerns of human engineering: the selection and design of machine displays and controls; the layout and design of workplaces; design for maintainability; and the work environment.

Components of the Man-Machine Model

  1. human operator first has to sense what is referred to as a machine display, a signal that tells him something about the condition or the functioning of the machine
  2. Having sensed the display, the operator interprets it, perhaps performs some computation, and reaches a decision. In so doing, the worker may use a number of human abilities, Psychologists commonly refer to these activities as higher mental functions; human-factors engineers generally refer to them as information processing.
  3. Having reached a decision, the human operator normally takes some action. This action is usually exercised on some kind of a control—a pushbutton, lever, crank, pedal, switch, or handle.
  4. action upon one or more of these controls exerts an influence on the machine and on its output, which in turn changes the display, so that the cycle is continuously repeated

 

Driving an automobile is a familiar example of a simple man-machine system. In driving, the operator receives inputs from outside the vehicle (sounds and visual cues from traffic, obstructions, and signals) and from displays inside the vehicle (such as the speedometer, fuel indicator, and temperature gauge). The driver continually evaluates this information, decides on courses of action, and translates those decisions into actions upon the vehicle’s controls—principally the accelerator, steering wheel, and brake. Finally, the driver is influenced by such environmental factors as noise, fumes, and temperature.

 

hfactorconsideroutcomes

How BD Uses Human Factors to Design Drug-Delivery Systems

Posted in Design Services by Jamie Hartford on August 30, 2013

 Human factors testing has been vital to the success of the company’s BD Physioject Disposable Autoinjector.

Improving the administration and compliance of drug delivery is a common lifecycle strategy employed to enhance short- and long-term product adoption in the biotechnology and pharmaceutical industries. With increased competition in the industry and heightened regulatory requirements for end-user safety, significant advances in product improvements have been achieved in the injectable market, for both healthcare professionals and patients. Injection devices that facilitate preparation, ease administration, and ensure safety are increasingly prevalent in the marketplace.

Traditionally, human factors engineering addresses individualized aspects of development for each self-injection device, including the following:

  • Task analysis and design.
  • Device evaluation and usability.
  • Patient acceptance, compliance, and concurrence.
  • Anticipated training and education requirements.
  • System resilience and failure.

To achieve this, human factors scientists and engineers study the disease, patient, and desired outcome across multiple domains, including cognitive and organizational psychology, industrial and systems engineering, human performance, and economic theory—including formative usability testing that starts with the exploratory stage of the device and continues through all stages of conceptual design. Validation testing performed with real users is conducted as the final stage of the process.

To design the BD Physioject Disposable Autoinjector System , BD conducted multiple human factors studies and clinical studies to assess all aspects of performance safety, efficiency, patient acceptance, and ease of use, including pain perception compared with prefilled syringes.5 The studies provided essential insights regarding the overall user-product interface and highlighted that patients had a strong and positive response to both the product design and the user experience.

As a result of human factors testing, the BD Physioject Disposable Autoinjector System provides multiple features designed to aide in patient safety and ease of use, allowing the patient to control the start of the injection once the autoinjector is placed on the skin and the cap is removed. Specific design features included in the BD Physioject Disposable Autoinjector System include the following:

  • Ergonomic design that is easy to handle and use, especially in patients with limited dexterity.
  • A 360° view of the drug and injection process, allowing the patient to confirm full dose delivery.
  • A simple, one-touch injection button for activation.
  • A hidden needle before and during injection to reduce needle-stick anxiety.
  • A protected needle before and after injection to reduce the risk of needle stick injury.

 

YouTube VIDEO: Integrating Human Factors Engineering (HFE) into Drug Delivery

 

Notes:

 

 

The following is a slideshare presentation on Parental Drug Delivery Issues in the Future

 The Dangers of Medical Devices

The FDA receives on average 100,000 medical device incident reports per year, and more than a third involve user error.

In an FDA recall study, 44% of medical device recalls are due to design problems, and user error is often linked to the poor design of a product.

Drug developers need to take safe drug dosage into consideration, and this consideration requires the application of thorough processes for Risk Management and Human Factors Engineering (HFE).

Although unintended, medical devices can sometimes harm patients or the people administering the healthcare. The potential harm arises from two main sources:

  1. failure of the device and
  2. actions of the user or user-related errors. A number of factors can lead to these user-induced errors, including medical devices are often used under stressful conditions and users may think differently than the device designer.

Human Factors: Identifying the Root Causes of Use Errors

Instead of blaming test participants for use errors, look more carefully at your device’s design.

Great posting on reasons typical design flaws creep up in medical devices and where a company should integrate fixes in product design.
Posted in Design Services by Jamie Hartford on July 8, 2013

 

 

YouTube VIDEO: Integrating Human Factors Engineering into Medical Devices

 

 

Notes:

 

 Regulatory Considerations

  • Unlike other medication dosage forms, combination products require user interaction
  •  Combination products are unique in that their safety profile and product efficacy depends on user interaction
Human Factors Review: FDA Outlines Highest Priority Devices

Posted 02 February 2016By Zachary Brennan on http://www.raps.org/Regulatory-Focus/News/2016/02/02/24233/Human-Factors-Review-FDA-Outlines-Highest-Priority-Devices/ 

The US Food and Drug Administration (FDA) on Tuesday released new draft guidance to inform medical device manufacturers which device types should have human factors data included in premarket submissions, as well final guidance from 2011 on applying human factors and usability engineering to medical devices.

FDA said it believes these device types have “clear potential for serious harm resulting from use error and that review of human factors data in premarket submissions will help FDA evaluate the safety and effectiveness and substantial equivalence of these devices.”

Manufacturers should provide FDA with a report that summarizes the human factors or usability engineering processes they have followed, including any preliminary analyses and evaluations and human factors validation testing, results and conclusions, FDA says.

The list was based on knowledge obtained through Medical Device Reporting (MDRs) and recall data, and includes:

  • Ablation generators (associated with ablation systems, e.g., LPB, OAD, OAE, OCM, OCL)
  • Anesthesia machines (e.g., BSZ)
  • Artificial pancreas systems (e.g., OZO, OZP, OZQ)
  • Auto injectors (when CDRH is lead Center; e.g., KZE, KZH, NSC )
  • Automated external defibrillators
  • Duodenoscopes (on the reprocessing; e.g., FDT) with elevator channels
  • Gastroenterology-urology endoscopic ultrasound systems (on the reprocessing; e.g., ODG) with elevator channels
  • Hemodialysis and peritoneal dialysis systems (e.g., FKP, FKT, FKX, KDI, KPF ODX, ONW)
  • Implanted infusion pumps (e.g., LKK, MDY)
  • Infusion pumps (e.g., FRN, LZH, MEA, MRZ )
  • Insulin delivery systems (e.g., LZG, OPP)
  • Negative-pressure wound therapy (e.g., OKO, OMP) intended for home use
  • Robotic catheter manipulation systems (e.g., DXX)
  • Robotic surgery devices (e.g., NAY)
  • Ventilators (e.g., CBK, NOU, ONZ)
  • Ventricular assist devices (e.g., DSQ, PCK)

Final Guidance

In addition to the draft list, FDA finalized guidance from 2011 on applying human factors and usability engineering to medical devices.

The agency said it received over 600 comments on the draft guidance, which deals mostly with design and user interface, “which were generally supportive of the draft guidance document, but requested clarification in a number of areas. The most frequent types of comments requested revisions to the language or structure of the document, or clarification on risk mitigation and human factors testing methods, user populations for testing, training of test participants, determining the appropriate sample size in human factors testing, reporting of testing results in premarket submissions, and collecting human factors data as part of a clinical study.”

In response to these comments, FDA said it revised the guidance, which supersedes guidance from 2000 entitled “Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management,” to clarify “the points identified and restructured the information for better readability and comprehension.”

Details

The goal of the guidance, according to FDA, is to ensure that the device user interface has been designed such that use errors that occur during use of the device that could cause harm or degrade medical treatment are either eliminated or reduced to the extent possible.

FDA said the most effective strategies to employ during device design to reduce or eliminate use-related hazards involve modifications to the device user interface, which should be logical and intuitive.

In its conclusion, FDA also outlined the ways that device manufacturers were able to save money through the use of human factors engineering (HFE) and usability engineering (UE).

– See more at: http://www.raps.org/Regulatory-Focus/News/2016/02/02/24233/Human-Factors-Review-FDA-Outlines-Highest-Priority-Devices/#sthash.cDTr9INl.dpuf

 

Please see an FDA PowerPoint on Human Factors Regulatory Issues for Combination Drug/Device Products here: MFStory_RAPS 2011 – HF of ComboProds_v4

 

 

 

 

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