Modern Medical Laboratory Journal

FDA no longer requires all drugs to be tested on animals before human trials. In a victory for animal rights advocates, drugmakers can take their products to human clinical trials using alternative testing methods that don't involve animals. According to a new law, signed by President Joe Biden at the end of last year, the mandate that all drugs be tested on animals before progressing to human trials has been waived.
In place of the 1938 stipulation that potential drugs be tested for safety and efficacy in animals, the law allows FDA to promote a drug or biologic—a larger molecule such as an antibody to human trials after either animal or nonanimal tests. 
Animal alternatives include organ chip technology, organoids, and 3D clusters of cells that are derived from stem cells and mimic specific tissues. They have shown promise in predicting liver and cardiac toxicities. Proponents also tout the potential of digital artificial neural networks for rapidly identifying the toxic effects of drugs. however, some scientists argue that non-animal technologies are still “in their infancy” and won’t be able to replace animal models for “many, many years.” FDA still retains tremendous discretion to require animal tests, they note, and they don’t expect the agency to change tack anytime soon.
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Rheumatoid arthritis affects millions worldwide and often leaves patients debilitated with chronic pain and joint inflammation. Scientists have long struggled to figure out the core causes of the condition. Now, research involving mice and a small group of patients has connected the early stages of rheumatoid arthritis to a newly discovered species of bacteria found in the gut microbiome — the vast community of microbes that assist digestion and influence human health. The new study, published in the October 26 issue of Science Translational Medicine, revealed that this bacterial species could trigger the formation of autoantibodies, or antibodies that target the body's own tissues. 
The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast–derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, they identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae. After generating bacterial isolates within the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum from the feces of an individual, they confirmed monoclonal antibody binding and CD4⁺ T cell activation in individuals with RA compared to control individuals. In addition, when Subdoligranulum isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T_H17 cell expansion, serum RA–relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4⁺ T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.
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The US Food and Drug Administration (FDA) has approved lecanemab, the second-ever treatment for Alzheimer’s disease intended to tackle the root of the condition and slow cognitive decline. Researchers welcome the decision, but the excitement is clouded by patient deaths and reports that the FDA acted improperly when approving the first such drug last year. Lecanemab, which will be sold under the brand name Leqembi, is the first Alzheimer’s treatment to slow cognitive decline in a robust clinical trial and the second to be approved in less than two years. It is made by the biopharmaceutical companies Eisai, in Tokyo, Japan, and Biogen in Cambridge, Massachusetts. The drug, a monoclonal antibody, is intravenously infused into patients, enters the brain and clears the amyloid plaques believed to cause cognitive impairment and dementia in Alzheimer’s. Lecanemab was authorized under the agency’s ‘accelerated approval’ pathway, which is reserved for therapies for diseases that have few treatments; it also does not require phase III clinical trial data. But researchers are hopeful about Biogen and Eisai’s phase III data, which were published in November 2022. That trial, conducted in about 1,800 people with early-stage Alzheimer’s, found that the antibody slowed cognitive decline by 27% over 18 months of treatment.
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Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. In this regard, from the National Eye Institute (NEI), part of the National Institutes of Health, printed a combination of cells that form the outer blood-retina barrier - eye tissue that supports the retina's light-sensing photoreceptors. The technique provides a theoretically unlimited supply of patient-derived tissue to study degenerative retinal diseases such as age-related macular degeneration (AMD). 

They engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE–choriocapillaris interactions under healthy and diseased conditions.
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Researchers at the University of Washington has developed a laboratory test that can measure levels of amyloid beta oligomers in blood samples. They showed The presence of α–sheet Aβ oligomers in plasma, as detected with SOBA, is highly correlated with Alzheimer's disease. They show that a designed α–sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic α–sheet-containing Aβ oligomers produce strong SOBA signals, while monomeric and β-sheet protofibrillar Aβ do not. α–sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, they developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected Aβ oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, they adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson’s disease and Lewy body dementia.
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Spinal cord injury (SCI) is a traumatic event which often results in the loss of sensory and motor function, at or below the site of injury. New hybrid biomaterials developed at UL in the form of nanoparticles and building on existing practice in the tissue engineering field, were successfully synthesised to promote repair and regeneration following spinal cord injury, according to the researchers.  The research team described a growing interest in the use of electroconductive tissue engineered scaffolds that has emerged due to the improved cell growth and proliferation when cells are exposed to a conductive scaffold. In this study, The conductive PEDOT NPs were incorporated with gelatin and hyaluronic acid (HA) to create gel:HA:PEDOT-NPs scaffolds. Based on the results of this study, the incorporation of PEDOT NPs into Gel:HA biomaterial scaffolds enhances not only the conductive capabilities of the material, but also the provision of a healing environment around lesions in SCI. Hence, gel:HA:PEDOT-NPs scaffolds are a promising TE option for stimulating regeneration for SCI.
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Circulating tumor DNA (ctDNA) has been proposed as a prognostic indicator in advanced cancers. In this regard, numerous small cohort studies investigated the indication of ctDNA in non–small-cell lung cancer, colorectal cancer, breast cancer, etc.  In one of the latest studies published in 2022, Nature Medicine, Jee et al. evaluated an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. the results of their study indicated that minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.
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A research team at the University of Cambridge and NHS Blood and Transplant conducted the world’s first clinical trial of red blood cells that have been grown in a laboratory for transfusion into another person. The manufactured blood cells were grown from stem cells from donors. The red cells were then transfused into volunteers in the RESTORE randomised controlled clinical trial. This is the first time in the world that red blood cells that have been grown in a laboratory have been given to another person as part of a trial into blood transfusion. The trial is studying the lifespan of the lab grown cells compared with infusions of standard red blood cells from the same donor. The lab-grown blood cells are all fresh, so the trial team expect them to perform better than a similar transfusion of standard donated red cells, which contains cells of varying ages. If this trial, the first such in the world, is successful, it will mean that patients who currently require regular long-term blood transfusions will need fewer transfusions in future, helping transform their care. 
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Lung cancer has one of the highest incidence rates and mortality rates among all common cancers worldwide. Early detection of suspicious lung nodules is crucial in fighting lung cancer. In recent years, with the proliferation of clinical data like low-dose computed tomography (LDCT), histology whole slide images, electronic health records, and sensor readings from medical IoT devices etc., many artificial intelligence tools have taken more important roles in lung cancer management. Artificial intelligence (AI) is good at handling a large volume of computational and repeated labor work and is suitable for assisting doctors in analyzing image-dominant diseases like lung cancer. Scientists have shown long-standing efforts to apply AI in lung cancer screening via CXR and chest CT since the 1960s. Several grand challenges were held to find the best AI model. Currently, the FDA have approved several AI programs in CXR and chest CT reading, which enables AI systems to take part in lung cancer detection. Following the success of AI application in the radiology field, AI was applied to digitalized whole slide imaging (WSI) annotation. Integrating with more information, like demographics and clinical data, the AI systems could play a role in decision-making by classifying EGFR mutations and PD-L1 expression. AI systems also help clinicians to estimate the patient’s prognosis by predicting drug response, the tumor recurrence rate after surgery, radiotherapy response, and side effects.
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In a study published Aug. 31 in The BMJ, researchers found that men who consumed high rates of ultra-processed foods were at 29% higher risk for developing colorectal cancer. Colorectal cancer is the third most commonly diagnosed malignancy among both men and women in the United States and the second leading cause of death from cancer worldwide. Diet has been recognized as an important modifiable risk factor for colorectal cancer. Meanwhile, ultra-processed foods (that is, industrial ready-to-eat or ready-to-heat formulations made of little or no whole foods) now contribute 57% of total daily calories consumed by American adults, which has been continuously increasing in the past two decades. This study links men who consumed high rates of ultra-processed foods to a 29% higher risk for developing colorectal cancer than men who consumed much smaller amounts. The researchers did not find the same association in women.
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Axolotls have the ability to regenerate brain areas following an injury. Researchers have mapped cell types and genes associated with neurodegeneration in the axolotl brain, discovering some similarities in the human brain. The findings could pave the way for new neurodegenerative therapies. They etermined the cellular diversity of the axolotl telencephalon using single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq), as well as spatial transcriptomics. They identified regionally distributed neuron, ependymoglia, and neuroblast populations and determined their conservation with amniotes by using comparative analyses. They found that the axolotl telencephalon contains glutamatergic neurons with transcriptional similarities to neurons of the turtle and mouse hippocampus, dorsal cortex, and olfactory cortex. Olfactory cortex–like neurons also show conserved neuronal input projections from the olfactory bulb. Axolotl γ-aminobutyric acid–releasing (GABAergic) inhibitory neurons show signatures of different subregions of the ganglionic eminence and resemble turtle and mouse GABAergic inhibitory neurons. They conclude that in the postembryonic axolotl, telencephalon neurogenesis progresses through diverse neuroblast progenitors, which are associated with specific neuron types and dependent on shared as well as specific regulatory programs. They found implementation of these same programs in regenerative neurogenesis, which indicates that brain injury activates neurogenesis through existing pathways after inducing an injury-specific ependymoglia state. Regenerated neurons reestablish their previous connections to distant brain regions, suggesting potential functional recovery. Their insight into how the axolotl brain regenerates may inform studies of brain regeneration in other organisms.
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Scientists from the University of Cambridge have created model embryos without eggs or sperm from mouse stem cells that form a brain, a beating heart, and the foundations of all the other organs of the body. It represents a new avenue for recreating the first stages of life. The recipe for mammalian life is simple: take an egg, add sperm and wait. But a new paper demonstrates that there’s another way. Under the right conditions, stem cells can divide and self-organize into an embryo on their own. Embryonic stem cells (ESC) can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem cells (TSCs), extraembryonic endoderm stem cells (XEN), and inducible-XEN cells (iXEN). In this study, they assembled stem-cell-derived embryos in vitro from mouse ESCs, TSCs and iXEN cells and showed that they recapitulate whole natural mouse embryo development in utero to day 8.5. Their embryo model displays head-folds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extra-embryonic yolk sac that initiates blood island development. Importantly, they demonstrate that the neurulating embryo model assembled from Pax6 knockout-ESCs aggregated with wild-type TSCs and iXENs recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6 knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse lineages and genes in development. Their results demonstrate the self-organization ability of embryonic and two types of extra-embryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
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Scientists from the Terasaki Institute for Biomedical Innovation (TIBI) have developed a contact lens that can capture and detect exosomes, nanometer-sized vesicles found in bodily secretions which have the potential for being diagnostic cancer biomarkers. Exosomes, a form of small extracellular vesicles, play a crucial role in the metastasis of cancers and thus are investigated as potential biomarkers for cancer diagnosis. However, conventional detection methods like immune-based assay and microRNA analyses are expensive and require tedious pretreatments and lengthy analysis time. Since exosomes related to cancers are reported to exist in tears, a poly(2-hydroxyethyl methacrylate) contact lens embedded with antibody-conjugated signaling microchambers (ACSM-PCL) capable of detecting tear exosomes is reported. The ACSM-PCL exhibits high optical transparency and mechanical properties, along with extraordinary biocompatibility and good sensitivity to exosomes. A gold nanoparticle colorimetric assay is employed to visualize captured exosomes. The ACSM-PCL can detect exosomes in the pH range of 6.5–7.4 (similar to the human tear pH) and have a strong recovery yield in bovine serum albumin solutions. In particular, the ACSM-PCL can detect exosomes in various solutions, including regular buffer, cell culture media from various cell lines, and human tears. Finally, the ACSM-PCL can differentiate expression of exosome surface proteins hypothesized as cancer biomarkers. With these encouraging results, this ACSM-PCL is promised to be the next generation smart contact lens as an easy-to-use, rapid, noninvasive monitoring platform of cancer pre-screening and supportive diagnosis.
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A team of Yale scientists developed a new technology, OrganEx, which restored cell, organ function in pigs one hour after death. this technology consists of a perfusion device similar to heart-lung machines -- which do the work of the heart and lungs during surgery -- and an experimental fluid containing compounds that can promote cellular health and suppress inflammation throughout the pig's body. 
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. In this study which is published by Nature, they describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Their analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.

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Brazilian twins (Three-year-olds Bernardo and Arthur Lima) who were joined at the head have been successfully separated with the help of virtual reality, last week. For the first time, surgeons in separate countries wore headsets and operated in the same "virtual reality room" together. The teams spent months trialling techniques using virtual reality projections of the twins, based on CT and MRI scans. The twins had seven surgeries, involving more than 27 hours of operating time in the final operation alone, and almost 100 medical staff.
Virtual reality is the name given to the technology that allows a user to simulate a situation or experience of interest, using a VR headset, within an interactive but computer-generated environment. The simulation is immersive and may require the use of special 3-D goggles with a screen, or gloves that provide sensory feedback, to help the user learn from experience in this virtual world. Virtual reality can be used to help medical professionals visualize the interior of the human body, thus unveiling otherwise inaccessible areas. For one, the dissection of cadavers, which was a norm for every new medical student, has given way to the study of human anatomy via virtual reality.
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Ultrasound is widely used for the noninvasive imaging of tissues and organs, but this method requires close contact between the transducer and the target area. This can make it difficult to acquire images over a long period of time, especially if the patient needs to be mobile. Continuous imaging of internal organs over days could provide crucial information about health and diseases and enable insights into developmental biology. Engineers at Massachusetts Institute of Technology report a bioadhesive ultrasound (BAUS) device that consists of a thin and rigid ultrasound probe robustly adhered to the skin via a couplant made of a soft, tough, antidehydrating, and bioadhesive hydrogel-elastomer hybrid. The BAUS device provides 48 hours of continuous imaging of diverse internal organs, including blood vessels, muscle, heart, gastrointestinal tract, diaphragm, and lung. The BAUS device could enable diagnostic and monitoring tools for various diseases.
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Heart disease — the leading cause of death in the U.S. — is so deadly in part because the heart, unlike other organs, cannot repair itself after injury. That is why tissue engineering, ultimately including the wholesale fabrication of an entire human heart for transplant, is so important for the future of cardiac medicine.

To build a human heart from the ground up, researchers need to replicate the unique structures that make up the heart. This includes recreating helical geometries, which create a twisting motion as the heart beats. It’s been long theorized that this twisting motion is critical for pumping blood at high volumes, but proving that has been difficult, in part because creating hearts with different geometries and alignments has been challenging.
Helical alignments within the heart’s musculature have been speculated to be important in achieving physiological pumping efficiencies. Testing this possibility is difficult, however, because it is challenging to reproduce the fine spatial features and complex structures of the heart’s musculature using current techniques.
For the first time, bioengineers have developed the first biohybrid model of human ventricles with helically aligned beating cardiac cells, and have shown that muscle alignment does, in fact, dramatically increase how much blood the ventricle can pump with each contraction. In this study, they report focused rotary jet spinning (FRJS), an additive manufacturing approach that enables rapid fabrication of micro/nanofiber scaffolds with programmable alignments in three-dimensional geometries. Seeding these scaffolds with cardiomyocytes enabled the biofabrication of tissue-engineered ventricles, with helically aligned models displaying more uniform deformations, greater apical shortening, and increased ejection fractions compared with circumferential alignments. The ability of FRJS to control fiber arrangements in three dimensions offers a streamlined approach to fabricating tissues and organs, with this work demonstrating how helical architectures contribute to cardiac performance.
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Sound—including music and noise—can relieve pain in humans, but the underlying neural mechanisms remain unknown. Scientists have identified the neural mechanisms through which sound blunts pain in mice. The findings could inform development of safer methods to treat pain. They discovered that analgesic effects of sound depended on a low (5-decibel) signal-to-noise ratio (SNR) relative to ambient noise in mice. Viral tracing, microendoscopic calcium imaging, and multitetrode recordings in freely moving mice showed that low-SNR sounds inhibited glutamatergic inputs from the auditory cortex (ACx^Glu) to the thalamic posterior (PO) and ventral posterior (VP) nuclei. Optogenetic or chemogenetic inhibition of the ACx^Glu→PO and ACx^Glu→VP circuits mimicked the low-SNR sound–induced analgesia in inflamed hindpaws and forepaws, respectively. Artificial activation of these two circuits abolished the sound-induced analgesia. a new study revealed the corticothalamic circuits underlying sound-promoted analgesia by deciphering the role of the auditory system in pain processing.

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A team of scientists from the University of Tokyo has developed a skin-equivalent coating for robotic limbs, with the resulting tissue-engineered material boasting water-repellant and self-healing properties. The covering materials of humanoid robots have gone through transformations from stiff and heavy materials to soft and compliant materials to better mimic the appearance and function of human beings. In this study, they reported a biohybrid approach to generate robots covered with tissue-engineered skin. The skin coverage not only results in a human-like appearance but also enables self-healing functions. They demonstrated the seamless coverage of a three-joint robotic finger by culturing a single piece of skin tissue surrounding the robotic finger. Furthermore, inspired by the medical treatment of deeply burned skin using grafted hydrogels, they demonstrated wound repair of a dermis equivalent covering a robotic finger by culturing the wounded tissue grafted with a collagen sheet. Taken together, these findings showed the potential of a paradigm shift from traditional robotics to the new scheme of biohybrid robotics that leverage the advantages of both living materials and artificial materials.
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