Long-term Animal Studies Research Articles

From Seasonality to Species Conservation: Chronobiological Research on European Hamsters in Strasbourg, France.

The first monograph on the European hamster from the Strasbourg region dates back to 1765. By the 1930s, a long and continuous chronobiological research tradition was established for this species, starting with the works of Charles Kayser, who published between 1938 and 1971. Another early key researcher in this area was Bernhard Canguilhem with publications from 1966 to 1999. From the 1980s onwards, "the Pévets," Paul Pévet and his wife, Mireille Masson-Pévet, gave new energy to European hamster research. They broadened the research scope from basic hibernation research to mechanistic studies of circannual rhythms and from physiological aspects to molecular details. One main underlying question in their research was the role of melatonin. Thanks to their enthusiasm and vision, the European hamster is today one of the best - if not the best - studied circannual species. At least 73 parameters are described to cycle. Thirty-two of them have been shown to be driven by a circannual clock. Moreover, ground-breaking advances in our understanding of the mechanistic of hibernation, circannual clock functioning, and its entrainment were made. With most of this research being conducted in Strasbourg, Paul Pévet was instrumental in providing the necessary resources that made these innovative and unconventional long-term animal studies possible, contributing to fundamental research and, ultimately, to species conservation.

Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment

The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.

Abstract 5802: An orally available small molecule JMBI-001 elicits MYC-synthetic lethality and anti-tumor immunity by disabling MKLP2-mediated cellular processes

Abstract The MYC oncogene, a pivotal regulator of various cellular processes, is deregulated in approximately 70 % of human malignancies. Mitotic Kinesin-like Protein 2 (MKLP2) plays a versatile role in both interphase and mitosis and has emerged as a significant prognostic indicator and therapeutic target in cancer. The undruggability of MYC and the scarcity of MKLP2 inhibitors, however, have impeded clinical translation. Our development of JMBI-001, a potent and orally bioavailable small-molecule compound, overcomes these barriers. JMBI-001 elicits loss of function phenotypes in MKLP2 and a synthetic lethal interaction with MYC overexpression. Extensive kinome and safety profiling have revealed no significant off-target effects, and the compound is well-tolerated in long-term animal studies. In preclinical models, JMBI-001 has demonstrated an average tumor growth inhibition rate of 75 % across more than 20 MYC-overexpressing tumor models, including those in the stomach, lung, colon, liver, breast, kidney, skin, and hematopoietic system. Its anti-tumor activity positively correlates with high MYC abundance, aligning with the selective eradication of cells with abundant MYC both in vitro and in vivo. Notably, JMBI-001 also robustly stimulates systemic anti-tumor immunity, enhancing NK and CD3+ T cell infiltration in tumors of syngeneic cancer models. Moreover, additive or synergistic effects have been observed when combined with anti-PD1 therapy even in tumors refractory to the immune checkpoint blockade (ICB) therapy. The dual therapeutic actions of JMBI-001 stem from its disruption of MKLP2 functionalities, leading to anomalies, such as Golgi fragmentation in interphase and multipolarity in pro-metaphase. These disruptions lead to two key outcomes: apoptosis and immunogenic cell death, marked by secreted ATP, released high mobility group protein B1 (HMGB1), and surface-exposed calreticulin. These abnormalities, primed and amplified by deregulated MYC, are not observed in non-transformed cells, suggesting their potential as pharmacodynamic markers for monitoring JMBI-001's activity in vivo. In conclusion, JMBI-001 represents a novel class of anticancer agents that simultaneously triggers MYC synthetic lethality and anticancer immunity by targeting MKLP2-mediated cellular processes. Its unique mechanisms of action, exceptional bioavailability, potency at low nanomolar concentrations, wide-spectrum efficacy, and favorable safety profile establish JMBI-001 as a promising clinical study-ready drug candidate for treating MYC-driven cancers. Citation Format: Ting Zhang, Qiong Shi, Julia Kalashova, Xumei Liu, Xiaohu Zhou, Chenglu Yang, Yan Long, Hongmei Li, Jinhua Li, Gang Lv, Duo Yu, Xuejiao Jiang, Shenqiu Zhang, Jing Zhang, Hong Liu, Dun Yang. An orally available small molecule JMBI-001 elicits MYC-synthetic lethality and anti-tumor immunity by disabling MKLP2-mediated cellular processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5802.

TRANSLATIONAL MODELS FOR OSTEOARTHRITIS: SPEEDING UP FROM BENCH TO BEDSIDE

Translational models for OA have used a variety of small (mouse, rat) and large (sheep, pig) animal models to evaluate the efficacy of a specific therapy. Clinical trials based on the results of these animal models have yielded mixed results with respect to the treatment of the disease. Due to greater stringency in EU regulations in the use of animal models for research, ex vivo models of OA (e.g. cartilage explants, bioreactors) are being developed to mimic human joint motion as well as the inflammatory milieu (e.g. IL-1β) that can be used to understand efficacy of therapy in a physiological environment. The development of these models can enable therapies to undergo clinical trials in patients without the necessity for long-term animal studies. This presentation will describe the state of the art in this field and will discuss whether there is potential to speed up translation from bench to bedside in the future.

UVB-emitting LEDs for reptile lighting: Identifying the risks of nonsolar UV spectra.

UVB lamps are used to provide reptiles housed indoors with the UV radiation necessary to synthesize vitamin D3 in their skin. Since 2019, UVB-LED lamps have been on sale for use in reptile husbandry. We performed spectral analysis and mapped the UV irradiance for 18 of these lamps. The positive benefits of UVB-LED lamps over traditional products include greater energy efficiency, freedom from mercury and easy installation without external ballasts. However, the spectra of all the UVB-LED lamps tested had little similarity to the solar UV spectrum. Some lamps emitted short-wavelength, non-terrestrial, radiation known to cause acute photo-kerato-conjunctivitis; we report one case. All lamps were lacking significant output in the range 315-335 nm, essential for natural self-regulation of cutaneous vitamin D3 synthesis, preventing overproduction. We describe a possible risk of serious hypervitaminosis D based on our spectral analysis. We call for long-term animal studies to assess this risk, in which the reptiles under these lamps are exposed to species-appropriate UV index levels according to their Ferguson Zone allocation and serum levels of vitamin D3 and 25(OH)D3 monitored. Spectral modifications of the lamps to make the spectrum more like sunlight may be an essential way of mitigating this risk.

Rationale of the PAPAartis trial.

Surgical and interventional repair of thoracoabdominal aortic aneurysms improve survival significantly compared to the natural history of the disease. However, both strategies are associated with a substantial risk of spinal cord ischemia, which has been reported to occur-even in contemporary series by expert centers-in up to 12% of patients, depending on the extent of the disease. Following improved neurological outcomes after staged approaches in extensive clinical and long-term large animal studies, and the description of the "collateral network", the concept of "Minimally Invasive Staged Segmental Artery Coil Embolization" (MIS2ACE) was introduced by Etz et al. This concept of priming the collateral network in order to improve spinal cord blood supply showed promising experimental and early clinical outcomes, and consequently led to the initiation of the randomized controlled multicenter PAPAartis trial (Paraplegia Prevention in Aortic Aneurysm Repair by Thoracoabdominal Staging). This Keynote Lecture describes the background and rationale for this trial and gives an update on the current status.

Could Microplastics Be a Driver for Early Onset Colorectal Cancer?

Introduction: The incidence of colorectal cancer in those under 50 years of age (early onset colorectal cancer (EOCRC)) is increasing throughout the world. This has predominantly been an increase in distal colonic and rectal cancers, which are biologically similar to late onset colorectal cancer (LOCRC) but with higher rates of mucinous or signet ring histology, or poorly differentiated cancers. The epidemiology of this change suggests that it is a cohort effect since 1960, and is most likely driven by an environmental cause. We explore the possible role of microplastics as a driver for this change. Review: The development of sporadic colorectal cancer is likely facilitated by the interaction of gut bacteria and the intestinal wall. Normally, a complex layer of luminal mucus provides colonocytes with a level of protection from the effects of these bacteria and their toxins. Plastics were first developed in the early 1900s. After 1945 they became more widely used, with a resultant dramatic increase in plastic pollution and their breakdown to microplastics. Microplastics (MPs) are consumed by humans from an early age and in increasingly large quantities. As MPs pass through the gastrointestinal tract they interact with the normal physiological mechanism of the body, particularly in the colon and rectum, where they may interact with the protective colonic mucus layer. We describe several possible mechanisms of how microplastics may disrupt this mucus layer, thus reducing its protective effect and increasing the likelihood of colorectal cancer. Conclusions: The epidemiology of increase in EOCRC suggests an environmental driver. This increase in EOCRC matches the time sequence in which we could expect to see an effect of rapid increase of MPs in the environment and, as such, we have explored possible mechanisms for this effect. We suggest that it is possible that the MPs damage the barrier integrity of the colonic mucus layer, thus reducing its protective effect. MPs in CRC pathogenesis warrants further investigation. Future directions: Further clarification needs to be sought regarding the interaction between MPs, gut microbiota and the mucus layer. This will need to be modelled in long-term animal studies to better understand how chronic consumption of environmentally-acquired MPs may contribute to an increased risk of colorectal carcinogenesis.

BONE TISSUE INTERACTION WITH 3D-PRINTED TITANIUM IMPLANTS IN A BIOREACTOR TESTING MACHINE: A PRECLINICAL ASSESSMENT METHODOLOGY FOR NEW IMPLANT DESIGNS

The success of cementless orthopaedic implants relies on bony ingrowth and active bone remodelling. Much research effort is invested to develop implants with controllable surface roughness and internal porous architectures that encourage these biological processes. Evaluation of these implants requires long-term and costly animal studies, which do not always yield the desired outcome requiring iteration. The aim of our study is to develop a cost-effective method to prescreen design parameters prior to animal trials to streamline implant development and reduce live animal testing burden.Ex vivo porcine cancellous bone cylinders (n=6, Ø20×12mm) were extracted from porcine knee joints with a computer-numerically-controlled milling machine under sterile conditions within 4 hours of animal sacrifice. The bone discs were implanted with Ø6×12mm additive manufactured porous titanium implants and were then cultured for 21days. Half underwent static culture in medium (DMEM, 10% FBS, 1% antibiotics) at 37°C and 5% CO2. The rest were cultured in novel high-throughput stacked configuration in a bioreactor that simulated physiological conditions after surgery: the fluid flow and cyclic compression force were set at 10ml/min and 10–150 N (1Hz,5000 cycles/day) respectively. Stains were administered at days 7 and 14. Samples were evaluated with widefield microscopy, scanning electron microscopy (SEM) and with histology.More bone remodelling was observed on the samples cultured within the bioreactor: widefield imaging showed more remodelling at the boundaries between the implant-bone interface, while SEM revealed immature bone tissue integration within the pores of the implant. Histological analysis confirmed these results, with many more trabecular struts with new osteoid formation on the samples cultured dynamically compared to static ones.Ex vivo bone can be used to analyse new implant technologies with lower cost and ethical impact than animal trial. Physiological conditions (load and fluid flow) promoted bone ingrowth and remodelling.

Engineering exosomes by three-dimensional porous scaffold culture of human umbilical cord mesenchymal stem cells promote osteochondral repair.

Improving the poor microenvironment in the joint cavity has potential for treating cartilage injury, and mesenchymal stem cell (MSC)-derived exosomes (MSC-Exos), which can modulate cellular behavior, are becoming a new cell-free therapy for cartilage repair. Here, we used acellular cartilage extracellular matrix (ACECM) to prepare 3D scaffolds and 2D substrates by low-temperature deposition modeling (LDM) and tape casting. We aimed to investigate whether MSC-Exos cultured on scaffolds of different dimensions could improve the poor joint cavity microenvironment caused by cartilage injury and to explore the related mechanisms. In vitro experiments showed that exosomes derived from MSCs cultured on three-dimensional (3D) scaffolds (3D-Exos) had increased efficiency. In short-term animal experiments, compared with exosomes derived from MSCs cultured in a two-dimensional (2D) environment (2D-Exos), 3D-Exos had a stronger ability to regulate the joint cavity microenvironment. Long-term animal studies confirmed the therapeutic efficacy of 3D-Exos over 2D-Exos. Thus, 3D-Exos were applied in the rat knee osteochondral defect model after adsorption in the micropores of the scaffold and combined with subsequent articular cavity injections, and they showed a stronger cartilage repair ability. These findings provide a new strategy for repairing articular cartilage damage. Furthermore, miRNA sequencing indicated that the function of 3D-Exos may be associated with high expression of miRNAs. Thus, our study provides valuable insights for the design of 3D-Exos to promote cartilage regeneration.

Fully Implantable Neurostimulation System for Long-Term Behavioral Animal Study.

Spinal cord stimulation (SCS) is an emerging therapeutic option for patients with neuropathic pain due to spinal cord injury (SCI). Numerous studies on pain relief effects with SCS have been conducted and demonstrated promising results while the mechanisms of analgesic effect during SCS remain unclear. However, an experimental system that enables large-scale long-term animal studies is still an unmet need for those mechanistic studies. This study proposed a fully wireless neurostimulation system that can efficiently support a long-term animal study for neuropathic pain relief. The developed system consists of an implantable stimulator, an animal cage with an external charging coil, and a wireless communication interface. The proposed device has the feature of remotely controlling stimulation parameters via radio-frequency (RF) communication and wirelessly charging via magnetic induction in freely moving rats. Users can program stimulation parameters such as pulse width, intensity, and duration through an interface on a computer. The stimulator was packaged with biocompatible epoxy to ensure long-term durability under in vivo conditions. Animal experiments using SCI rats were conducted to demonstrate the functionality of the device, including long-term usability and therapeutic effects. The developed system can be tailored to individual user needs with commercially available components, thus providing a cost-effective solution for large-scale long-term animal studies on neuropathic pain relief.

Research Trends of Acupuncture Therapy on Fibromyalgia from 2000 to 2021: A Bibliometric Analysis.

Fibromyalgia Syndrome causes great physical and mental discomfort and incurs high costs. Acupuncture has been regarded as the mainstay of treatment for Fibromyalgia Syndrome while the bibliometric analysis of this field has not been summarized properly. Thus, the purpose of this study is to analyze the hotspot of acupuncture for Fibromyalgia Syndrome. The core collection database of Web of Science were searched for relevant publications from 2000 to 2021, and countries, institutions, authors, keywords, and literature were analyzed and visualized by bibliometric software CiteSpace V software and Vosviewer software, to explore the scientific achievements, research collaboration networks, research hot spots, and research trends. 868 publications were included in this study. The publications have increased steadily over time, and the type published the most is Article. Pain is the most cited journal. The most prolific country is the USA while the most prolific institution is Univ Michigan. The most prolific and influential authors were Yiwen Lin and Wolfe F respectively. The analysis of keywords and literature showed that long-term efficacy, animal studies, alternative medicine, and electroacupuncture will be the scientific hotspots in acupuncture for fibromyalgia. This study shows that the number of research studies, researchers, and research institutions on acupuncture for fibromyalgia is increasing from year to year. Future research hotspots will focus on the long-term efficacy of acupuncture in the treatment of fibromyalgia, experimental animal studies, and the development of other alternative medical therapies. In addition, electroacupuncture is receiving more and more attention as a new application of traditional acupuncture therapy.

Computational Fluid Dynamics Model of Continuous-Flow Total Artificial Heart: Right Pump Impeller Design Changes to Improve Biocompatibility.

Cleveland Clinic is developing a continuous-flow total artificial heart (CFTAH). This novel design operates without valves and is suspended both axially and radially through the balancing of the magnetic and hydrodynamic forces. A series of long-term animal studies with no anticoagulation demonstrated good biocompatibility, without any thromboemboli or infarctions in the organs. However, we observed varying degrees of thrombus attached to the right impeller blades following device explant. No thrombus was found attached to the left impeller blades. The goals for this study were: (1) to use computational fluid dynamics (CFD) to gain insight into the differences in the flow fields surrounding both impellers, and (2) to leverage that knowledge in identifying an improved next-generation right impeller design that could reduce the potential for thrombus formation. Transient CFD simulations of the CFTAH at a blood flow rate and impeller rotational speed mimicking in vivo conditions revealed significant blade tip-induced flow separation and clustered regions of low wall shear stress near the right impeller that were not present for the left impeller. Numerous right impeller design variations were modeled, including changes to the impeller cone angle, number of blades, blade pattern, blade shape, and inlet housing design. The preferred, next-generation right impeller design incorporated a steeper cone angle, a primary/splitter blade design similar to the left impeller, and an increased blade curvature to better align the incoming flow with the impeller blade tips. The next-generation impeller design reduced both the extent of low shear regions near the right impeller surface and flow separation from the blade leading edges, while maintaining the desired hydraulic performance of the original CFTAH design.

Fully Guided Third Molar Tooth Bud Ablation in Pigs

The purpose of this study was to selectively ablate the entire volume of targeted third molar (3M) tooth buds in a pig model. This study demonstrates the potential for a less-invasive alternative to contemporary surgical techniques for removal of 3Ms. The investigator developed a mandibular split-mouth animal model study design. The model used pigs because the animals' 3M tooth buds are dimensionally similar to those of humans. The study sample consisted of 5 female Yorkshire-cross pigs at 20weeks of age. The investigator delivered microwave energy thermal doses to thermocoagulate tooth bud tissues inside the bony crypts of targeted 3M tooth buds. Based on the bony crypt dimensions obtained from computed tomography scans of each subject, the microwave thermal dose was predetermined. The mandibles were dissected to visually compare thermocoagulated right-side 3M tooth bud tissues to left-side untreated controls. All 5 study animals were successfully treated. All 5 fully guided third molar tooth bud ablation (3TBA) procedures resulted in thermocoagulation of the entire volume of targeted 3M tooth bud tissues, with no visual evidence of damage to structures beyond the bony crypt. The animal model developed for this study enabled the demonstration of a fully guided 3TBA protocol. The animal model and 3TBA procedure employed in this study appear to be appropriate for use in future long-term animal studies designed to demonstrate the efficacy of 3TBA for inducing molar agenesis.

Therapeutic applications of mesenchymal cells derived from human placenta: A comprehensive meta-review

There has been an increase in the incidence of diseases and injuries which has encouraged the advancements in treatments that could repair tissues as well as minimize the dependence on organ transplantation and tissue loss. Regenerative medicine based on stem cells is a newer integrative domain that has the potential to facilitate the regeneration of diseased and damaged tissues and organs. Stem cells can be effectively exploited for medical purposes with no severe challenges, according to a wide range of literature as well as long-term human and animal studies conducted on them. Amongst several types of stem cells, placenta-derived mesenchymal stem cells possess unique immunomodulatory characteristics as well as the potential to differentiate into various cell types, which make them suitable candidates for cellular therapies for many chronic diseases including cancers, heart and liver disorders, ulcers, bone damage, and neurological diseases, etc. The present study thus aims at providing a comprehensive overview of placenta-derived mesenchymal stem cells, their types, and potentially therapeutic for various chronic and non-chronic diseases. Recent pre-clinical and clinical studies conducted on them have also been incorporated.

A Multichannel Flexible Optoelectronic Fiber Device for Distributed Implantable Neurological Stimulation and Monitoring.

Optical fibers made of polymeric materials possess high flexibility that can potentially integrate with flexible electronic devices to realize complex functions in biology and neurology. Here, a multichannel flexible device based on four individually addressable optical fibers transfer-printed with flexible electronic components and controlled by a wireless circuit is developed. The resulting device offers excellent mechanics that is compatible with soft and curvilinear tissues, and excellent diversity through switching different light sources. The combined configuration of optical fibers and flexible electronics allows optical stimulation in selective wavelengths guided by the optical fibers, while conducting distributed, high-throughput biopotential sensing using the flexible microelectrode arrays. The device has been demonstrated in vivo with rats through optical stimulation and simultaneously monitoring of spontaneous/evoked spike signals and local field potentials using 32microelectrodes in four brain regions. Biocompatibility of the device has been characterized by behavior and immunohistochemistry studies, demonstrating potential applications of the device in long-term animal studies. The techniques to integrate flexible electronics with optical fibers may inspire the development of more flexible optoelectronic devices for sophisticated applications in biomedicine and biology.

Long-Term Non Anesthetic Preclinical Study Available Extra-Cranial Brain Activator (ECBA) System for the Future Minimally Invasive Human Neuro Modulation.

In recent years, electroceuticals have been spotlighted as an emerging treatment for various severe chronic brain diseases, owing to their intrinsic advantage of electrical interaction with the brain, which is the most electrically active organ. However, the majority of research has verified only the short-term efficacy through acute studies in laboratory tests owing to the lack of a reliable miniaturized platform for long-term animal studies. The construction of a sufficient integrated system for such a platform is extremely difficult because it requires multi-disciplinary work using state-of-the-art technologies in a wide range of fields. In this study, we propose a complete system of an implantable platform for long-term preclinical brain studies. Our proposed system, the extra-cranial brain activator (ECBA), consists of a titanium-packaged implantable module and a helmet-type base station that powers the module wirelessly. The ECBA can also be controlled by a remote handheld device. Using the ECBA, we performed a long-term non-anesthetic study with multiple canine subjects, and the resulting PET-CT scans demonstrated remarkable enhancement in brain activity relating to memory and sensory skills. Furthermore, the histological analysis and high-temperature aging test confirmed the reliability of the system for up to 31 months. Hence, the proposed ECBA system is expected to lead a new paradigm of human neuromodulation studies in the near future.

Effect of laser treatment on outcomes of tooth replantation - A systematic review.

ObjectivesOver the last few years, several studies have investigated the effect of laser treatment on the replantation of avulsed teeth. We conducted this study to systematically analyse and assess the outcomes and quality of these studies.MethodsUsing the keywords ‘laser’, ‘tooth’, and ‘replantation’, two investigators conducted an electronic search of the PubMed, MEDLINE, Embase, ISI Web of Knowledge and Google Scholar databases. Any studies not meeting the inclusion criteria were excluded. The focused question was ‘Does laser treatment influence the outcomes of tooth replantation?’ResultsNine studies were included and assessed in this review. In the majority of the selected studies, laser treatment had a positive outcome on preventing root resorption and in promoting periodontal regeneration. However, only three studies were given a quality score of ‘medium’, while six were marked as ‘low’.ConclusionLaser irradiation may reduce root resorption and favour periodontal regeneration following replantation of the avulsed tooth. However, more well-designed long-term animal and human studies are needed before lasers can be used clinically to improve the outcomes for replanted teeth.

Acute and Chronic Pre-Clinical Implants of the CorWave LVAD: Hydraulic, Hemocompatibility and Hemodynamic Results

The CorWave LVAD employs a unique "wave membrane" technology, inspired from the motion of aquatic animals, to generate blood flow. This low shear method of blood propulsion can be rapidly modulated to produce a physiologic pulse. The present study evaluated the hydraulic, hemodynamic and hemocompatibility performance of the device in vitro and in animal implants. The pump membrane, oscillation frequency and magnitude, and blood flow path were simulated by CFD analysis in COMSOL and refined to improve hydraulic efficiency and eliminate areas of flow stagnation. Hydraulic testing in a mock circulatory loop and hemolysis measurements in static and pulsatile conditions were then performed in vitro. Acute and chronic implants of the improved pumps were carried out in sheep. The device was successfully operated in 4 different modes: continuous or fixed (similar to rotary VADs with a constant operating point), synchronous co-pulsation and counter-pulsation, and asynchronous pulsation modes. Sensorless detection of native ventricle systole was developed using a mock circulatory loop, with performance confirmed in acute implants in sheep with induced heart failure. The pump could generate average flow rates of 6+ lpm against physiologic pressure, and instantaneous flow rates exceeding 12 LPM during pulsatile operation. Acute and chronic animal implants (up to 60+ days) demonstrated low hemolysis and an absence of significant thrombus or thromboembolic events. The first long-term chronic animal studies of the CorWave LVAD validated the hemocompatibility and hemodynamic performance of the pump. The ability to restore physiologic pulsatility by sensorless synchronization with the native heart was demonstrated in pre-clinical implants. Extensive computational simulation and bench top testing were used to optimize this unique LVAD, displaying the full flow capacity and adding physiologically relevant pulsatility without excessive shear rates.

A Novel Rotary Blood Pump for HFpEF

Purpose Heart Failure with preserved ejection fraction (HFpEF) currently has no treatment options for improving symptoms or survival. We have developed a long-term novel pulsed assist device for treatment of patients with HFpEF. Methods We have developed a small diagonal centrifugal rotary blood pump which utilizes hydrodynamic suspension for magnetically elevated support of a four-blade impeller with partial unloading from the left atrium (LA) to the descending aorta. The pump is adaptive: the physiological needs of the patient are adjusted by both ECG and sensor feedback algorithms. Pulsed power and speed (rpm) maintain pulse pressure at a normal level. The device is designed for minimally invasive Implantation through a 9 × 3 cm thoracotomy. Repeated animal testing (sheeps) is performed. Results Animal studies testing a spectrum of unloading with simultanous hemodynamic and echocardiographic monitoring, have demonstrated adequate pulsed pump unloading between 1.5-3.0 l/min. ECG gated rpm increase in systole avoids LA suction, interference with mitral valve opening and ventricular filling. Blood pressure was maintained at 95-70 mmHg, central venous pressure (CVP) at 10 mmHg and native cardiac output of 3 l/m. Repeated studies with human whole blood without added anticoagulation in a mock loop for 8 hours have demonstrated no hemolysis, no increase in energy consumption or heat, and no clotting inside the pump. Long-term animal studies are planned. Conclusion Partial systolic pulsed unloading of the LA using a novel rotary blood pump demonstrated adequate hemodynamics and maintained normal pulse pressure. This novel pump may become the first possible treatment for patients with HFpEF.

Addressing systematic inconsistencies between in vitro and in vivo transcriptomic mode of action signatures

Because of their broad biological coverage and increasing affordability transcriptomic technologies have increased our ability to evaluate cellular response to chemical stressors, providing a potential means of evaluating chemical response while decreasing dependence on apical endpoints derived from traditional long-term animal studies. It has recently been suggested that dose-response modeling of transcriptomic data may be incorporated into risk assessment frameworks as a means of approximating chemical hazard. However, identification of mode of action from transcriptomics lacks a similar systematic framework. To this end, we developed a web-based interactive browser—MoAviz—that allows visualization of perturbed pathways. We populated this browser with expression data from a large public toxicogenomic database (TG-GATEs). We evaluated the extent to which gene expression changes from in-life exposures could be associated with mode of action by developing a novel similarity index—the Modified Jaccard Index (MJI)—that provides a quantitative description of genomic pathway similarity (rather than gene level comparison). While typical compound-compound similarity is low (median MJI = 0.026), clustering of the TG-GATES compounds identifies groups of similar chemistries. Some clusters aggregated compounds with known similar modes of action, including PPARa agonists (median MJI = 0.315) and NSAIDs (median MJI = 0.322). Analysis of paired in vitro (hepatocyte)-in vivo (liver) experiments revealed systematic patterns in the responses of model systems to chemical stress. Accounting for these model-specific, but chemical-independent, differences improved pathway concordance by 36% between in vivo and in vitro models.