Large animal models of pressure overload-induced cardiac left ventricular hypertrophy to study remodelling of the human heart with aortic stenosis.

Pathologic cardiac hypertrophy is a common consequence of many cardiovascular diseases, including aortic stenosis (AS). AS is known to increase the pressure load of the left ventricle, causing a compensative response of the cardiac muscle, which progressively will lead to dilation and heart failure. At a cellular level, this corresponds to a considerable increase in the size of cardiomyocytes, known as cardiomyocyte hypertrophy, while their proliferation capacity is attenuated upon the first developmental stages. Cardiomyocytes, in order to cope with the increased workload (overload), suffer alterations in their morphology, nuclear content, energy metabolism, intracellular homeostatic mechanisms, contractile activity, and cell death mechanisms. Moreover, modifications in the cardiomyocyte niche, involving inflammation, immune infiltration, fibrosis, and angiogenesis, contribute to the subsequent events of a pathologic hypertrophic response. Considering the emerging need for a better understanding of the condition and treatment improvement, as the only available treatment option of AS consists of surgical interventions at a late stage of the disease, when the cardiac muscle state is irreversible, large animal models have been developed to mimic the human condition, to the greatest extend. Smaller animal models lack physiological, cellular and molecular mechanisms that sufficiently resemblance humans and in vitro techniques yet fail to provide adequate complexity. Animals, such as the ferret (Mustello purtorius furo), lapine (rabbit, Oryctolagus cunigulus), feline (cat, Felis catus), canine (dog, Canis lupus familiaris), ovine (sheep, Ovis aries), and porcine (pig, Sus scrofa), have contributed to research by elucidating implicated cellular and molecular mechanisms of the condition. Essential discoveries of each model are reported and discussed briefly in this review. Results of large animal experimentation could further be interpreted aiming at prevention of the disease progress or, alternatively, at regression of the implicated pathologic mechanisms to a physiologic state. This review summarizes the important aspects of the pathophysiology of LV hypertrophy and the applied surgical large animal models that currently better mimic the condition.

Overview of Benchtop Models for Comparison of Surgical Treatments for Benign Prostatic Hyperplasia.

PURPOSE OF REVIEW: Benign prostatic hyperplasia (BPH) is a disease of the lower urinary tract which often requires surgical treatment. Recently, there has been a deluge of new treatment options, rarely validated or compared to current treatments on a benchtop model. The purpose of this review is to examine the literature and report which benchtop models are currently being used, which therapies have been tested on them, and what outcomes are being studied on each model. RECENT FINDINGS: There are various benchtop models to choose from, each with their unique benefits and drawbacks. Perfused porcine kidney models are used to assess bleeding on the benchtop, ex-vivo human prostate helps to see specific interactions of devices with the prostatic tissue, and all other models have evaluated tissue ablation rates and depth of coagulation. There are currently no synthetic or non-animal tissues being used for this purpose, and surgical techniques such as enucleation, water-jet ablation, prostate stents, and water vapor thermal therapy have no representation in these benchtop tests. Benchtop testing serves an important role in the evaluation and comparison of surgical treatments for BPH. This testing allows these therapies to be objectively compared to one another, helping novel medical devices in their path to market and urologists make treatment decisions. Future directions may include further validation of the animal models currently being used and development of synthetic models which mimic the prostate on the benchtop.

Effects of standardized language on remote ultrasound-guided percutaneous nephrolithotomy training: A mixed-methods explorative pilot study.

Background: Remote teaching of procedural skills has demonstrated equivalence in knowledge acquisition compared to in-person teaching. Variations in terminology for probe and needle movements may serve as a barrier in remote training of ultrasound (US)-guided renal access for percutaneous nephrolithotomy (PCNL). This pilot study investigated the utility of standardized terminology in remote training of US-guided renal access for PCNL. Hypothesis: Standardization of verbal terminology to describe US probe and needle movement instruction improves remote teaching of US-guided renal access. Methods: Fifteen urology residents (PGY1-6) were stratified by year and randomized into two groups. We provided participants with images illustrating US probe and needle movements labeled with predetermined standardized terminology for the intervention group and images without labels for the control group. Both groups were asked to perform US-guided renal access on a training mannequin with a remote faculty educator with (intervention) or without (control) use of standardized movement instructions. Quantitative outcomes included number of attempts and time to achieve access. All trainees completed pre- and post-session surveys and participated in focus groups; authors conducted thematic analysis of focus group transcripts. Results: Differences in primary outcomes between groups, including number of attempts and time to achieve access of the renal pole, were not statistically significant. Analysis of focus group interviews revealed that the use of standardized terminology in the setting of remote training can reduce trainee confusion by clarifying ambiguity in educator feedback. Discussion: Use of standardized terminology during remote surgical skills training allows for more effective feedback to trainees.

Patient-specific 3D printed models for enhanced learning of immediate implant procedures and provisionalization.

INTRODUCTION: This study aimed to describe the fabrication, implementation and evaluation of 3D-printed patient-specific models for unskilled students to enhance learning in immediate implant procedures and provisionalization. MATERIALS AND METHODS: The individualized simulation models were designed and processed based on CT and digital intraoral scanning of a patient. Thirty students performed simulation implant surgery and provisionalized the implant sites on the models and answered questionnaires to assess their perceptions before and after the training. The scores of the questionnaires were analysed using the Wilcoxon signed-rank test. RESULTS: Significant differences before and after training were found in the students' responses. Students reported better results in understanding of surgical procedures, knowledge in prosthetically driven implantology, understanding of minimally invasive tooth extraction, confirming the accuracy of surgical template, usage of the guide rings and usage of the surgical cassette after simulation training. The overall expenditure on the simulation training involving 30 students amounted to 342.5 USD. CONCLUSIONS: The patient-specific and cost-efficient 3D printed models are helpful for students to improve theoretical knowledge and practical skills. Such individualized simulation models have promising application prospects.

A review on experimental surgical models and anesthetic protocols of heart failure in rats.

Heart failure (HF) is a serious health and economic burden worldwide, and its prevalence is continuously increasing. Current medications effectively moderate the progression of symptoms, and there is a need for novel preventative and reparative treatments. The development of novel HF treatments requires the testing of potential therapeutic procedures in appropriate animal models of HF. During the past decades, murine models have been extensively used in fundamental and translational research studies to better understand the pathophysiological mechanisms of HF and develop more effective methods to prevent and control congestive HF. Proper surgical approaches and anesthetic protocols are the first steps in creating these models, and each successful approach requires a proper anesthetic protocol that maintains good recovery and high survival rates after surgery. However, each protocol may have shortcomings that limit the study's outcomes. In addition, the ethical regulations of animal welfare in certain countries prohibit the use of specific anesthetic agents, which are widely used to establish animal models. This review summarizes the most common and recent surgical models of HF and the anesthetic protocols used in rat models. We will highlight the surgical approach of each model, the use of anesthesia, and the limitations of the model in the study of the pathophysiology and therapeutic basis of common cardiovascular diseases.

Evaluation of veterinary students' confidence and competence with surgical entrustable professional activities after repeated use of low-fidelity training models.

BACKGROUND: This study aimed to evaluate whether low-fidelity surgical training models increased veterinary students' surgical confidence and competence and decreased procedural stress related to core surgical entrustable professional activities (EPAs). METHODS: Final-year veterinary students repeatedly performed one of three surgical EPAs on a low-fidelity surgical training model (canine castration, subcutaneous lump removal and eyelid laceration repair) and completed a survey at set time points. In addition, a grading rubric was used to assess participants' competence in performing the assigned EPA at two different time points. Survey results and competency gradings were compiled and analysed. RESULTS: Students' self-assessed confidence significantly increased, and stress significantly decreased, between assessment points on all three EPA surgical training models. Graded competence significantly improved between the assessment points on all training models, and most students deemed the models to be realistic and helpful for student practices. LIMITATIONS: Limitations relate to the study involving a single cohort from a single institute and the reliance on student self-assessment. CONCLUSIONS: Repeated exposure to low-fidelity surgical training models increased final-year students' surgical confidence and competence and reduced procedural stress related to three key surgical EPAs. Assessment of competence using a grading rubric was successful and could be incorporated into a competence-based veterinary education assessment framework to allow screening of competence prior to graduation.

Use of wound edge inversion (epibole) to generate recalcitrant and inflamed diabetic wounds.

Robust and predictive pre-clinical models of recalcitrant diabetic wounds are critical for advancing research efforts toward improving healing. Murine models have logistic and genetic benefits versus larger animals; however, native murine healing inadequately represents clinically recalcitrant wounds in humans. Furthermore, current humanization techniques employing devices, deleterious mutations or chemical agents each carry model-specific limitations. To better replicate human wounds in a mouse, we developed a novel wound-edge inversion (WEI) technique that mimics the architecture of epibole and mitigates contracture, epithelialization, and consequently wound closure. In this study, we evaluated the reliability and durability of the WEI model in wild-type and obese diabetic mice and compared to healing after (i) punch biopsy, (ii) mechanical/silicone stenting or (iii) exogenous oxidative stressors. In wild-type mice, WEI demonstrated favourable closure characteristics compared to both control and stented wounds, however, wounds progressed to closure by 4 weeks. In contrast, diabetic WEI wounds persisted for 6-10 weeks with reduced contracture and epithelialization. In both diabetic and wild-type mice, WEI sites demonstrated persistence of inflammatory populations, absence of epithelialization, and histologic presence of alpha-SMA positive granulation tissue when compared to controls. We conclude that the WEI technique is particularly valuable for modelling recalcitrant diabetic wounds with sustained inflammation and dysfunctional healing.

RELSA-A multidimensional procedure for the comparative assessment of well-being and the quantitative determination of severity in experimental procedures.

Good science in translational research requires good animal welfare according to the principles of 3Rs. In many countries, determining animal welfare is a mandatory legal requirement, implying a categorization of animal suffering, traditionally dominated by subjective scorings. However, how such methods can be objectified and refined to compare impairments between animals, subgroups, and animal models remained unclear. Therefore, we developed the RELative Severity Assessment (RELSA) procedure to establish an evidence-based method based on quantitative outcome measures such as body weight, burrowing behavior, heart rate, heart rate variability, temperature, and activity to obtain a relative metric for severity comparisons. The RELSA procedure provided the necessary framework to get severity gradings in TM-implanted mice, yielding four distinct RELSA thresholds L1<0.27, L2<0.59, L3<0.79, and L4<3.45. We show further that severity patterns in the contributing variables are time and model-specific and use this information to obtain contextualized between animal-model and subgroup comparisons with the severity of sepsis > surgery > restraint stress > colitis. The bootstrapped 95% confidence intervals reliably show that RELSA estimates are conditionally invariant against missing information but precise in ranking the quantitative severity information to the moderate context of the transmitter-implantation model. In conclusion, we propose the RELSA as a validated tool for an objective, computational approach to comparative and quantitative severity assessment and grading. The RELSA procedure will fundamentally improve animal welfare, data quality, and reproducibility. It is also the first step toward translational risk assessment in biomedical research.

Procedure Increasing the Accuracy of Modelling and the Manufacturing of Surgical Templates with the Use of 3D Printing Techniques, Applied in Planning the Procedures of Reconstruction of the Mandible.

The application of anatomical models and surgical templates in maxillofacial surgery allows, among other benefits, the increase of precision and the shortening of the operation time. Insufficiently precise anastomosis of the broken parts of the mandible may adversely affect the functioning of this organ. Applying the modern mechanical engineering methods, including computer-aided design methods (CAD), reverse engineering (RE), and rapid prototyping (RP), a procedure used to shorten the data processing time and increase the accuracy of modelling anatomical structures and the surgical templates with the use of 3D printing techniques was developed. The basis for developing and testing this procedure was the medical imaging data DICOM of patients treated at the Maxillofacial Surgery Clinic of the Fryderyk Chopin Provincial Clinical Hospital in Rzeszów. The patients were operated on because of malignant tumours of the floor of the oral cavity and the necrosis of the mandibular corpus, requiring an extensive resection of the soft tissues and resection of the mandible. Familiarity with and the implementation of the developed procedure allowed doctors to plan the operation precisely and prepare the surgical templates and tools in terms of the expected accuracy of the procedures. The models obtained based on this procedure shortened the operation time and increased the accuracy of performance, which accelerated the patient's rehabilitation in the further course of events.

Preclinical models of acute liver failure: a comprehensive review.

Acute liver failure is marked by the rapid deterioration of liver function in a previously well patient over period of days to weeks. Though relatively rare, it is associated with high morbidity and mortality. This makes it a challenging disease to study clinically, necessitating reliance on preclinical models as means to explore pathophysiology and novel therapies. Preclinical models of acute liver failure are artificial by nature, and generally fall into one of three categories: surgical, pharmacologic or immunogenic. This article reviews preclinical models of acute liver failure and considers their relevance in modeling clinical disease.

Recent approaches in clinical applications of 3D printing in neonates and pediatrics.

Neonates and pediatric populations are vulnerable subjects in terms of health. Proper screening and early optimal treatment would reduce infant and child mortality, improving the quality of life. Researchers and clinicians all over the world are in pursuit of innovations to improve the medical care delivery system. Infant morphometrics changes drastically due to the rapid somatic growth in infancy and childhood, demanding for patient-specific customization of treatment intervention accordingly. 3D printing is a radical technology that allows the generation of physical 3D products from digital images and addresses the patient-specific requirement. The combination of cost-effective and on-demand customization offers a boundless opportunity for the enhancement of neonates and pediatric health.Conclusion: The advanced technology of 3D printing proposes a pioneering breakthrough in bringing physiologically and anatomically appropriate treatment strategies addressing the unmet needs of child health problems. What is Known: • The potential application of 3D printing is observed across a multitude of fields within medicine and surgery. • The unprecedented effect of this technology on pediatric healthcare is still very much a work in progress. What is New: • The recent clinical applications of 3D printing provide better treatment modalities to infants and children. • The review provides an overview of the comparison between conventional treatment methods and 3DP regarding specific applications.

An Overview of Rodent Models of Obesity and Type 2 Diabetes.

Many animal models that are currently used in appetite and obesity research share at least some main features of human obesity and its comorbidities. Hence, even though no animal model replicates all aspects of "common" human obesity, animal models are imperative in studying the control of energy balance and reasons for its imbalance that may eventually lead to overt obesity. The most frequently used animal models are small rodents that may be based on mutations or manipulations of individual or several genes and on the exposure to obesogenic diets or other manipulations that predispose the animals to gaining or maintaining excessive weight. Characteristics include hyperphagia or changes in energy metabolism and at least in some models the frequent comorbidities of obesity, like hyperglycemia, insulin resistance, or diabetes-like syndromes. Some of the most frequently used animal models of obesity research involve animals with monogenic mutations of the leptin pathway which in fact are useful to study specific mechanistic aspects of eating controls, but typically do not recapitulate "common" obesity in the human population. Hence, this review will mention advantages and disadvantages of respective animal models in order to build a basis for the most appropriate use in biomedical research.

Case report: The use of three-dimensional biomodels for surgical planning of rib fixation.

BACKGROUND: Prosthetic titanium plates are frequently used in the stabilization of rib fractures and are typically contoured to the patient's anatomy at the time of implant in the operating room. Smith et al. [17] described the use of a 3D prototype biomodel of his patient's skeletal anatomy for preoperative customization of standard titanium plates for rib fractures. This process facilitated the preoperative planning and provided implants appropriate for a patient's unique anatomy. Further, the approach facilitated repair of complex fractures and may decrease operating time. Besides that, it provides idealized conditions for plate shaping and may facilitate implantation. METHODS: We performed rib fixation combined with 3D biomodels for surgical planning for the first time in Brazil, achieving reduced operating time with a good outcome for our patient. RESULTS: Surgical planning was conducted one day before the surgery using a 3D printer to make a patient-specific model. The printing time of the model was 16 h. The 3D biomodel was used for simulating the surgical procedure, pre-molding the titanium plates, and measuring the screw sizes that would be used in the procedure. All five fractures were fixed on the 3D biomodel and the total simulation time was 58 min. We used four pre-contoured titanium plates of 1.5 mm thickness and one straight 1.5 mm thickness titanium plate. We used the printed model to measure screw size, as we would do in the surgery. After planning, the material was processed and sterilized according to the hospital standards to be implanted in the patient the following day. CONCLUSION: This is the second reported case of surgical stabilization of rib fractures using a 3D model. Both cases demonstrated the advantages of this approach. More studies are needed to validate the safety and benefits for the patient, as well as the impact on cost savings.

Animal Models of Peripheral Pain: Biology Review and Application for Drug Discovery.

Pain is a complex constellation of cognitive, unpleasant sensory, and emotional experiences that primarily serves as a survival mechanism. Pain arises in the peripheral nervous system and pain signals synapse with nerve tracts extending into the central nervous system. Several different schemes are used to classify pain, including the underlying mechanism, tissues primarily affected, and time-course. Numerous animal models of pain, which should be employed with appropriate Institutional Animal Care and Use approvals, have been developed to elucidate pathophysiology mechanisms and aid in identification of novel therapeutic targets. The variety of available models underscores the observations that pain phenotypes are driven by several distinct mechanisms. Pain outcome measurement encompasses both reflexive (responses to heat, cold, mechanical and electrical stimuli) and nonreflexive (spontaneous pain responses to stimuli) behaviors. However, the question of translatability to human pain conditions and potential treatment outcomes remains a topic of continued scrutiny. In this review we discuss the different types of pain and their mechanisms and pathways, available rodent pain models with an emphasis on type of pain stimulations and pain outcome measures and discuss the role of pathologists in assessing and validating pain models.

Surgical and physiological challenges in the development of left and right heart failure in rat models.

Rodent surgical animal models of heart failure (HF) are critically important for understanding the proof of principle of the cellular alterations underlying the development of the disease as well as evaluating therapeutics. Robust, reproducible rodent models are a prerequisite to the development of pharmacological and molecular strategies for the treatment of HF in patients. Due to the absence of standardized guidelines regarding surgical technique and clear criteria for HF progression in rats, objectivity is compromised. Scientific publications in rats rarely fully disclose the actual surgical details, and technical and physiological challenges. This lack of reporting is one of the main reasons that the outcomes specified in similar studies are highly variable and associated with unnecessary loss of animals, compromising scientific assessment. This review details rat circulatory and coronary arteries anatomy, the surgical details of rat models that recreate the HF phenotype of myocardial infarction, ischemia/reperfusion, left and right ventricular pressure, and volume overload states, and summarizes the technical and physiological challenges of creating HF. The purpose of this article is to help investigators understand the underlying issues of current HF models in order to reduce variable results and ensure successful, reproducible models of HF.

Choosing a Mouse Model of Venous Thrombosis.

Murine models are widely used valuable tools to study deep vein thrombosis. Leading experts in venous thrombosis research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of venous thrombosis. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of venous thrombosis. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

Animal Models and Cardiac Extracellular Matrix Research.

Cardiovascular disease has been the leading cause of death worldwide for the last 15 years, accounting for 15 million deaths per year. While interventions are saving more lives, more than 20% of survivors will end up in heart failure. Cell-based and other types of therapy for advanced heart and vascular disease may offer new hope for those afflicted. Although a variety of cell types are under investigation, common issues include cell survival, retention, engraftment, and proliferation. Cardiac extracellular matrix (C-ECM) has compelling features that offer advantages to not only aid cell survival, retention, engraftment, and proliferation but likely has independent therapeutic (paracrine) and mechanical effects. Animal studies and clinical trials are underway to characterize the role of C-ECM and demonstrate efficacy for acute and chronic heart disease. This chapter reviews animal models used to enhance our knowledge of C-ECMs in heart disease and its use in the treatment of heart disease.

3D Printed Surgical Simulation Models as educational tool by maxillofacial surgeons.

INTRODUCTION: The aim of this study was to evaluate whether inexpensive 3D models can be suitable to train surgical skills to dental students or oral and maxillofacial surgery residents. Furthermore, we wanted to know which of the most common filament materials, acrylonitrile butadiene styrene (ABS) or polylactic acid (PLA), can better simulate human bone according to surgeons' subjective perceptions. MATERIALS AND METHODS: Upper and lower jaw models were produced with common 3D desktop printers, ABS and PLA filament and silicon rubber for soft tissue simulation. Those models were given to 10 blinded, experienced maxillofacial surgeons to perform sinus lift and wisdom teeth extraction. Evaluation was made using a questionnaire. RESULTS: Because of slightly different density and filament prices, each silicon-covered model costs between 1.40-1.60 USD (ABS) and 1.80-2.00 USD (PLA) based on 2017 material costs. Ten experienced raters took part in the study. All raters deemed the models suitable for surgical education. No significant differences between ABS and PLA were found, with both having distinct advantages. CONCLUSION: The study demonstrated that 3D printing with inexpensive printing filaments is a promising method for training oral and maxillofacial surgery residents or dental students in selected surgical procedures. With a simple and cost-efficient manufacturing process, models of actual patient cases can be produced on a small scale, simulating many kinds of surgical procedures.

Comparison of swallowing outcomes of laryngotracheal separation versus total laryngectomy in a validated ovine model of profound oropharyngeal dysphagia.

OBJECTIVES: To validate the ovine model of profound oropharyngeal dysphagia and compare swallowing outcomes of laryngotracheal separation with those of total laryngectomy. METHODS: Under real-time fluoroscopy, swallowing trials were conducted using the head and neck of two Dorper cross ewes and one human cadaver, secured in lateral fluoroscopic orientation. Barium trials were administered at baseline, pre- and post-laryngohyoid suspension, following laryngotracheal separation, and following laryngectomy in the ovine model. RESULTS: Mean pre-intervention Penetration Aspiration Scale and National Institutes of Health Swallow Safety Scale scores were 8 ± 0 and 6 ± 0 respectively in sheep and human cadavers, with 100 per cent intra- and inter-species reproducibility. These scores improved to 1 ± 0 and 2 ± 0 post-laryngohyoid suspension (p < 0.01). Aerodigestive tract residue was 18.6 ± 2.4 ml at baseline, 15.4 ± 3.8 ml after laryngotracheal separation and 3.0 ± 0.7 ml after total laryngectomy (p < 0.001). CONCLUSION: The ovine model displayed perfect intra- and inter- species reliability for the Penetration Aspiration Scale and Swallow Safety Scale. Less aerodigestive tract residue after narrow-field laryngectomy suggests that swallowing outcomes after total laryngectomy are superior to those after laryngotracheal separation.