Despite changing attitudes towards animal testing and current legislation to protect experimental animals, the rate of animal experiments seems to have changed little in recent years. On May 15–16, 2013, the In Vitro Testing Industrial Platform (IVTIP) held an open meeting to discuss the state of the art in alternative methods, how companies have, can, and will need to adapt and what drives and hinders regulatory acceptance and use. Several key messages arose from the meeting. First, industry and regulatory bodies should not wait for complete suites of alternative tests to become available, but should begin working with methods available right now (e.g., mining of existing animal data to direct future studies, implementation of alternative tests wherever scientifically valid rather than continuing to rely on animal tests) in non-animal and animal integrated strategies to reduce the numbers of animals tested. Sharing of information (communication), harmonization and standardization (coordination), commitment and collaboration are all required to improve the quality and speed of validation, acceptance, and implementation of tests. Finally, we consider how alternative methods can be used in research and development before formal implementation in regulations. Here we present the conclusions on what can be done already and suggest some solutions and strategies for the future.
BACKGROUND: Patients who underwent surgery for aortic coarctation (COA) have an increased risk of arterial hypertension. We aimed at evaluating (1) differences between hypertensive and non-hypertensive patients and (2) the value of cardiopulmonary exercise testing (CPET) to predict the development or progression of hypertension. METHODS: Between 1999 and 2010, CPET was performed in 223 COA-patients of whom 122 had resting blood pressures of <140/90 mmHg without medication, and 101 were considered hypertensive. Comparative statistics were performed. Cox regression analysis was used to assess the relation between demographic, clinical and exercise variables and the development/progression of hypertension. RESULTS: At baseline, hypertensive patients were older (p=0.007), were more often male (p=0.004) and had repair at later age (p=0.008) when compared to normotensive patients. After 3.6 ± 1.2 years, 29/120 (25%) normotensive patients developed hypertension. In normotensives, VE/VCO2-slope (p=0.0016) and peak systolic blood pressure (SBP; p=0.049) were significantly related to the development of hypertension during follow-up. Cut-off points related to higher risk for hypertension, based on best sensitivity and specificity, were defined as VE/VCO2-slope ≥ 27 and peak SBP ≥ 220 mmHg. In the hypertensive group, antihypertensive medication was started/extended in 48/101 (48%) patients. Only age was associated with the need to start/extend antihypertensive therapy in this group (p=0.042). CONCLUSIONS: Higher VE/VCO2-slope and higher peak SBP are risk factors for the development of hypertension in adults with COA. Cardiopulmonary exercise testing may guide clinical decision making regarding close blood pressure control and preventive lifestyle recommendations.
Organ-on-a-chip technology holds great promise to revolutionize pharmaceutical drug discovery and development which nowadays is a tremendously expensive and inefficient process. It will enable faster, cheaper, physiologically relevant, and more reliable (standardized) assays for biomedical science and drug testing. In particular, it is anticipated that organ-on-a-chip technology can substantially replace animal drug testing with using the by far better models of true human cells. Despite this great potential and progress in the field, the technology still lacks standardized protocols and robust chip devices, which are absolutely needed for this technology to bring the abovementioned potential to fruition. Of particular interest is heart-on-a-chip for drug and cardiotoxicity screening. There is presently no preclinical test system predicting the most important features of cardiac safety accurately and cost-effectively. The main goal of this project is to fabricate standardized, robust generic heart-on-a-chip demonstrator devices that will be validated and further optimized to generate new physiologically relevant models to study cardiotoxicity in vitro. To achieve this goal various aspects will be considered, including (i) the search for alternative chip materials to replace PDMS, (ii) inner chip surface modification and treatment (chemistry and topology), (iii) achieving 2D/3D cardiomyocyte (long term) cell culture and cellular alignment within the chip device, (iv) the possibility of integrating in-line sensors in the devices and, finally, (v) the overall chip design. The achieved standardized heart-on-a-chip technology will be adopted by pharmaceutical industry. This proposed project offers a unique opportunity for the Netherlands, and Twente in particular, which has relevant expertise, potential, and future perspective in this field as it hosts world-leading companies pioneering various core aspects of the technology that are relevant for organs-on-chips, combined with two world-leading research institutes within the University of Twente.
