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Abstract

This article discusses the implantable and external telemetry systems that are currently available to researchers, and the various ways that telemetry can help to reduce animal use and refine animal research methods.

Keywords: telemetry, transmitter, implantable, external, group-housing, in vivo, reduction, refinement

Background

Despite numerous advances in research techniques that avoid the use of animals, such as in vitro methods and advanced computer modelling, there is still the need for a whole system approach to preclinical research and for data from conscious animals free from the effects of anaesthesia. For example, understanding the complex physiological interactions between the cardiovascular, respiratory and central nervous systems is critical for the development of many human pharmaceuticals and therapies. As such, telemetry systems serve as useful in vivo test tools that allow for remote and long-term monitoring of physiological and bioelectrical variables (e.g. blood pressure, heart rate, ECG) in conscious, unrestrained animals (see Figure 1).

Figure 1. Drawing of an unrestrained rat implanted with a transmitter capable of monitoring blood pressure via the abdominal aorta.

Telemetry transmitters are surgically implanted or externally mounted devices that sense, process and transmit physiological information via electromagnetic radio waves (typically in the range of 3Hz-300GHz), from a freely moving animal to an externally located receiver. Once the signal is received, it is transferred to a data acquisition computer for processing. Each transmitter contains one or more sensors for recording blood pressure, biopotential (see Glossary), body temperature, respiration and physical activity data, and a battery (rechargeable or with a finite battery life). Transmitters are available for animals of all sizes from mice to larger animals, such as dogs and non-human primates (primates hereafter).

For nearly 25 years, implanted and externally mounted telemetry devices have been used in drug research and development, or for basic research in academic or government laboratories, as alternatives to tethered monitoring systems (see Glossary). The absence of tethering, handling and restraint provides a unique opportunity to study laboratory animals with reduced stress and physiological disturbance over a longer period of time in their normal housing. Telemetry can also provide objective biological data on animal wellbeing to help implement humane endpoints (see Glossary), such as variations in body temperature that may reflect acute or chronic pain or distress. Using telemetry is therefore widely regarded as benefiting animal welfare (refinement). Because telemetry can improve data quality and quantity, it can also lead to a reduction in the number of animals required for in vivo studies.

However, it is important to recognise that implanted or external telemetry devices can have an adverse impact on animal welfare in the short- and long-terms if appropriate procedures and refinements are not implemented. Implanted devices require the animals to undergo surgery with anaesthesia, whilst external devices and mountings, which are usually protected in a jacket worn by the animal, can cause discomfort and distress (see references 1 and 2 for advice on refining telemetry procedures and husbandry for telemetered animals).

Dr Lewis Kinter was perhaps the first to highlight telemetry and its contributions to the advancement of animal welfare in his article "Cardiovascular telemetry and laboratory animal welfare: New reduction and refinement alternatives"(3). The article discusses specific methods that can be used in telemetry studies to improve experimental design and data quality, whilst enhancing animal welfare, and reducing animal use and research costs. At the time of publication, the methods that Dr. Kinter described were at the forefront of non-clinical scientific research. Today, practices such as reviewing information from toxicology and cardiovascular safety pharmacology studies prior to planning new experiments, or re-using study animals after appropriate washout periods, have become widely adopted throughout the life science industry.

Data Sciences International (DSI™; www.datasci.com) pioneered telemetry technology and was quickly followed by Integrated Telemetry Systems (ITS; www.dissdata.com) and Mini Mitter® (www.minimitter.com). Other telemetry providers (e.g. Remo Techologies; www.remotechnologies.com) have emerged in recent years. Manufacturers have demonstrated support for the 3Rs - in particular refinement and reduction - and continue to respond to animal welfare concerns and customer needs by:

• Developing external telemetry systems
• Refining surgical procedures for implanted devices
• Developing smaller devices that are better tolerated by the animals
• Adapting devices to accommodate group-housing
• Developing transmitters capable of recording more signals per animal
• Designing devices with increased battery life, replaceable batteries or recharging mechanisms.

Telemetry advances that promote refinement

External telemetry systems

External telemetry systems are typically used for toxicology and other short-term, high-throughput studies involving large numbers of animals. They provide a more humane, non-invasive alternative to implantable or hard-wired systems (see Glossary) and can be used for small or large animals that are singly- or group-housed (see Figures 2 and 3). Traditional implantable telemetry devices range in size from approximately 1 to 35 cubic centimetres (cc), are biocompatible, typically have permanently affixed leads, and can transmit signals up to 5 metres (m). External devices are approximately 150 to 200cc; the larger size accommodates a bigger battery and the electronics required to transmit many signals from a single animal in a room that may contain up to 36 animals. Many animals are curious and like to examine external devices that are new to them; therefore manufacturers recommend that the animals wear jackets to cover external leads and protect the telemetry device in a pocket. All of the lead sets on external devices are detachable. The animals are trained to tolerate the jackets before the study begins.

Figure 2. Diagram of a beagle wearing an external telemetry device and projective jacket.

Figure 3. Diagram of an external telemetry system with group-housed, freely-moving beagles, three per pen.

Recently, external telemetry has been assessed as an alternative to the traditional monitoring methods used in toxicology and safety pharmacology studies. Studies that involve collecting respiratory data have historically required restraining the animals and placing a pneumotach (see Glossary) on their face to collect respiratory data. This method can be stressful for the animal and thus limits data collection to short periods of time. Alternatively, with external telemetry and respiratory inductive plethysmography (RIP; see Glossary), the animal is unrestrained and is therefore presumably less stressed, allowing continuous data to be collected. In published comparisons of methods of collecting ECG data from primates that were unrestrained versus chemically or physically restrained, it was found that physical restraint stimulates the sympathetic nervous system, increasing heart rate, and in addition, that anaesthetics can potentially interfere with the test compound. This demonstrated a need for an alternative data collection method that eliminates the effects of restraint or anaesthesia, while providing high-quality data (4,5).

External telemetry systems can also be used to collect the cardiovascular endpoint data that are occasionally required in long-term toxicology studies. The external systems are a more cost-effective alternative than implantable telemetry as the batteries can be replaced easily, and devices can be re-used numerous times on multiple animals without refurbishment (6). Companies currently manufacturing external telemetry devices include DSI, ITS and EMKA Technologies (see Table 1 for system specifications).

Table 1. Comparison of available external telemetry devices by vendor

Refined surgical implantation procedures

Appropriate surgical training is required in order to implant a telemetry device into the body cavity of an animal. Measures that can be taken to refine surgical implantation procedures include ensuring that the animals have adequate recovery time, using appropriate anaesthetics (Isoflurane is recommended for telemetry procedures), using appropriate analgesia, and proper aseptic technique (7).

Surgical training opportunities include:

• Surgical workshops held at annual conferences for organizations that include the American Association for Laboratory Animal Science (AALAS; 8), Canadian Association for Laboratory Animal Science (CALAS/ASCAL; 9), Academy of Surgical Research (ASR; 10), Federation of European Laboratory Animal Science Associations (FELASA; 11)
• DSI transmitter implantation training in rodents at the St. Paul facility in the United States of America
• ITS surgical implantation training at a customer's facility.

Charles River Laboratories (12), The Jackson Laboratory (13), Harlan (14), Hilltop Labs (15) and Taconic (16) offer surgical implantation services for some DSI telemetry devices, and most telemetry vendors offer surgical implantation training videos and manuals.

Reduced device size

Smaller transmitters are less invasive, involve potentially shorter surgical procedures, improve animal tolerance of implantable devices, and can be used with smaller or younger animals. However, smaller devices often have a shorter battery life and may have a limited transmission range. Nonetheless, devices have been developed that have reduced transmitter size whilst offering characteristics comparable to previously available products.

A mouse (extra-small) device may be used in place of a larger rat version to aid implantation in juvenile rats used in longitudinal studies. A smaller device, implanted long-term, may promote better tolerance or allow the use of animals with unique physiological characteristics that might not otherwise tolerate implantation. Researchers should keep in mind battery life, housing requirements and effective transmission distances when considering the use of smaller transmitters.

The externally worn DSI Repeater device communicates with implanted DSI transmitters of any size within 10 centimetres of the implanted transmitter. Some large animal transmitter models (≥25cc in volume) may have a small animal equivalent that is one-third to one-half the volume. DSI has also developed miniature transmitters (1.1cc) for researchers using transgenic or knockout mice to record blood pressure or biopotential signals in animals as small as 17grams (g) (see Figure 4). Mini Mitter also offers very small transmitters (0.52cc or 1.13cc) for recording heart rate, activity and body temperature in rodents.

Figure 4. The PA-C10 blood pressure and activity transmitter; 1.1cc in volume.

Systems for group housing

Implantable telemetry systems have historically consisted of multiple transmitters that operate on the same frequency. To be effective, each individual implanted transmitter requires predefined spacing between singly-housed animals. Following technological development, newer products can be used that permit group housing. For large animal species, including dogs, pigs and primates, available systems offer longer transmission distances and multiple transmission frequencies virtually free of crosstalk or interference permitting larger, more humane monitoring environments where four or more animals can co-habit. Telemetry systems for group-housed small animals (primarily rodents) that operate at multiple frequencies, accommodating varying numbers of animals and providing different transmission distances, continue to be developed.

DSI developed a dual-module transmitter (the 4ET) capable of recording up to four biopotential signals, temperature and locomotor activity in rodents weighing more than 200g. This device is targeted at central nervous system (CNS) applications and is available in two frequencies to accommodate pair housing (see Figure 5). Data obtained from animals that are pair- or group-housed is generally considered to be of higher quality due to the presence of companion animals and a more social living environment, which reduces stress and allows the animals to exhibit more natural behaviours (17,18,19).

Figure 5. Diagram of two rats implanted with telemetry devices, with a single receiver beneath the cage.

DSI's multi-frequency telemetry repeater system (Repeater) works in concert with existing transmitters for applications that require an extended transmission range and group housing (20). The Repeater is an externally worn device that is placed in a jacket pocket or attached to a collar or harness worn by the animal. It communicates with an implanted transmitter's signal and retransmits this signal at distances equal to 3 or 8m, depending on the distance setting chosen for the study environment. Between four and eight animals can be monitored per system depending on geographical location.

Remo Technologies, TeleMetronics® (www.telemetronics.com) and Telemetry Research (www.telemetryresearch.com) all manufacture rodent group housing systems. Multiple Remo transmitters (models Remo200, 300 and 400) can co-exist in a single space with no restrictions on the type of enclosure. ITS manufactures fully implantable transmitters with multiple frequencies and a 5m transmission distance to accommodate group-housed large animal species. Telemetronics provides rechargeable PhysioLinQ® and TemPlanT® transmitters for use with group housed animals. The TemPlanT® devices have a 20m transmission distance and collect temperature data.

Telemetry Research devices can accommodate groups of up to 12 rodents (or large animals). Each animal equipped with a Telemetry Research transmitter requires its own receiver dedicated to one of 12 available frequencies enabling simultaneous sampling within a transmission distance of 5m. Telemetry Research devices also enable a scheduled, non-simultaneous sampling protocol using a single receiver, limiting the scheduled sampling to one animal at a time for up to 12 group-housed animals. Legal frequencies are established on a country-by-country basis and must be verified before using.

Telemetry advances that promote reduction

Recording multiple signals

While telemetry offers many opportunities for refinement, it also offers ways to reduce the number of animals used. Every external telemetry system has options to collect ECG, respiration and activity data; some systems can also collect body temperature or blood pressure recordings (see Table 1). Collecting multiple datasets maximises the information gained from each animal and each experiment, ultimately contributing to a reduction in the total number of animals used.

Using this additional information, researchers can also detect negative impacts earlier, thereby avoiding passing a drug candidate to the next phase, preventing unnecessary animal use, and saving time and money. For example, in toxicology and pharmacology studies, telemetry may be able to identify dose-limiting effects of a compound, evidenced by subtle changes in blood pressure and heart rate, so that higher dosing studies are not required.

Rechargeable transmitters and extended battery life

Technological improvements, including rechargeable transmitters manufactured by companies including Remo Technologies, Mini Mitter and Telemetry Research, have eliminated or significantly reduced the need for transmitter refurbishment. DSI supplies the 4ET dual module transmitter, which has a sensing module that can be implanted for up to 1 year, and a battery module that is replaced after 3 months. Replacing the battery when necessary allows continuous data collection from a single animal for up to one year; previous systems required three transmitter exchanges and three additional animals.

Other methods of achieving reduction using telemetry

Consolidating study data

Combining or consolidating studies allows researchers to collect several data parameters via multiple collection methods from a single animal. Examples of how studies using telemetry can be combined to achieve reduction include:

Example 1: Using implantable blood pressure telemetry in rodents together with VisualSonics' high-resolution ultrasound equipment (www.visualsonics.com). The VisualSonics' Vevo® Integrated Rail System can detect surface ECG, heart rate and body temperature data from anesthetized mice and rats resting on a heated monitoring platform; blood flow can be detected via ultrasound imaging. When monitoring blood pressure collected via DSI telemetry, the signal can be inputted via analogue connection to the Vevo system; pressure-volume or pressure-diameter loops can then be calculated by combining the pressure and flow signals, thus allowing a researcher to examine the cardiac structure or vasculature of choice. Using both systems together to combine the data maximises the information gained from the analysis.

Example 2: Synchronising data collected from implantable telemetry and respiratory chambers. DSI-Ponemah offers time-synchronised data collection from DSI or Buxco (www.buxco.com) head-out chambers (see Glossary), free-roaming chambers or pneumotachs (see Glossary) with an intra-pleural pressure telemetry signal in a variety of animal species (see Figure 6). This application was originally developed in primates and rats (21); but it has since been modified for use in dogs and mice as well. Combining these techniques allows a researcher to calculate pulmonary compliance and resistance data, whereas, only intra-pleural pressure or pulmonary airflow would be available if collected individually.

Figure 6. Simultaneous collection of implantable telemetry and respiratory chamber data using DSI OpenART/Ponemah Acquisition and Analysis platform

Example 3: Merging cardiovascular telemetry data collection with calorimetry studies in rodents to determine metabolic rates in normal or exercise states. By housing a rodent implanted with a transmitter in a metabolic cage, researchers have access to continuous cardiovascular data while also monitoring variables such as oxygen consumption and carbon dioxide production (22).

Example 4: Collecting telemetry and activity data simultaneously for circadian rhythm studies using Mini Mitter E-Mitters® and running wheels. Respironics (Mini Mitter) sells both products and their VitalView® software allows synchronized analysis of all data to reduce the number of programs required, and reduce the number of animals used to complete a circadian rhythm study.

Optimising data analysis

Data acquisition and analysis software systems are continually upgraded, offering a greater capability to extract the maximum information from the physiological signals collected from each animal, thereby contributing to reduction. Versatile systems such as ADInstruments® (www.adinstruments.com) and Biopac® (www.biopac.com) can be customised, and can accept and process multiple data inputs of both hard-wired (including video) and telemetered signals into a single system for time-synchronized data. This maximises efficiency by minimising the number of systems and time required to review the data. EMKA (iox2®), Notocord® (www.notocord.com) and DSI (Ponemah) are examples of powerful, Good Laboratory Practices (GLP) compliant software programs that are modular and can be tailored to a user's specific study needs (see Figure 7).

Figure 7. Simultaneous review of physiological video data in Ponemah software.

Re-using animals

Telemetry systems facilitate the re-use of some animals. Implantable telemetry devices, which can be turned off magnetically or by some other means when not in use, are commonly used in pharmaceutical development for safety pharmacology studies. When a study is complete, a principal investigator can determine whether or not animals can be re-used in subsequent studies. If re-use is deemed appropriate after a defined washout period, the number of animals used over many studies could be significantly reduced. The Latin square experimental design (see Glossary) is a practical way of maximising animal use in multiple studies.

Additional benefits of telemetry

Telemetry systems also offer the possibility of collecting valuable data at earlier phases of the drug development process. For example, where the study design does not require specific animal models to be used, DSI's combined pressure and biopotential transmitter (C50-PXT), designed for use in animals as small as 175g, could be implanted in a ferret as opposed to a dog or primate using the large animal equivalent device (D70-PCT). Both transmitters are capable of collecting in vivo pressure, biopotential and temperature data. Using the C50-PXT in ferrets as a non-rodent species during early safety or discovery studies rather than a phylogenetically higher species, such as a dog or primate, may be ethically desirable. It can also reduce the amount of compound required to determine a dose effect and potentially reduce study costs.

Conclusions

Telemetry systems (both implantable and external) are versatile and enable valuable physiological information to be collected from animals for a variety of different research needs. Combining telemetry- and hard-wired-derived data can help to maximise the information gained from every animal and every experiment, contributing to reduction. External telemetry systems allow more humane, non-invasive data collection. In addition, many systems are suitable for animals group-housed in large enclosures, allowing the animals to exhibit more natural behaviours due to the presence of companion animals. Any laboratory considering using telemetry systems should fully assess the appropriate situations in which to use them, the associated animal welfare considerations, and the areas where the 3Rs can be applied.

Glossary

Biopotential: An electric signal generated from a biological source, e.g. electrocardiogram (ECG) below.
Electrocardiogram (ECG): The acronym for electrocardiogram, which is the graphic record of minute differences in electrical potential of the heart during contraction. Also referred to as an EKG.
Hard-wired: A method of collecting physiological data that requires cables or wires to be physically connected between an animal and piece of hardwire (e.g. a signal amplifier, or a signal conditioner, which converts one type of electronic signal, that is typically difficult to read, into a another type of signal that is in a more easily read format).
Head-out chamber: Is a plethysmography chamber used to monitor pulmonary flow-derived parameters from conscious, restrained animals for respiratory studies. The animal's body is placed within the chamber, with its head externalized; a seal forms between the chamber and the animal's neck.
Humane endpoint: Is the point at which an experimental animal's pain and/or distress is terminated, minimised or reduced, by taking action such as killing the animal humanely, terminating a painful procedure, or giving treatment to relieve pain and/or distress.
Latin square: An experimental design where each animal randomly receives all of the doses being compared once over the course of the study with no interaction between the animals.
Non-invasive: A procedure that does not require a surgeon to enter the body cavity or disturb body tissue.
Pneumotachs: A shortened version of the official term "pneumotachometer" a device that measures the inspiratory and expiratory flow of gas through a pressure transducer.
Respiratory Inductive Plethysmography (RIP): A method for measuring changes in respiratory volume by evaluating changes in the electrical characteristics of a set of bands around both the chest and abdomen.
Tethered monitoring systems: A method in which a wire is physically connected to an animal to collect physiological data. The wire often has a limited radius, which restricts the animal's movement.

Acknowledgements

DSI would like to thank Dr. Paul Taylor, King's College London, for his contribution to this article.

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All views or opinions expressed in this article are those of the author and do not necessarily reflect the views and opinions of the NC3Rs.