SBIR-STTR Award

Rats represent the most commonly used physiologically and pharmacological experimental model for studying human disease. The ability to genetically modify rats through methods of gene transfer in fertilized rat embryos or by gene targeting in embryonic stem (ES) cells has significantly increased the capabilities of rats in biomedical and pharmaceutical research. Until now, the production of targeted gene- modifications in rats requires the surgical transfer of embryos. This surgery is cost and labor intensive since it requires anesthesia (with potential complications), post-operative care of female rats (which may include the use of analgesics), as well as technical expertise on the part of the person carrying out the surgery. At the same time, there is a strong desire in the animal research community to reduce the morbidity, stress, and pain of animals used for research purposes. To overcome these problems we propose to develop a Non-Surgical Embryo Transfer (NSET) device that can be used for the non-surgical transfer of embryos into female rats. We have previously developed a device for use in mice that is rapid, does not require surgery (including the associated anesthesia and post-operative care), requires little expertise, and preliminarily is as efficacious as standard surgical embryo transfer in the production of transgenic mice. Although the rat reproductive tract anatomy is significantly different than that of mice, we believe we can successfully develop a rat NSET device prototype. The aims of this proposal are to design a rat NSET prototype, manufacture the prototype device, and demonstrate device efficacy for non-surgical transfer of embryos. Success in these aims will provide the foundation to seek a Phase II award and for the commercialization of the NSET device for academic and bio/pharma rat research facilities.

Public Health Relevance:
The development of a device for the non-surgical transfer of embryos into recipient female rats represents a substantial advance over existing methods for generating gene-modified rats by eliminating surgery, anesthesia, and post-operative care. The goal of this proposal is to develop, manufacture, and determine the efficacy of a non- surgical embryo transfer prototype device for the transfer of rat embryos.

Thesaurus Terms:
"analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Anatomic; Anatomical Sciences; Anatomy; Anesthesia; Anesthesia Procedures; Animal Experimental Use; Animal Experimentation; Animal Research; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Award; Caliber; Caring; Catheters; Common Rat Strains; Communities; Derivation; Derivation Procedure; Development; Device Or Instrument Development; Devices; Diagnosis, Ultrasound; Diameter; Distress; Es Cell; Echography; Echotomography; Embryo; Embryo Transfer; Embryonic; Experimental Models; Experimental Models, Other; Female; Foundations; Gene Targeting; Gene Transfer; Gene-Modified; Goals; Grant; Imagery; Implant; Length; Mammals, Mice; Mammals, Rats; Medical; Medical Imaging, Ultrasound; Methods; Methods And Techniques; Methods, Other; Mice; Models, Experimental; Modification; Morbidity; Morbidity - Disease Rate; Morphology; Murine; Mus; Nih; National Institutes Of Health; National Institutes Of Health (U.S.); Operation; Operative Procedures; Operative Surgical Procedures; Pain; Painful; Performance; Persons; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Post-Operative; Postoperative; Postoperative Period; Production; Rat; Rat Strains; Rattus; Research; Sbir; Sbirs (R43/44); Science Of Anatomy; Small Business Innovation Research; Small Business Innovation Research Grant; Source; Stress; Surgical; Surgical Interventions; Surgical Procedure; Targetings, Gene; Technical Expertise; Techniques; Testing; Time; Transgenic Mice; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; United States National Institutes Of Health; Visualization; Work; Analgesia; Anatomy; Animal Pain; Base; Commercialization; Cost; Design; Designing; Device Development; Diagnostic Ultrasound; Embryo Culture; Embryo Transplantation; Embryonic Stem Cell; Flexibility; Human Disease; Improved; Innovate; Innovation; Innovative; Instrument Development; Prototype; Public Health Relevance; Reproductive; Research Facility; Skills; Sonogram; Sonography; Sound Measurement; Stem; Stem Cell Of Embryonic Origin; Success; Surgery; Tool; Transfer Of A Gene; Ultrasound; Ultrasound Imaging; Ultrasound Scanning"

ParaTechs Corporation develops innovative technologies for biomedical research while seeking to improve animal welfare for laboratory animals. One of ParaTechs' major goals is to further the guiding principles of ethical animal use by 'reducing, replacing and refining' the use of animals in research, according to the guidelines of Russell and Burch's 3Rs of animal research. ParaTechs already has brought to market a non-surgical embryo transfer device (NSETTM) for mice, which replaces surgical embryo transfers with a non-surgical method that has been proven to cause less stress in research animals. The goal of this project is to develop a device and a research protocol for nonsurgical embryo transfer in rats. The device and protocol is to be rapid, easy to use, cost effective, and efficien for embryo transfer. Poof of principle for the project was established during Phase I, where multiple prototypes of a rat NSET device were designed, manufactured, and tested. Rat embryos were transferred and viable rat pups were obtained, demonstrating the first successful nonsurgical embryo transfer in rats. The goal of Phase II is to further establish the parameters of rat NSET technology and to develop the device for commercialization to the biomedical research community. Four objectives are proposed to achieve this goal. First, we will determine the efficiency of non-surgical embryo transfer relative to surgical embryo transfer in Sprague-Dawley and Fischer 344 rats, for both morula and blastocyst stage embryos. This study will have broad applications for transfer of cryopreserved embryos and for transfer of genetically modified embryos after introduction of embryonic stem cells. Second, we will transfer in vitro cultured embryos using the rNSET and compared efficiency to surgical embryo transfer techniques. This aim will address successful transfer of rat embryos that may be modified very early in development; for example, after pronuclear injection for the purpose of genetic modification. Third, we will test the use of the rat NSET for artificial insemination as an alternative to surgical techniques. This aim will support the use of the device as an alternative t surgical artificial insemination and as a possible alternative to in vitro fertilization. Fourth, w will assess the level of stress reduction of the NSET procedure compared to surgical embryo transfer. These aims are consistent with ParaTechs' overall goal to improve animal welfare and support more effective and humane use of animal models in biomedical research.

Public Health Relevance Statement:


Public Health Relevance:
The ability to genetically modify the laboratory rat is producing increasingly valuable and unique strains to investigate human disease. Currently, this technology is dependent on implanting embryos in female rats by surgical means. ParaTechs proposes to develop and commercialize a unique device and technology for fast, simple, and painless nonsurgical embryo transfer (NSET) in rats, which will support the Office of Laboratory Animal Welfare (OLAW) objectives of reducing pain and distress for laboratory animals, because it will provide an alternative to surgical methods for assisted reproductive techniques.

NIH Spending Category:
Bioengineering

Project Terms:
Address; Adopted; Animal Experimentation; Animal Model; Animal Welfare; Animals; Artificial Insemination; Assisted Reproductive Techniques; Award; Behavior; Biological Markers; Biomedical Research; Birth; blastocyst; Businesses; Cardiovascular Diseases; Categories; Cell Culture Techniques; Collaborations; commercialization; Communities; cost; cost effective; Data; design; Development; Device Designs; Devices; Distress; Embryo; embryo culture; Embryo Transfer; embryonic stem cell; Ethics; Female; Fertilization in Vitro; Funding; Gene-Modified; Genetic; genetic manipulation; Goals; Guidelines; human disease; human tissue; Implant; improved; In Vitro; Individual; Injection of therapeutic agent; innovative technologies; Institution; Knock-out; Laboratories; Laboratory Animals; Laboratory Rat; Laboratory Research; Lead; Letters; Life; Maintenance; Marketing; Measures; meetings; method development; Methods; Modeling; Modification; Morals; Morula; mouse model; Mus; Operative Surgical Procedures; Outcome; Pain; Painless; Pharmaceutical Preparations; Phase; Physiology; Procedures; Protocols documentation; prototype; public health relevance; pup; Rat Strains; Rattus; Relative (related person); Research; Research Personnel; Resources; Rivers; Services; Societies; sperm cell; Staging; Stress; Techniques; Technology; Testing; tissue culture; Tissue Sample; Toxicology; Transgenic Organisms