**3. Biomimetic models and their potential for replacing, refining and reducing laboratory animal models in research**

The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) based in London, UK recently carried out some research to demonstrate that poor or incomplete reporting of studies that use animals have made it difficult to derive the maximum scientific knowledge from animal research. In addition, over the last few decades many research laboratories in academia and industry have used laboratory animals unnecessarily. A survey published by the National Institutes of Health (NIH) Office of Laboratory Animal Welfare (OLAW)1 , and the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs2 ) has demonstrated that many peer-reviewed scientific publications reporting publicly funded animal research from the UK and US lacked key information on how the study was designed, conducted and analysed, which could limit their value in informing future scientific studies and policy. In response to these findings the NC3Rs has recently published the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines [9], which were specifically introduced to improve reporting of animal experiments. These new guidelines have been published in PLoS Biology and several other prestigious scientific journals. Many biomedical research organisations and international scientific societies have already begun to implement these guidelines. The guidelines were developed by the NC3Rs to improve standards of reporting and ensure that the data from animal experiments can be fully evaluated and utilised. The ARRIVE guidelines consist of a 20-point checklist of the essential information that should be included in publications reporting animal

and molecular characteristics of muscle and joint tissues *in vivo*. These *in vitro* models allow researchers to perform original, hypothesis-or curiosity-driven research without using animals while still accurately mimicking musculoskeletal tissues in real life. *In vitro* models also enable screening for new drugs to treat musculoskeletal diseases in a more efficient and cost-effective

Tissue engineering is an interdisciplinary field that applies the principles of biology and engineering to the development of functional substitutes for damaged tissue [1]. The loss or failure of an organ or tissue is one of the most frequent, devastating, and costly problems in human health care. By applying the basic principles of engineering and cell biology tissue engineering is helping us to move toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ [2]. The new tissues can be used as test beds in basic research and development and have potential for future use in transplan‐

Biomimetics is defined as the study of the structure and function of biological systems as models for the design and engineering of biomaterials. The term biomimetics was coined by Otto Schmitt in the 1950s for the transfer of ideas and analogues from biology to technology [4]. It generally refers to human-made and engineered processes, substances, devices, or systems that imitate and therefore *mimic* natural processes and biological systems. It extends to the study of the formation, structure and function of biological substances and materials (i.e. enzymes, polymers, surfaces) and biological mechanisms or processes (i.e. catalysis, protein synthesis) aimed at synthesizing similar products by artificial mechanisms that mimic natural ones. Therefore, a biomimetic model aims to *mimic* the structure and function of a

Organ, tissue and cell culture have been used for decades as biomimetic models of cells, tissues and organs. The pioneering work of eminent scientists such as Sydney Ringer, Wilhelm Roux and Ross Harrison from 1880 to the early 1900s helped to establish the principles and meth‐ odology of tissue culture. Ringer developed salt solutions containing the chlorides of sodium, potassium, calcium and magnesium suitable for developing organ culture. He used this model to maintain the beating of an isolated animal heart outside of the body. Roux maintained a portion of the medullary plate of an embryonic chicken in a warm saline solution for several days, establishing the principle of tissue culture. Harrison published the first paper that successfully introduced tissue culture to settle the argument of how nerve fibres originated [5]. Although other scientists had examined cells *in vitro* several decades earlier, none of them had successfully manage to culture them and it was Harrison who first successfully overcame basic culture problems and created a technique that other investigators could follow [6]. The first permanent fibroblast-like cell line was developed by Earle in 1943 from subcutaneous mouse tissue [7]. This allowed the development of techniques for generating the first human "trans‐ formed" cell line, the HeLa cell, derived from a cervical carcinoma [8]. This resulted in the

way such that real progress is achieved more quickly.

**2. Biomimetic models**

510 Regenerative Medicine and Tissue Engineering

tation and reconstructive surgery [3].

biological system in its structure or function.

<sup>1</sup> http://grants.nih.gov/grants/olaw/

<sup>2</sup> http://www.nc3rs.org.uk/

research. Developed in consultation with the scientific community, including researchers, statisticians, journal editors, and funders, the guidelines request essential information that should be included in publications reporting animal research. Essentially the guidelines are intended to improve reporting of research using animals; guide authors as to the essential information to include in a manuscript, and not be absolutely prescriptive; be flexible to accommodate reporting a wide range of research areas and experimental protocols; promote reproducible, transparent, accurate, comprehensive, concise, logically ordered, well written manuscripts and improve the communication of the research findings to the broader scientific community. The UK's major bioscience funding bodies, including the Medical Research Council, the Biotechnology and Biological Sciences Research Council, Department for Envi‐ ronment, Food and Rural Affairs (Defra3 ), the Natural Environment Research Council (NERC4 ), the European Research Council (ERC5 ) and the Wellcome Trust6 , have all incorpo‐ rated adherence to the guidelines into a revised version of 'Responsibility in the use of animals in bioscience research: Expectations of the major research council and charitable funding bodies', which was originally published in May 2008.

Although the ARRIVE guidelines are primarily aimed at scientists writing up their research for publication and for those who are involved in peer review and intended to improve standards of reporting data from animal experiments, they have also highlighted the potential of biomimetic and tissue engineered *in vitro* models for replacing, refining and reducing the use of laboratory animals in research.
