We are pleased to follow-up with our new subsection in our quarterly newsletter, Preclinical Press, which highlights exciting approaches and initiatives aligned with the 3R principle. The 3R principle (replace, reduce, refine), introduced by Russell and Burch in 1959, serves as a framework for ethically using animals in research and enhancing scientific quality and integrity in studies involving animals. Get inspired, stay informed, and begin implementation!

NIH Clarifies Stance on Animal Testing and NAMs
Authors: Anna E Rapp, PhD, University of Pennsylvania; Annemarie Lang, PhD, University of Michigan

Earlier this year, NIH and FDA announced a roadmap to reduce the use of animal testing in favor of New Approach Methodologies (NAMs), which created significant confusion in the scientific community. At first, it seemed that NIH would no longer consider any grant applications containing only animal studies. Such a shift would have made entire lines of research, for example, in developmental biology, impossible. It also overlooked the reality in musculoskeletal research, where promising NAMs are emerging but the complexity of the conditions and diseases we study cannot yet be fully modeled without animal research.

In July, NIH clarified its position: it will “no longer develop new funding opportunities focused exclusively on animal models of human disease” to ensure that different model systems remain open for proposal. However, applications that rely exclusively on laboratory animals will still be accepted and evaluated through peer review for scientific merit and suitability. NIH emphasized that it “will continue to support grants that use laboratory animal models if scientifically appropriate, justifiable, and with appropriate animal welfare oversight.”

At the same time, NIH reinforced its commitment to reducing animal use over the long term and supporting the development of alternative approaches. This is a development our community should follow closely. Within ORS and our section, we already draw on a wide variety of models and approaches. This evolving landscape can be seen as an opportunity to establish new collaborations and explore innovative ways to integrate in vitro and in vivo preclinical models, all in service of advancing musculoskeletal health.

References:

Improving the Use of Enrichment for Laboratory Rodents
Authors: Kait Link, DVM, Wu Tsai Human Performance Alliance, University of Oregon

In the early 1990s, animal behavior and welfare scientists began to reevaluate the long-standing “Five Freedoms” paradigm, which had shaped welfare thinking since the 1960s.¹ This shift led to the development of the Five Domains Model, which placed greater emphasis on animals’ mental states. Rather than focusing solely on the absence of negative experiences, the model highlights the importance of promoting positive ones – what David Mellor (2016) described as moving “towards a life worth living.” By the early 2000s, this framework had gained wide acceptance.1,2

At its core, the model recognizes that an animal’s welfare is best understood as the sum of its mental experiences, shaped by both physical and social environments. It underscores the need to create conditions that foster positive affective states, not merely minimize suffering. In alignment with this approach, The Guide emphasizes that environmental enrichment is a critical component of animal well-being. Enrichment provides opportunities for species-typical behaviors, exercise, exploration, and problem-solving, while also supporting psychological health through cognitive and sensory challenges tailored to each species’ needs. ³

Mieske et al., 20224 conducted a systematic review examining 186 studies on the impact of environmental enrichment on laboratory rats and mice. The authors found that conventional housing is typically barren leading to poor welfare, inactivity while awake. This suggested that laboratory rodents were experiencing potential boredom. Enriched housing, which included more space, objects, nesting materials, and social contact was consistently linked to better welfare outcomes. These outcomes included improved cognition, motor skills, social behavior, and affective state. There was a reduction in abnormal behaviors such as stereotypies and a decreased depression-like and drug-seeking behaviors. Additionally, benefits were seen across sexes and ages, though most studies used young male rodents. Longer enrichment periods produced stronger welfare improvements. The review concludes that enrichment should not be seen as a luxury but as a necessity for rodent welfare, helping ensure both animal well-being and the reliability of scientific outcomes.

Recent work has begun to address enrichment preferences and durability in laboratory settings. Inotiv scientists conducted a pilot study to identify which items were most engaging for different mouse and rat strains while also assessing durability over a full cage-change cycle5. Tested enrichments, provided in addition to standard bedding and housing, included wooden blocks, cardboard tunnels, KimWipe sheets, Iso-Blox pads, and either Nylabone chews (rats) or huts (mice), with Diamond Twist serving as the control. Items encouraged natural behaviors such as hiding, gnawing, shredding, and nest building.

Results showed hiding-type enrichments generated the highest interaction across both inbred and outbred strains, requiring little acclimation. Outbred mice showed a preference for tunnels, whereas inbred mice preferred huts. Iso-Blox pads also appeared to be heavily used, although evidence of use was indirect. By the end of the 7-day cycle, 23% of mouse cages with Iso-Blox pads and 27–31% of rat cages with Diamond Twists, KimWipes, or Iso-Blox pads had no enrichment remaining. Outbred strains consumed enrichment faster than inbred strains, suggesting a need for more frequent offerings. The study concluded that facilities should replenish less durable items before cage-change cycles end and prioritize high-engagement items in rotational programs to maximize welfare.

With this in mind, the key question remains: how can we provide the most effective enrichment for our rodent models?

  1. Hampton, J. O., Hemsworth, L. M., Hemsworth, P. H., Hyndman, T. H., & Sandøe, P. (2023). Rethinking the utility of the Five Domains model. Animal Welfare, 32, e62. https://doi.org/10.1017/awf.2023.84
  2. Mellor, D.J. (2016). Updating Animal Welfare Thinking: Moving beyond the “Five Freedoms” towards “A Life Worth Living.” Animals, 6(3), 21. https://doi.org/10.3390/ani6030021
  3. National Research Council 2011. Guide for the Care and Use of Laboratory Animals: Eighth Edition. Washington, DC: The National Academies Press. https://doi.org/10.17226/12910.
  4. Mieske, P., Hobbiesiefken, U., Fischer-Tenhagen, C., Heinl, C., Hohlbaum, K., Kahnau, P., Meier, J., Wilzopolski, J., Butzke, D., Rudeck, J., Lewejohann, L., & Diederich, K. (2022). Bored at home?—A systematic review on the effect of environmental enrichment on the welfare of laboratory rats and mice. Frontiers in Veterinary Science, 9, 899219. https://doi.org/10.3389/fvets.2022.899219
  5. Luskey, L. (2025). Pilot Evaluation of Rodent Enrichment Preference in Common Laboratory Stocks and Strains [Webinar]. Inotiv. Presented May 21, 2025.