**7. Conclusions**

This review combines information from di fferent fields with the aim of providing an interdisciplinary view of the biological context and design principles for in vitro models of blood cancers with BM homing. The BMN is a complex cellular and non-cellular microenvironment and an important factor in tumor progression and drug resistance. The use of more physiologically relevant cultures would improve in vitro model prediction of drug response and should therefore be further explored. This model would ideally incorporate all the tumor components and microenvironment, with a trade-o ff between complexity and physiological relevance with reproducibility, ease of use and cost. Some authors recommend the simple incorporation of specific elements of the in vivo environment into models to better evaluate the response of a given therapy. However, TERM strategies are now available and there are a wide range of aspects of the ideal BM model in which the degree of mimicry should

be further explored, such as vascularization, architecture or cell fate regulation by the biomaterials. One of the challenges still to be addressed is the development of complex models based entirely on human cells, which would provide a powerful platform for basic research and clinical translation. In our view, most attempts at modeling blood cancers have involved "deconstructing rather than reconstructing" the complexity of native BM. Although this has limited the contributions, at the same time it has made it possible for the models to advance clinical and basic research, and more dynamic and biomimetic TERM strategies are now emerging for blood cancer modeling.

**Author Contributions:** Conceptualization and writing, S.C.-T., G.G.F., J.L.G.R.; original draft preparation, review and editing, S.C.-T., G.G.F., J.L.G.R. All authors have read and agree to the proofread version of the manuscript.

**Funding:** PROMETEO/2016/063 project is acknowledged. The CIBER-BBN initiative is funded by the VI National R&D&I Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program. CIBER actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. This work was also supported by the Spanish Ministry of Science, Innovation and Universities through Grant FPU17/05810 awarded to Sandra Clara-Trujillo.

**Conflicts of Interest:** The authors declare no conflict of interest.
