Research review paper Towards the design of 3D multiscale instructive tissue engineering constructs: Current approaches and trends Sara M. Oliveira, Rui L. Reis, João F. Mano ⁎ 3B's Research Group — Biomaterials, Biodegradables and Biomimetics, Dept. of Polymer Engineering, University of Minho, Avepark - Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco- Guimarães, Portugal ICVS/3B's — PT Government Associate Laboratory, Braga/Guimarães 4805-017 Barco-Guimarães, Portugal abstract article info Article history: Received 30 January 2015 Received in revised form 21 May 2015 Accepted 23 May 2015 Available online xxxx Keywords: Scaffolds Construct Multiscale Instructive Integrative Bottom-up Top-down Building-blocks Nanobiomaterials The design of 3D constructs with adequate properties to instruct and guide cells both in vitro and in vivo is one of the major focuses of tissue engineering. Successful tissue regeneration depends on the favorable crosstalk be- tween the supporting structure, the cells and the host tissue so that a balanced matrix production and degrada- tion are achieved. Herein, the major occurring events and players in normal and regenerative tissue are overviewed. These have been inspiring the selection or synthesis of instructive cues to include into the 3D con- structs. We further highlight the importance of a multiscale perception of the range of features that can be includ- ed on the biomimetic structures. Lastly, we focus on the current and developing tissue-engineering approaches for the preparation of such 3D constructs: top-down, bottom-up and integrative. Bottom-up and integrative ap- proaches present a higher potential for the design of tissue engineering devices with multiscale features and higher biochemical control than top-down strategies, and are the main focus of this review. © 2015 Elsevier Inc. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. Tissue/cell niches as regenerative inspiration for biomaterials design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3. Multiscale construct design features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.1. Geometry — macro, sub-macro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.2. Cell-anchorage — sub-macro, micro, sub-micro, nano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.3. Release systems — micro, sub-micro, nano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.4. Cellularity — micro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.5. Topographical cues — micro, sub-micro, nano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.6. Biochemical cues — nano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4. Differentiation biases and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5. Approaches for 3D construct fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.1. Top-down approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.2. Bottom-up approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.2.1. Random assembling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.2.2. Mediated assembling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.2.3. Specific assembling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.3. Integrative approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.3.1. Sequential integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.3.2. Combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Biotechnology Advances xxx (2015) xxx–xxx ⁎ Corresponding author at: ICVS/3B's — PT Government Associate Laboratory, Braga/Guimarães 4805-017 Barco-Guimarães, Portugal. E-mail address: jmano@dep.uminho.pt (J.F. Mano). JBA-06943; No of Pages 14 http://dx.doi.org/10.1016/j.biotechadv.2015.05.007 0734-9750/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv Please cite this article as: Oliveira, S.M., et al., Towards the design of 3D multiscale instructive tissue engineering constructs: Current approaches and trends, Biotechnol Adv (2015), http://dx.doi.org/10.1016/j.biotechadv.2015.05.007