1. Introduction 2. Tissue bioengineering and HTS 3. Recent models of normal tissues 4. Recent models of cancerous tissues 5. The challenge of angiogenesis 6. Assays and scalability of 3D cultures 7. Conclusion 8. Expert opinion Review 3D in vitro tissue models and their potential for drug screening Lauren Kimlin, Jareer Kassis & Victoria Virador † † Bethesda, MD, USA Introduction: The development of one standard, simplified in vitro three- dimensional tissue model suitable to biological and pathological investiga- tion and drug-discovery may not yet be feasible, but standardized models for individual tissues or organs are a possibility. Tissue bioengineering, while concerned with finding methods of restoring functionality in disease, is devel- oping technology that can be miniaturized for high throughput screening (HTS) of putative drugs. Through collaboration between biologists, physicists and engineers, cell-based assays are expanding into the realm of tissue analy- sis. Accordingly, three-dimensional (3D) micro-organoid systems will play an increasing role in drug testing and therapeutics over the next decade. Never- theless, important hurdles remain before these models are fully developed for HTS. Areas covered: We highlight advances in the field of tissue bioengineering aimed at enhancing the success of drug candidates through pre-clinical opti- mization. We discuss models that are most amenable to high throughput screening with emphasis on detection platforms and data modeling. Expert opinion: Modeling 3D tissues to mimic in-vivo architecture remains a major challenge. As technology advances to provide novel methods of HTS analysis, so do potential pitfalls associated with such models and methods. We remain hopeful that integration of biofabrication with HTS will signifi- cantly reduce attrition rates in drug development. Keywords: 3D models, bioengineering, cell sheet stacking, cocultures, high throughput screening, organoids, spheroids, tissue regeneration, tissue repair, vascularization Expert Opin. Drug Discov. [Early Online] 1. Introduction There is an abundance of convincing literature that tissue composition plays a key role in signaling gene expression, differentiation and function [1,2]. Concordantly, three-dimensional tissue cultures are a fast-growing method to investigate cell biology [3]. Small molecules that show high efficacy against cells assayed as mono- layers often do not reproduce their effectiveness in 3D cultures [4] thus providing misleading toxicological and functional data [5,6]. Such observations strongly sug- gest that screening methods utilizing 3D systems of cell culture are more instruc- tive and predictive than 2D. Developing any high throughput system for drug testing involves considering toxicity and efficacy, both measures required for drugs moving from the lab to the clinic. As both toxicity and efficacy are sometimes tis- sue- or organ- specific, in vitro tissue models can more accurately predict drug dosage [7,8]. We intend to cover advances in tissue bioengineering that are or may be amena- ble to HTS in the near future. Tissue bioengineering simulates native living tissues using isolated cell cultures generally embedded in scaffolds - biocompatible net- works of synthetic or natural polymers - which serve as extracellular matrix (ECM) mimics to provide vital extracellular support [7]. Alternative grafts are scaf- fold-free, self-assembly based methods that can be envisioned as catalysts in the 10.1517/17460441.2013.852181 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 1 All rights reserved: reproduction in whole or in part not permitted Expert Opin. Drug Discov. Downloaded from informahealthcare.com by 69.140.33.169 on 10/22/13 For personal use only.