3D bioprinting for drug discovery and development in pharmaceutics

PubMedID: 28501712Successful launch of a commercial drug requires significant investment of time and financial resources wherein late-stage failures become a reason for catastrophic failures in drug discovery. This calls for infusing constant innovations in technologies, which can give reliable prediction of efficacy, and more importantly, toxicology of the compound early in the drug discovery process before clinical trials. Though computational advances have resulted in more rationale in silico designing, in vitro experimental studies still require gaining industry confidence and improving in vitro-in vivo correlations. In this quest, due to their ability to mimic the spatial and chemical attributes of native tissues, three-dimensional (3D) tissue models have now proven to provide better results for drug screening compared to traditional two-dimensional (2D) models. However, in vitro fabrication of living tissues has remained a bottleneck in realizing the full potential of 3D models. Recent advances in bioprinting provide a valuable tool to fabricate biomimetic constructs, which can be applied in different stages of drug discovery research. This paper presents the first comprehensive review of bioprinting techniques applied for fabrication of 3D tissue models for pharmaceutical studies. A comparative evaluation of different bioprinting modalities is performed to assess the performance and ability of fabricating 3D tissue models for pharmaceutical use as the critical selection of bioprinting modalities indeed plays a crucial role in efficacy and toxicology testing of drugs and accelerates the drug development cycle. In addition, limitations with current tissue models are discussed thoroughly and future prospects of the role of bioprinting in pharmaceutics are provided to the reader. Statement of Significance Present advances in tissue biofabrication have crucial role to play in aiding the pharmaceutical development process achieve its objectives. Advent of three-dimensional (3D) models, in particular, is viewed with immense interest by the community due to their ability to mimic in vivo hierarchical tissue architecture and heterogeneous composition. Successful realization of 3D models will not only provide greater in vitro-in vivo correlation compared to the two-dimensional (2D) models, but also eventually replace pre-clinical animal testing, which has their own shortcomings. Amongst all fabrication techniques, bioprinting- comprising all the different modalities (extrusion-, droplet- and laser-based bioprinting), is emerging as the most viable fabrication technique to create the biomimetic tissue constructs. Notwithstanding the interest in bioprinting by the pharmaceutical development researchers, it can be seen that there is a limited availability of comparative literature which can guide the proper selection of bioprinting processes and associated considerations, such as the bioink selection for a particular pharmaceutical study. Thus, this work emphasizes these aspects of bioprinting and presents them in perspective of differential requirements of different pharmaceutical studies like in vitro predictive toxicology, high-throughput screening, drug delivery and tissue-specific efficacies. Moreover, since bioprinting techniques are mostly applied in regenerative medicine and tissue engineering, a comparative analysis of similarities and differences are also expounded to help researchers make informed decisions based on contemporary literature. © 2017 Acta Materialia Inc.China Scholarship Council: 201308360128 BIDEP 2219 Jiangxi University of Science and Technology Diabetes Action Research and Education Foundation: 426 Türkiye Bilimsel ve Teknolojik Araştirma Kurumu 1624515This work has been supported by National Science Foundation Awards # 1624515, Diabetes in Action Research and Education Foundation grant # 426 and the China Scholarship Council 201308360128 and the Oversea Sailing Project from Jiangxi Association for Science and Technology ( 2013 ). The authors also acknowledge Department of Science and Technology , Government of India, INSPIRE Faculty Award to P.D. The authors are grateful to the support from the Turkish Ministry of National Education for providing graduate scholarship to B. A. and International Postdoctoral Research Scholarship Program (BIDEP 2219) of the Scientific and Technological Research Council of Turkey for providing scholarship to V. O. The authors thank Dr. Christopher Barnatt from http://www.explainingthefuture.com for the bioprinting concept image used in the graphical abstract. In the graphical abstract, the drug screening image was reproduced/adapted with permission from [161] and the ADME assay image was reproduced/adapted from [162] . The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome

Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment

Abstract Breast cancer can reoccur, often as bone metastasis, many years if not decades after the primary tumor has been treated. The factors that stimulate dormant metastases to grow are not known, but bone metastases are often associated with skeletal trauma. We used a dormancy model of MDA-MB-231BRMS1, a metastasis-suppressed human breast cancer cell line, co-cultured with MC3T3-E1 osteoblasts in a long term, three dimensional culture system to test the hypothesis that bone remodeling cytokines could stimulate dormant cells to grow. The cancer cells attached to the matrix produced by MC3T3-E1 osteoblasts but grew slowly or not at all until the addition of bone remodeling cytokines, TNFa and IL-b. Stimulation of cell proliferation by these cytokines was suppressed with indomethacin, an inhibitor of cyclooxygenase and of prostaglandin production, or a prostaglandin E2 (PGE2) receptor antagonist. Addition of PGE2 directly to the cultures also stimulated cell proliferation. MCF-7, non-metastatic breast cancer cells, remained dormant when co-cultured with normal human osteoblast and fibroblast growth factor. Similar to the MDA-MB-231BRMS1 cells, MCF-7 proliferation increased in response to TNFa and IL-b. These findings suggest that changes in the bone microenvironment due to inflammatory cytokines associated with bone repair or excess turnover may trigger the occurrence of latent bone metastasis

3D printing of poly(epsilon-caprolactone)/poly(D,L-lactide-co-glycolide)/hydroxyapatite composite constructs for bone tissue engineering

WOS: 000440179300005Three-dimensional (3D) printing technology is a promising method for bone tissue engineering applications. For enhanced bone regeneration, it is important to have printable ink materials with appealing properties such as construct interconnectivity, mechanical strength, controlled degradation rates, and the presence of bioactive materials. In this respect, we develop a composite ink composed of polycaprolactone (PCL), poly(D,L-lactide-co-glycolide) (PLGA), and hydroxyapatite particles (HAps) and 3D print it into porous constructs. In vitro study revealed that composite constructs had higher mechanical properties, surface roughness, quicker degradation profile, and cellular behaviors compared to PCL counterparts. Furthermore, in vivo results showed that 3D-printed composite constructs had a positive influence on bone regeneration due to the presence of newly formed mineralized bone tissue and blood vessel formation. Therefore, 3D printable ink made of PCL/PLGA/HAp can be a highly useful material for 3D printing of bone tissue constructs.National Science FoundationNational Science Foundation (NSF) [1600118]; Osteology Foundation [15-042]; International Postdoctoral Research Scholarship Program of the Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [BIDEP 2219]This work was partially supported by the National Science Foundation Award No. 1600118 and Osteology Foundation Award No. 15-042. The authors are thankful to Dr. Wu Yang for his assistance with the histology study. Dr. Veli Ozbolat acknowledges the support from the International Postdoctoral Research Scholarship Program (BIDEP 2219) of the Scientific and Technological Research Council of Turkey (TUBITAK). The authors are also thankful to Materials Research Institute at the Pennsylvania State University in supporting the X-ray scattering experiment. The authors also thank Dr. Abhishek Shetty from Anton-Paar USA, Inc. for his assistance with the rheology experiments. The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome