The activities of the Tissue Bioprinting program include: i) Develop bioprinting protocols to fabricate native-like, functional human tissues. Ii) Validate of printed tissues: develop morphological and physiological biomarkers of tissue architecture and function by using microscopy, histology, gene sequencing, electrophysiological and other methodologies. iii) Use printed tissues for the screening of focused libraries of compounds for drug discovery. iv) Develop a framework for the sharing of validated protocols as a readily available resource for researchers to exchange data on optimized conditions for bioinks, culture techniques, cell types, and software tools as well as techniques to quantify and validate printed tissues. Bioprinting of dermal tissue for modeling skin diseases: Skin is a complex, hierarchical and stratified tissue that provides protection from the external environment by acting as an active physical barrier into the body and regulating transport of water and other metabolites out of the body. Bioprinted human native skin models can provide fundamental insights into the etiology of skin diseases as well as elucidate the pathophysiological mechanisms in skin disease progression and discovery of treatments. Current efforts are directed to the bioprinting of consistent and reproducible human native-like dermis and epidermis layers of the skin using normal human fibroblasts and keratinocytes. Once this is achieved, we will introduce available disease patient cells to reproduce disease skin tissues that will be used as disease-in-dish models for screening. Currently have several collaborative projects using 3D Bioprinted skin tissues: 1) development of a psoriasis skin disease model (Dr. Angela Christiano, Columbia U); 2) development of a skin model of SCC together with a confocal reflectance microscopy for quantitation of disease phenotypes; 3) using skin models for permeability measurements (collaboration with FDA); 4) using bioprinted skin tissues for microbiome studies (collaboration with Dr. Segre and Belkaid); using bioprinted skin tissues to screen for toxicity (collaboration with NACTS Tox21 group). Bioprinting of blood retinal barrier for a disease model of wet age related macular degeneration (wet AMD): Retinal degenerative diseases are the leading cause of irreversible vision loss in developed countries. In many cases the diseases originate in the homeostatic unit in the back of the eye that contains the retina, retinal pigment epithelium (RPE) and the choriocapillaris. In diseases like age-related macular degeneration (AMD), it is thought that RPE dysfunctions cause disease-initiating events and as the RPE degenerates photoreceptors begin to die and patients start losing vision. Patient-specific induced pluripotent stem (iPS) cell-derived RPE provides direct access to a patients genetics and allow the possibility of identifying the initiating events of RPE-associated degenerative diseases. Three-dimensional models of the RPE, neuroretina, and the choriocapillaris are being developed using tissue bioprinting combined with iPS cell technology and fundamental developmental biology. Analysis of disease processes at the level of this entire homeostatic unit will likely provide more insight into molecular mechanisms of retinal degenerative diseases, as well as providing a native disease model for the discovery of new treatments for AMD. This is a collaboration with the group of Dr. Kapil Bharti at NEI. Bioprinting of a blood vessel wall model for modeling Progeria and cardiovascular diseases: Hutchinson-Gilford Progeria syndrome (HGPS) is a genetic disorder that, although rare, has devastating consequences to the affected children. Those with HGPS undergo accelerated aging and have an average life expectancy of just 13.4 years. Patients with HGPS suffer from accelerated vascular disease, and death almost always results from coronary artery disease or stroke. Previous studies have shown a massive loss of smooth muscle cells (SMCs) in the medial layer of large vessels in HGPS patients and animal models, suggesting a possible link between this SMC loss phenotype and the deadly cardiovascular malfunction associated with HGPS. 3D bioprinting techniques are being used to build and characterize a tissue engineered blood vessel wall system using HGPS and normal control iPSC-derived SMCs as disease-in-a-dish models for the discovery of treatments for HGPS. The 3D bioprinted tissue models of blood vessel walls in multi-well plates will be validated biologically and pharmacologically using treatment options previously described. We expect that this 3D vessel system of HGPS will be of great importance for future drug screening and therapeutic development for HGPS and age-related cardiovascular diseases, especially since the toxic protein that causes HGPS is also made in small quantities in normal individuals, and increases as cells approach senescence. This is a collaboration with Dr. Can Kao at University of Maryland, College Park, and Dr. Francis Collins, at NIH/NHGRI. Bioprinting of tissue models for cancer metastasis: Metastasis is the process of spreading of tumor cells to different parts of the body and in most cases it is the pathology that leads to ultimate death in cancer. A 3D assay that recreated the human omentum using cells from ovarian cancer patients undergoing surgery was successfully used to discover compounds that would prevent attachment of tumor cells to the omentum, an early site of metastasis in ovarian cancer. We are currently using tissue bioprinting techniques to increase the relevance on the ovarian cancer metastasis omentum model by introducing additional cell types that are important for the tumor-microenvironment interaction in the omentum metastatic site, including vasculature, adipose cells and leukocytes. Once a native omentum model is recreated, we will study the growth of cancer cells and screen for pharmacological agents that prevent tumor metastasis. This is a collaboration with Dr. Ernst Lengyels group at the Universtiy of Chicago. In addition, we have initiated a collaboration with Dr. Rosie Kaplan (NCI) to develop a vascularized lung model to study breast cancer metastasis. Development of quantitative tissue imaging technologies for screening. The ability to quantitate disease phenotypes in tissues will be critical to enabling the use of this diseases models for screening. Although histology is extensively used during tissue development, imaging techniques will be key to have the throughput required for screening. Efforts are ongoing to develop tissue clearing and segmentation protocols for the quantitation of per cell phenotypes in tissues using confocal fluorescence microscopy. In addition, a collaboration in on-going with Dr. Chao Zhou at Lehigh U to adapt optical coherence tomography (OCT) as a non-invasive imaging technique currently used in a clinical setting to microtiter-based settings to enable its use for screening of tissues. We also have an on-going collaboration with Dr. Peggi Angel at the Medical Center of South Carolina University to use tissue MALDI-MS technologies available in her laboratory to further characterize the tissues produce by measuring metabolites, lipids, proteins and proteoglycans.

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Lal-Nag, Madhu; McGee, Lauren; Guha, Rajarshi et al. (2017) A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth. SLAS Discov 22:494-506
Lal-Nag, Madhu; McGee, Lauren; Titus, Steven A et al. (2017) Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays. SLAS Discov 22:537-546