A miniaturized model of human skin and lymph node for drug discovery and testing Contact dermatitis in the United States is thought to be the third most common reason for patients to seek consultation with a dermatologist and accounting for nearly 95% of all reported occupational skin diseases. The main culprits are chemicals that we encounter on a daily basis as ingredients of drugs, personal care and cosmetic products or in an occupational context (e.g. workers in food, solvent, plastic and chemical industries). Therefore, predicting allergenic potential of chemicals and drug leads is an important safety and regulatory concern. There are currently in excess of 30,000 chemicals used by different industries where no human based safety data exist and an average of 200-300 new chemicals are introduced to the market annually. The current animal tests are informative, but take a long time to perform, are expensive and most importantly have poor physiological relevance to humans and at the same time tend to result in a large number of sacrificed animals. Hence, there is an urgent need to establish novel biomimetic human based in vitro testing models which could successfully replace and improve current animal testing. The goal of this proposal is to engineer a miniaturized and integrated model of human skin and lymph node for high throughput testing of allergenic potential of chemicals. Several tissue engineered models of human skin have been developed both by the investigators and others for clinical applications, yet these systems do not have the immune competency required for sensing skin sensitizers or potential for high throughput applications nor can be easily integrated into other crucial effector immune cells like T cells. In this proposal, we will combine our expertise in microfabrication, immunobiology, skin tissue engineering and microscale tissue constructs to develop a miniaturized model of immunocompetent skin and lymph node which is scalable and has 'self-reporting'capabilities. This proposal builds on ongoing collaborations between applicants on developing immunocompetent biomimetic tissue models. This platform will not only overcome a number of major limitations in using biologically relevant and scalable human based in vitro models for testing skin sensitization potential of chemicals and drug compounds, but could have wider applications in drug testing and discovery, toxicology and addressing fundamental questions in the biology of immune diseases affecting skin.

Public Health Relevance

Through this work, we will develop a miniaturized and integrated model of human skin and lymph node which is amenable to high throughput screening and can be used as a platform for drug discovery and safety testing. We will first fabricate perforated microwells to enable culturing skin model at air-liquid interface. We will the engineer an immunocompetent model of epidermis consist of keratinocytes and dermal fibroblasts interspersed with dendritic cells within perforated microwells. Fibroblasts and dendritic cells will be encapsulated in a hydrogel, and keratinocytes will be seeded on top of this hydrogel layer allowing full differentiation of Keratinocytes at air-liquid interface. The cell ladn hydrogel will also contain T cells allowing cross-talk between activated dendritic cells and T cell simulating events in human lymph node. We will then conduct high throughput studies of chemicals with the engineered 'skin-lymph node'model and also implement a read- out system for monitoring the behavior of cells inside the microwells. We will also engineer a multi-parameter readout system using a combination of immobilized microarray of antibodies and fluorescence based assays to monitor cellular responses to chemicals in real-time and in situ. The new model will then be validated against data from in vivo animal models and parallel experiments using immunocompetent human skin explants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI105024-01A1
Application #
8915940
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Minnicozzi, Michael
Project Start
2014-09-04
Project End
2015-08-31
Budget Start
2014-09-04
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$442,396
Indirect Cost
$192,396
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhang, Yu Shrike; Davoudi, Farideh; Walch, Philipp et al. (2016) Bioprinted thrombosis-on-a-chip. Lab Chip 16:4097-4105
Hassanzadeh, P; Kazemzadeh-Narbat, M; Rosenzweig, R et al. (2016) Ultrastrong and Flexible Hybrid Hydrogels based on Solution Self-Assembly of Chitin Nanofibers in Gelatin Methacryloyl (GelMA). J Mater Chem B Mater Biol Med 4:2539-2543
Shim, Jin-Hyung; Jang, Ki-Mo; Hahn, Sei Kwang et al. (2016) Three-dimensional bioprinting of multilayered constructs containing human mesenchymal stromal cells for osteochondral tissue regeneration in the rabbit knee joint. Biofabrication 8:014102
Annabi, Nasim; Shin, Su Ryon; Tamayol, Ali et al. (2016) Highly Elastic and Conductive Human-Based Protein Hybrid Hydrogels. Adv Mater 28:40-9
Loessner, Daniela; Meinert, Christoph; Kaemmerer, Elke et al. (2016) Functionalization, preparation and use of cell-laden gelatin methacryloyl-based hydrogels as modular tissue culture platforms. Nat Protoc 11:727-46
Zhang, Yu Shrike; Chang, Jae-Byum; Alvarez, Mario Moisés et al. (2016) Hybrid Microscopy: Enabling Inexpensive High-Performance Imaging through Combined Physical and Optical Magnifications. Sci Rep 6:22691
Zhang, Yu Shrike; Yue, Kan; Aleman, Julio et al. (2016) 3D Bioprinting for Tissue and Organ Fabrication. Ann Biomed Eng :
Leijten, Jeroen; Khademhosseini, Ali (2016) From Nano to Macro: Multiscale Materials for Improved Stem Cell Culturing and Analysis. Cell Stem Cell 18:20-4
Riahi, Reza; Shaegh, Seyed Ali Mousavi; Ghaderi, Masoumeh et al. (2016) Automated microfluidic platform of bead-based electrochemical immunosensor integrated with bioreactor for continual monitoring of cell secreted biomarkers. Sci Rep 6:24598
Masoudi, Elham; Ribas, João; Kaushik, Gaurav et al. (2016) Platelet-Rich Blood Derivatives for Stem Cell-Based Tissue Engineering and Regeneration. Curr Stem Cell Rep 2:33-42

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