Faculty Fellow in BioSciences
Current/Future Research Activities:
3D prostate cancer metastasis models: In an ongoing project through Cindy Farach-Carson’s group, we are developing hyaluronic acid (HA)-based hydrogel systems for 3D prostate cancer cell line culture, and for modeling their interaction with bone marrow stromal cell lines. We are spearheading this effort among our colleagues and collaborators at the Texas Medical Center, in an effort to avoid the artifacts inherent in 2D cell culture. Cell-substrate interactions dramatically affect cell phenotype, and we are focusing on removing the features of 2D culture (e.g. hard, flat surfaces; minimal cell-cell contacts; altered focal adhesion structure) that might yield inaccurate in vitro models of in vivo conditions.
Additionally, Dr. Farach-Carson’s group has found that particular patient-derived cell lines which would not proliferate in traditional 2D culture (and could only be passaged in vivo) are now amenable to growth in 3D HA networks. We are examining the effects of mechanical properties and epitope concentration on cell behavior in these systems, as well as methods for identifying multiple cell types in a single culture, and tracking their behavior over time. These patient-derived cell lines have never been grown in vitro before, and we are combining them in multilayer hydrogel co-culture with bone-derived cells to derive more accurate models of metastasis.
Salivary gland regeneration models: In another ongoing project through Cindy Farach-Carson’s laboratory, we are investigating materials and methods for salivary gland regeneration, using crosslinkable HA polymers as a base scaffold. These systems are being investigated as a possible therapeutic for the tissue damage that results from radiation therapy used in treating oral cancers. Primary human tissues are acquired prior to radiotherapy, and individual cell lineages are separated and cultured for later reassembly in the neotissue. Epitopes derived from perlecan (Pln) are being selectively incorporated into the HA network structure to promote lumen formation and microscale growth factor depots (also made from tightly crosslinked HA) are added to promote branching morphogenesis and migration. We additionally incorporate peptidic sequences that enable cell adhesion and migration through these hydrogels.
High-Throughput Screening for anti-cancer drugs: In collaboration with industry partners, and with Drs. Dan Carson and Pam Constantinou, we are developing multiayered co-cultures of cancer, stroma, and other related cells in miniaturized multiwell plates, suitable for robotic screening of libraries of chemotherapeutics. These systems benefit from a true 3D environment and communication among the cell layers. Our early efforts demonstrate a closer correlation to clinical trial results for our 3D systems than for the traditional test method of cells plated on 2D plastic. We continue to improve this method by incorporating other features (cells, matrix, perfusion) present in the tumor microenvironment.
Supramolecular systems for growth factor delivery: As part of a collaboration with Dr. Carol Podlasek at Northwestern University, we are examining self-assembling peptide amphiphile (PA) hydrogels for the treatment of erectile dysfunction (ED) after radical prostatectomy (RP). Injury to the cavernous nerve or other surrounding peripheral nerves in the penis is a known complication of RP, and Sonic Hedgehog (Shh) protein is known to be involved in the maintenance – or malfunction – of penile smooth muscle function after RP. Shh signaling prevents smooth muscle apoptosis, and preserves penile function. We are using PA gels, loaded with Shh protein, as a delivery system within the penile smooth muscle, to help prevent ED in a rodent nerve crush model. Similarly, we are examining the use of “noodle” PAs, with greater mechanical integrity for surgical placement, as Shh delivery depots for cavernous nerve maintenance and/or regeneration. We have already observed significant improvements in nerve preservation and retention of physiological function due to Shh-PA. These studies have implications in ED treatment, both after RP and for diabetic-induced ED.
Xu X, Sabanayagam CR, Harrington DA, Farach-Carson MC, Jia X A Hydrogel-Based Tumor Model for the Evaluation of Nanoparticle-Based Cancer Therapeutics. Biomaterials, 35(10) 2014: 3319-3330
Pradhan-Bhatt S, Harrington DA, Duncan RL, Farach-Carson MC, Jia X, Witt RL A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland. Laryngoscope, 124(2) 2014: 456-61
Zarembinski TI, Engel BJ, Doty NJ, Constantinou PE, Onorato MV, Erickson IE, Fong ELS, Martinez M, Milton RL, Danysh BP, Delk NA, Harrington DA, Farach-Carson MC, Carson DD HyStem®, a Customizable Hyaluronan-Based Hydrogel Matrix for 3D Cell Culture. 3D Cell Culture: Technology and Application 2014
Fong ELS, Martinez M, Yang J, Mikos AG, Navone NM, Harrington DA, Farach-Carson MC Hydrogel-Based 3D Model of Patient-Derived Prostate Xenograft Tumors Suitable for Drug Screening. Molecular Pharmaceutics, 11(7) 2014: 2040-50
Harrington DA, Martinez M, Wu D, Pradhan-Bhatt S, Farach-Carson MC Salivary Gland Tissue Engineering and Future Diagnostics. Salivary Diagnostics 2014
Pradhan-Bhatt, S; Cannon, K; Zakheim, D; Harrington, DA; Duncan, RL; Jia, X; Farach-Carson, MC; Witt, RL; “Salivary Gland Tissue Engineering and Repair” in Stem Cell Biology and Tissue Engineering in Dental Sciences, ed. Vishwakarma A; Sharpe, P; Shi, S; Ramalingham, M; 2014, Elsevier.
Pradhan-Bhatt S, Harrington DA, Duncan RL, Jia X, Witt RL, Farach-Carson MC
Implantable three-dimensional salivary spheroid assemblies demonstrate fluid and
protein secretory responses to neurotransmitters
. Tissue Eng Part A, 19 2013: 1610-20
Farach-Carson MC, Warren CR, Harrington DA, Carson DD Border patrol: Insights
into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and
tissue borders. Matrix Biol , 34 2013: 64-79
Xu, X; Jha, AK; Harrington, DA; Farach-Carson, MC; Jia, X Hyaluronic Acid-Based Hydrogels: from a Natural Polysaccharide to Complex Networks. Soft Matter, 8(12) 2012: 3280-3294
Xu, X; Gurski, LA; Zhang, C; Harrington, DA; Farach-Carson, MC; Jia, X Recreating the Tumor Microenvironment in a Bilayer, Hyaluronic Acid Hydrogel Construct for the Growth of Prostate Cancer Spheroids. Biomaterials, 33(35) 2012: 9049-9060
Bond, CW; Angeloni, NL; Harrington, DA; Stupp, SI; Podlasek, CA Sonic Hedgehog Regulates Brain Derived Neurotrophic Factor in Normal and Regenerating Cavernous Nerves. Journal of Sexual Medicine 2012
Angeloni, NL; Bond, CW; Harrington, DA; Stupp, SI; Podlasek, CA Sonic hedgehog is Neuroprotective in the Cavernous Nerve with Crush Injury. Journal of Sexual Medicine 2012
Mishra, R; Vijayan, KV; Coletti, EC; Harrington, DA; Matthiesen, T; Goh, SK; Wold, LE; Backer,CA; Kaushal, S Characterization and Functionality of Cardiac Progenitor Cells in Congenital Heart Patients. Circulation, 123(4) 2011: 364-73
Angeloni, NL; Bond, CW; Tang, Y; Harrington, DA; Zhang, S; Stupp, SI; McKenna, KE; Podlasek, CA Regeneration of the Cavernous Nerve Using Aligned Peptide Amphiphile Nanofibers. Biomaterials, 32(4) 2011: 1091-101
Engel BJ, Constantinou PE, Sablatura LK, Doty NJ, Carson DD, Farach-Carson MC, Harrington DA, Zarembinski TI. Multilayered, Hyaluronic Acid-Based Hydrogel Formulations Suitable for Automated 3D High Throughput Drug Screening of Cancer-Stromal Cell Cocultures. Adv Healthc Mater. (2015) 4(11):1664-74
Fong ELS, Wang X, Yang J, Morgado M, Mikos AG, Harrington DA, Navone NM, Farach-Carson MC. A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials. (2016) 77:164-172