Engineered in vitro models of fibrosis:
Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease with no curative treatment. IPF drug candidates identified from pre-clinical animal studies have often failed human clinical trials, as animal models do not accurately recapitulate human disease progression. Therefore, there is a need for the development of advanced in vitro models that utilize human cells for pre-clinical drug testing. I have reviewed in detail, the different in vitro models that have been used to study pulmonary fibrosis within the Journal of Advanced Drug Delivery Reviews (https://doi.org/10.1016/j.addr.2017.12.013).
My doctoral research work led to the development of an in vitro engineered model of pulmonary fibrosis using silk fibroin biomaterials seeded with human pulmonary cells within a Flexcell bioreactor. The innovative aspect of the model is the use of silk fibroin biomaterials, which underwent de-novo stiffening, akin to fibrotic lung tissue. Additionally, by utilizing tissue engineering principles, the model reproduced the hallmark fibroblastic-foci pathology associated with pulmonary fibrotic disease. The in vitro model is an advancement over other models in that it could be used for anti-fibrotic drug testing, and it recapitulated different facets of pulmonary fibrotic disease including (1) epithelial injury and loss of basement membrane (2) fibroblast activation due to tissue stiffening and TGF-β1 cytokine and finally (3) immune cell recruitment. Results from this work are published within ACS Biomaterials Science & Engineering (https://doi.org/10.1021/acsbiomaterials.8b01262).
In addition to these research works, I contributed to the development of an algorithm that could be used for the automated quantification of 3D collagen fiber networks, which are often perturbed in fibrotic conditions, and this work is published in the Journal of Biomaterials (https://doi.org/10.1016/j.biomaterials.2016.11.041).
Lung developmental signaling:
The incidence of congenital pulmonary hypoplasia is 1.4 per 1000 births. The cellular and developmental mechanisms underlying pulmonary hypoplasia are currently unknown and deciphering the signaling pathways can lead to the development of novel treatments. For my postdoctoral training, I evaluated the effect of negative transmural pressure on cellular signaling in the developing lung using microfluidic devices. Results from my work showed that negative transmural pressure decreased lung branching and Fgf10 expression, along with other markers of lung maturity such as surfactant protein C (sftpc) and cystic fibrosis transmembrane conductance regulator (cftr). This work is published in the Journal of Frontiers in Cell and Developmental Biology (https://doi.org/10.3389/fcell.2021.725785).
Further, I contributed to the investigation of retinoic acid (RA) signaling in regulating transmural pressure and lung branching. Specifically, I conducted in vitro culture studies that showed that RA signaling is downstream of transmural pressure changes and YAP. This work is published in the Journal of Development (https://doi.org/10.1242/dev.199726).
Biomaterial sensors & drug delivery:
Biomaterials can be used as sensors by impregnating proteins or small molecules within the matrix. There is a demand for novel biosensors that enable real-time, accurate detection of biological signals in a non-invasive manner. Silk fibroin protein-based biosensors have received considerable interest due to their excellent biocompatibility. My graduate work resulted in the observation that phenol red dye crosslinks with the silk hydrogel matrix. Further research showed that silk fibroin proteins covalently crosslink with phenol red dye molecules during tyrosine crosslinking, resulting in the formation of a pH sensing hydrogel for in vitro applications, specifically for use within phenol red free environments. Results from this work are published in the Journal of Acta Biomaterialia (https://dx.doi.org/10.1016/j.actbio.2016.06.020). Apart from silk biomaterials, I have investigated the use of alginate biomaterial thin films for coating silicon microelectrodes and for delivering neuroprotective growth factors, and this is reviewed in detail within the Journal of Materials MDPI (https://doi.org/10.3390/ma2041762).