Mechanotransduction in Adverse Implant-Tissue Interactions
Jagannath Padmanabhan MD
PSRC/ PSF Research Grant
Wounds / Scar, General Reconstructive
Biomedical implant performance and longevity is primarily limited by foreign body reaction (FBR), which is a fibrotic reaction characterized by accumulation of cells, proteins, and other biological materials on the implant surface. Varying degrees of FBR towards biomedical implants has been well documented. Severe FBR leads to formation of thick collagen-rich encapsulations (FBR capsules), poor implant-tissue integration and implant rejection. We have previously shown that severe fibrosis during wound healing, a process closely related to FBR, is mediated by mechanical force in a process termed mechanotransduction. The role of mechanotransduction in FBR is not clear. In particular, which specific cells (i.e. transcriptionally activated subpopulations of macrophages, fibroblasts etc.) are involved in severe FBR and how mechanical cues activate these cells remains unknown. Our preliminary work has developed a novel animal model to study severe FBR, identified a mechanotransduction pathway that could mediate severe FBR and established a strategy to identify transcriptionally distinct cells in FBR capsules. Specifically, I have developed a prototype animal model termed "hyper FBR". Briefly, mechanical vibration of model silicone implants in mice using a coin motor results in increased fibrotic response (hyper FBR) as compared to non-vibrating control implants. I have also analyzed human FBR capsules using mass spectrometry, which revealed that that the PI3-Akt pathway is upregulated in FBR capsules. PI3-Akt pathway has been previously implicated in fibrotic wound healing. Further, our lab has developed a strategy combining single cell transcriptional analyses with surface marker screening to identify transcriptionally distinct cell subpopulations, which can be employed to interrogate cells that mediate FBR. My central hypothesis is that activation of cells expressing the PI3-Akt mechanotransduction pathway leads to adverse implant-tissue interactions. I propose to define key mechanoresponsive cells in human FBR capsules and the hyper FBR animal model. Specifically, single cells isolated from FBR capsules will be analyzed for the expression of PI3-Akt and related mechanotransduction pathway components to identify cells with high PI3-Akt expression that can be used as targets to limit FBR. Finally, we will test the efficacy of using inhibitors against the PI3-Akt pathway to limit FBR.
I'm a Postdoctoral Research Fellow at Stanford University in Dr. Geoffrey Gurtner's laboratory. I previously earned a PhD in Biomedical Engineering from Yale University and a Master's degree in Biomedical Engineering from Cornell University. I have more than 9 years of experience in interdisciplinary biomedical research and am working towards a career in Academia. In my postdoctoral work, I have developed a novel animal model termed "hyper-FBR" that mimics severe FBR observed in humans that can be used to study severe FBR in animals. I also co-wrote a human research protocol and have started collecting human FBR capsule samples for analysis. My overall goal for my postdoctoral work is to identify specific cellular subpopulations and mechanotransduction pathways that mediate FBR-mediated implant failure and design novel therapeutic interventions to limit FBR and improve biomedical implant performance. After completion of my postdoctoral training at Stanford, I plan to pursue a career as an Independent Investigator in a research-oriented University of Institute. As an Independent Investigator, my long-term research goal is to use single cell transcriptional analyses and bioinformatics to create a library with information about various biomaterial properties and their consequences on FBR, which will serve as a resource for scientists, surgeons and engineers who are working on designing the next-generation biomedical implants.