Research

The overarching goal of my research program is to understand the role of immune cells, senescent cells, and matrix mechanics in tissue regeneration and regulate them by engineering immunomodulatory materials and drug delivery vehicles to restore musculoskeletal tissues impaired by diseases, trauma, and aging. To this end, we:

1) Elucidate immune dysregulation and identify predictive biomarkers for musculoskeletal disease and trauma
2) Develop hybrid nanovesicles for targeted delivery of disease-modifying drugs
3) Study the influence of soft matrix mechanics on immune cell phenotype and function
4) Study the mechanobiology of macrophages and modulate their phenotype using biophysical cues

We use high-throughput modalities, such as single-cell and spatial transcriptomic modalities, imaging methods, \textit{in vitro} and \textit{in vivo} models, and computational and bioinformatic tools to achieve our aims. I have developed productive collaborations with engineers, clinicians, biologists, and bioinformaticians for carrying out my multidisciplinary work.

Below, I summarize my primary research projects and future goals.

i) Immune dysfunction in musculoskeletal tissues

Nonunion fractures pose significant clinical challenges due to limited treatment options. Our lab has developed an injectable mesenchymal stem cell therapy that successfully regenerates bone in small animals and is currently advancing to larger models and human trials. However, clinical application is hindered by reliance on external osteoinductive signals. To address this, we investigate macrophages—central immune regulators in fracture healing—to decode their role in recruiting progenitor cells and directing osteoblast differentiation. By leveraging these immune-driven mechanisms, we aim to engineer scaffolds that harness endogenous inflammatory signals to achieve robust bone regeneration without exogenous cues, bridging immune biology and regenerative medicine.

ii) Biomaterials for immunomodulation and immunoengineering

Macrophages and neutrophils infiltrate tissues swiftly after an injury or infection. Their invasiveness is mainly steered by their secretion of MMPs. Our recently published work showed that the material properties could be tuned to deliver growth factors in a spatiotemporally controlled manner by synchronizing their response with the local inflammatory milieu. Such ‘smart’ delivery vehicles are useful for targeted delivery of drugs and growth factors for healing recalcitrant wounds and inflammation-driven ailments. These ‘smart’ delivery vehicles can titrate the drug release to synchronize with the inflammatory response resulting in optimal therapeutic efficacy. This can reduce the washout of drugs during periods of low disease activity and hence prolong their therapeutic effect. Part of our research is to develop a flare-responsive ‘smart’ delivery system for osteoarthritis (OA). Our approach will tailor the chemistry of the microparticles to take advantage of the proteases-rich inflammatory milieu for the spatiotemporally controlled release of the loaded drugs.

iii) Enabling technologies for tissue vascularization

A rapid and functional vascularization is indispensable for reinforcing the functionality of an engineered tissue construct and also restoring the functionality of ischemic tissue. We have developed different vascularization strategies using chitosan-glycosaminoglycan microcapsules and vasculogenic fibrin microtissues for creating a network of microvessels. These modules are injectable and once delivered within a scaffold or a tissue they generate microvessels with the lumen. These microvessels inosculate and form a vessel network resembling a terminal vascular bed. Although these strategies are very promising, often they require pre-culturing or preconditioning with growth factors such as PDGF or VEGF, which isn’t clinically feasible.

Currently, we are studying the contributions of immune cells, especially macrophages in vessel formation both in vitro and in vivo. Macrophages play a critical role in tip cell migration and anastomosis. Our preliminary studies show enhanced endothelial sprouting in the presence of macrophages. Further, under certain stimulatory conditions, macrophages are found to secrete vasculogenic cytokines including VEGF-A and PDGF. Using gene and protein arrays, we have investigated and identified phenotypic states of macrophages that can be harnessed for vascularization of tissue constructs and as potential targets for tumor suppression. Our research will shed light on such immune contributions to physiological and pathological vascularization to engineer material-based therapies for vascular diseases.