Jagannath Padmanabhan

All Publications

• In Vivo Models for the Study of Fibrosis ADVANCES IN WOUND CARE Padnnanabhan, J., Maan, Z. N., Kwon, S., Kosaraju, R., Bonham, C. A., Gurtner, G. C. 2019

  View details for DOI 10.1089/wound.2018.0909

  View details for Web of Science ID 000462593400001

• In Vivo Models for the Study of Fibrosis. Advances in wound care Padmanabhan, J., Maan, Z. N., Kwon, S. H., Kosaraju, R., Bonham, C. A., Gurtner, G. C. 2019; 8 (12): 645–54

  Abstract

  Significance: Fibrosis and scar formation pose a substantial physiological and psychological burden on patients and a significant public health burden on the economy, estimated to be up to $12 billion a year. Fibrosis research is heavily reliant on in vivo models, but variations in animal models and differences between animal and human fibrosis necessitates careful selection of animal models to study fibrosis. There is also an increased need for improved animal models that recapitulate human pathophysiology. Recent Advances: Several murine and porcine models, including xenograft, drug-induced fibrosis, and mechanical load-induced fibrosis, for different types of fibrotic disease have been described in the literature. Recent findings have underscored the importance of mechanical forces in the pathophysiology of scarring. Critical Issues: Differences in skin, properties of subcutaneous tissue, and modes of fibrotic healing in animal models and humans provide challenges toward investigating fibrosis with in vivo models. While porcine models are typically better suited to study cutaneous fibrosis, murine models are preferred because of the ease of handling and availability of transgenic strains. Future Directions: There is a critical need to develop novel murine models that recapitulate the mechanical cues influencing fibrosis in humans, significantly increasing the translational value of fibrosis research. We advocate a translational pipeline that begins in mouse models with modified biomechanical environments for foundational molecular and cellular research before validation in porcine models that closely mimic the human condition.

  View details for DOI 10.1089/wound.2018.0909

  View details for PubMedID 31827979

  View details for PubMedCentralID PMC6904938

• Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation. The Journal of investigative dermatology Ma, K., Kwon, S. H., Padmanabhan, J., Duscher, D., Trotsyuk, A. A., Dong, Y., Inayathullah, M., Rajadas, J., Gurtner, G. C. 2018

  Abstract

  Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing, reduced collagen deposition and activation of scar forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications.

  View details for PubMedID 29775632

• Disease models: Method in the madness of fibrosis. Nature materials Gurtner, G. C., Padmanabhan, J. 2017; 16 (12): 1176–77

  View details for PubMedID 29170546

• Nanopatterned Bulk Metallic Glass Biosensors. ACS sensors Kinser, E. R., Padmanabhan, J., Yu, R., Corona, S. L., Li, J., Vaddiraju, S., Legassey, A., Loye, A., Balestrini, J., Solly, D. A., Schroers, J., Taylor, A. D., Papadimitrakopoulos, F., Herzog, R. I., Kyriakides, T. R. 2017

  Abstract

  Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt-BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10-12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 μA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity.

  View details for DOI 10.1021/acssensors.7b00455

  View details for PubMedID 29115132

• Regulation of cell-cell fusion by nanotopography. Scientific reports Padmanabhan, J., Augelli, M. J., Cheung, B., Kinser, E. R., Cleary, B., Kumar, P., Wang, R., Sawyer, A. J., Li, R., Schwarz, U. D., Schroers, J., Kyriakides, T. R. 2016; 6: 33277

  Abstract

  Cell-cell fusion is fundamental to a multitude of biological processes ranging from cell differentiation and embryogenesis to cancer metastasis and biomaterial-tissue interactions. Fusogenic cells are exposed to biochemical and biophysical factors, which could potentially alter cell behavior. While biochemical inducers of fusion such as cytokines and kinases have been identified, little is known about the biophysical regulation of cell-cell fusion. Here, we designed experiments to examine cell-cell fusion using bulk metallic glass (BMG) nanorod arrays with varying biophysical cues, i.e. nanotopography and stiffness. Through independent variation of stiffness and topography, we found that nanotopography constitutes the primary biophysical cue that can override biochemical signals to attenuate fusion. Specifically, nanotopography restricts cytoskeletal remodeling-associated signaling, which leads to reduced fusion. This finding expands our fundamental understanding of the nanoscale biophysical regulation of cell fusion and can be exploited in biomaterials design to induce desirable biomaterial-tissue interactions.

  View details for DOI 10.1038/srep33277

  View details for PubMedID 27615159

• Nanomaterials, Inflammation, and Tissue Engineering WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY Padmanabhan, J., Kyriakides, T. R. 2015; 7 (3): 355-370

  Abstract

  Nanomaterials exhibit unique properties that are absent in the bulk material because decreasing material size leads to an exponential increase in surface area, surface area to volume ratio, and effective stiffness, resulting in altered physiochemical properties. Diverse categories of nanomaterials such as nanoparticles, nanoporous scaffolds, nanopatterned surfaces, nanofibers, and carbon nanotubes can be generated using advanced fabrication and processing techniques. These materials are being increasingly incorporated in tissue engineering scaffolds to facilitate the development of biomimetic substitutes to replace damaged tissues and organs. Long-term success of nanomaterials in tissue engineering is contingent upon the inflammatory responses they elicit in vivo. This review seeks to summarize the recent developments in our understanding of biochemical and biophysical attributes of nanomaterials and the inflammatory responses they elicit, with a focus on strategies for nanomaterial design in tissue engineering applications.

  View details for DOI 10.1002/wnan.1320

  View details for Web of Science ID 000352811000008

  View details for PubMedID 25421333

• Engineering Cellular Response Using Nanopatterned Bulk Metallic Glass ACS NANO Padmanabhan, J., Kinser, E. R., Stalter, M. A., Duncan-Lewis, C., Balestrini, J. L., Sawyer, A. J., Schroers, J., Kyriakides, T. R. 2014; 8 (5): 4366-4375

  Abstract

  Nanopatterning of biomaterials is rapidly emerging as a tool to engineer cell function. Bulk metallic glasses (BMGs), a class of biocompatible materials, are uniquely suited to study nanopattern-cell interactions as they allow for versatile fabrication of nanopatterns through thermoplastic forming. Work presented here employs nanopatterned BMG substrates to explore detection of nanopattern feature sizes by various cell types, including cells that are associated with foreign body response, pathology, and tissue repair. Fibroblasts decreased in cell area as the nanopattern feature size increased, and fibroblasts could detect nanopatterns as small as 55 nm in size. Macrophages failed to detect nanopatterns of 150 nm or smaller in size, but responded to a feature size of 200 nm, resulting in larger and more elongated cell morphology. Endothelial cells responded to nanopatterns of 100 nm or larger in size by a significant decrease in cell size and elongation. On the basis of these observations, nondimensional analysis was employed to correlate cellular morphology and substrate nanotopography. Analysis of the molecular pathways that induce cytoskeletal remodeling, in conjunction with quantifying cell traction forces with nanoscale precision using a unique FIB-SEM technique, enabled the characterization of underlying biomechanical cues. Nanopatterns altered serum protein adsorption and effective substrate stiffness, leading to changes in focal adhesion density and compromised activation of Rho-A GTPase in fibroblasts. As a consequence, cells displayed restricted cell spreading and decreased collagen production. These observations suggest that topography on the nanoscale can be designed to engineer cellular responses to biomaterials.

  View details for DOI 10.1021/nn501874q

  View details for Web of Science ID 000336640600027

  View details for PubMedID 24724817

• Age-associated intracellular superoxide dismutase deficiency potentiates dermal fibroblast dysfunction during wound healing EXPERIMENTAL DERMATOLOGY Fujiwara, T., Dohi, T., Maan, Z. N., Rustad, K. C., Kwon, S., Padmanabhan, J., Whittam, A. J., Suga, H., Duscher, D., Rodrigues, M., Gurtner, G. C. 2019; 28 (4): 485–92

  View details for DOI 10.1111/exd.13404

  View details for Web of Science ID 000468323100023

• The Interplay of Mechanical Stress, Strain, and Stiffness at the Keloid Periphery Correlates with Increased Caveolin-1/ROCK Signaling and Scar Progression. Plastic and reconstructive surgery Dohi, T., Padmanabhan, J., Akaishi, S., Than, P. A., Terashima, M., Matsumoto, N. N., Ogawa, R., Gurtner, G. C. 2019; 144 (1): 58e–67e

  Abstract

  Fibroproliferative disorders result in excessive scar formation, are associated with high morbidity, and cost billions of dollars every year. Of these, keloid disease presents a particularly challenging clinical problem because the cutaneous scars progress beyond the original site of injury. Altered mechanotransduction has been implicated in keloid development, but the mechanisms governing scar progression into the surrounding tissue remain unknown. The role of mechanotransduction in keloids is further complicated by the differential mechanical properties of keloids and the surrounding skin.The authors used human mechanical testing, finite element modeling, and immunohistologic analyses of human specimens to clarify the complex interplay of mechanical stress, strain, and stiffness in keloid scar progression.Changes in human position (i.e., standing, sitting, and supine) are correlated to dynamic changes in local stress/strain distribution, particularly in regions with a predilection for keloids. Keloids are composed of stiff tissue, which displays a fibrotic phenotype with relatively low proliferation. In contrast, the soft skin surrounding keloids is exposed to high mechanical strain that correlates with increased expression of the caveolin-1/rho signaling via rho kinase mechanotransduction pathway and elevated inflammation and proliferation, which may lead to keloid progression.The authors conclude that changes in human position are strongly correlated with mechanical loading of the predilection sites, which leads to increased mechanical strain in the peripheral tissue surrounding keloids. Furthermore, increased mechanical strain in the peripheral tissue, which is the site of keloid progression, was correlated with aberrant expression of caveolin-1/ROCK signaling pathway. These findings suggest a novel mechanism for keloid progression.

  View details for DOI 10.1097/PRS.0000000000005717

  View details for PubMedID 31246819

• TOPICAL DELIVERY OF A FOCAL ADHESION KINASE INHIBITOR RESULTS IN ACCELERATED WOUND HEALING WITH REDUCED SCARRING IN A PORCINE WOUND MODEL Kwon, S., Ma, K., Duscher, D., Padmanabhan, J., Dong, Y., Inayathullah, M., Rajadas, J., Gurtner, G. C. WILEY. 2018: A13

  View details for Web of Science ID 000451464000057

• Nanopatterned bulk metallic glass-based biomaterials modulate macrophage polarization. Acta biomaterialia Shayan, M., Padmanabhan, J., Morris, A. H., Cheung, B., Smith, R., Schroers, J., Kyriakides, T. R. 2018

  Abstract

  Polarization of macrophages by chemical, topographical and mechanical cues presents a robust strategy for designing immunomodulatory biomaterials. Here, we studied the ability of nanopatterned bulk metallic glasses (BMGs), a new class of metallic biomaterials, to modulate murine macrophage polarization. Cytokine/chemokine analysis of IL-4 or IFNγ/LPS-stimulated macrophages showed that the secretion of TNF-α, IL-1α, IL-12, CCL-2 and CXCL1 was significantly reduced after 24-hour culture on BMGs with 55 nm nanorod arrays (BMG-55). Additionally, under these conditions, macrophages increased phagocytic potential and exhibited decreased cell area with multiple actin protrusions. These in vitro findings suggest that nanopatterning can modulate biochemical cues such as IFNγ/LPS. In vivo evaluation of the subcutaneous host response at 2 weeks demonstrated that the ratio of Arg-1 to iNOS increased in macrophages adjacent to BMG-55 implants, suggesting modulation of polarization. In addition, macrophage fusion and fibrous capsule thickness decreased and the number and size of blood vessels increased, which is consistent with changes in macrophage responses. Our study demonstrates that nanopatterning of BMG implants is a promising technique to selectively polarize macrophages to modulate the immune response, and also presents an effective tool to study mechanisms of macrophage polarization and function.Implanted biomaterials elicit a complex series of tissue and cellular responses, termed the foreign body response (FBR), that can be influenced by the polarization state of macrophages. Surface topography can influence polarization, which is broadly characterized as either inflammatory or repair-like. The latter has been linked to improved outcomes of the FBR. However, the impact of topography on macrophage polarization is not fully understood, in part, due to a lack of high moduli biomaterials that can be reproducibly processed at the nanoscale. Here, we studied macrophage interactions with nanopatterned bulk metallic glasses (BMGs), a class of metallic alloys with amorphous microstructure and formability like polymers. We show that nanopatterned BMGs modulate macrophage polarization and transiently induce less fibrotic and more angiogenic responses. Overall, we demonstrate nanopatterning of BMG implants as a technique to polarize macrophages and modulate the FBR.

  View details for DOI 10.1016/j.actbio.2018.05.051

  View details for PubMedID 29859902

• Topical Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Healing with Reduced Scarring in a Porcine Wound Model Kwon, S., Ma, K., Duscher, D., Padmanabhan, J., Dong, Y., Inayathullah, M., Rajadas, J., Gurtner, G. C. WILEY. 2018: A33

  View details for Web of Science ID 000430308600139

• Age-Associated Intracellular Superoxide Dismutase Deficiency Potentiates Dermal Fibroblast Dysfunction During Wound Healing. Experimental dermatology Fujiwara, T., Dohi, T., Maan, Z. N., Rustad, K. C., Kwon, S. H., Padmanabhan, J., Whittam, A. J., Suga, H., Duscher, D., Rodrigues, M., Gurtner, G. C. 2017

  Abstract

  Reactive oxygen species (ROS) impair wound healing through destructive oxidation of intracellular proteins, lipids, and nucleic acids. Intracellular superoxide dismutase (SOD1) regulates ROS levels and plays a critical role in tissue homeostasis. Recent evidence suggests that age-associated wound healing impairments may partially result from decreased SOD1 expression. We investigated the mechanistic basis by which increased oxidative stress links to age-associated impaired wound healing. Fibroblasts were isolated from unwounded skin of young and aged mice, and myofibroblast differentiation was assessed by measuring α-smooth muscle actin and collagen gel contraction. Excisional wounds were created on young and aged mice to study the healing rate, ROS levels, and SOD1 expression. A mechanistic link between oxidative stress and fibroblast function was explored by assessing the TGF-β1 signaling pathway components in young and aged mice. Age-related wounds displayed reduced myofibroblast differentiation and delayed wound healing, consistent with a decrease in the in vitro capacity for fibroblast-myofibroblast transition following oxidative stress. Young fibroblasts with normal SOD1 expression exhibited increased phosphorylation of ERK in response to elevated ROS. In contrast, aged fibroblasts with reduced SOD1 expression displayed a reduced capacity to modulate intracellular ROS. Collectively, age-associated wound healing impairments are associated with fibroblast dysfunction that is likely the result of decreased SOD1 expression and subsequent dysregulation of intracellular ROS. Strategies targeting these mechanisms may suggest a new therapeutic approach in the treatment of chronic non-healing wounds in the aged population. This article is protected by copyright. All rights reserved.

  View details for PubMedID 28677217

• The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression. International journal of molecular sciences Januszyk, M., Kwon, S. H., Wong, V. W., Padmanabhan, J., Maan, Z. N., Whittam, A. J., Major, M. R., Gurtner, G. C. 2017; 18 (9)

  Abstract

  Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte-specific FAK-deleted mice, cultured, and sorted into single cells. Keratinocytes were evaluated using a microfluidic-based platform for high-resolution transcriptional analysis. Partitive clustering, gene enrichment analysis, and network modeling were applied to characterize the significance of FAK on regulating keratinocyte subpopulations and fibrogenic pathways important for scar formation. Considerable transcriptional heterogeneity was observed within the keratinocyte populations. FAK-deleted keratinocytes demonstrated increased expression of genes integral to mechanotransduction and extracellular matrix production, including Igtbl, Mmpla, and Col4a1. Transcriptional activities upon FAK deletion were not identical across all single keratinocytes, resulting in higher frequency of a minor subpopulation characterized by a matrix-remodeling profile compared to wildtype keratinocyte population. The importance of keratinocyte FAK signaling gene expression was revealed. A minor subpopulation of keratinocytes characterized by a matrix-modulating profile may be a keratinocyte subset important for mechanotransduction and scar formation.

  View details for PubMedID 28880199

  View details for PubMedCentralID PMC5618564

• Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses. Scientific reports Liu, Y., Padmanabhan, J., Cheung, B., Liu, J., Chen, Z., Scanley, B. E., Wesolowski, D., Pressley, M., Broadbridge, C. C., Altman, S., Schwarz, U. D., Kyriakides, T. R., Schroers, J. 2016; 6: 26950

  Abstract

  Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design.

  View details for DOI 10.1038/srep26950

  View details for PubMedID 27230692

  View details for PubMedCentralID PMC4882501

• Introduction. Yale journal of biology and medicine Padmanabhan, J., Kinser, E. 2013; 86 (4): 525-?

  View details for PubMedID 24498668

  View details for PubMedCentralID PMC3848107

• The effects of extracellular matrix proteins on neutrophil-endothelial interaction--a roadway to multiple therapeutic opportunities. Yale journal of biology and medicine Padmanabhan, J., Gonzalez, A. L. 2012; 85 (2): 167-185

  Abstract

  Polymorphoneuclear leukocytes or neutrophils, a major component of white blood cells, contribute to the innate immune response in humans. Upon sensing changes in the microenvironment, neutrophils adhere to the vascular wall, migrate through the endothelial cell (EC)-pericyte bilayer, and subsequently through the extracellular matrix to reach the site of inflammation. These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes. While primarily mediators of tissue homeostasis, there are an increasing number of studies indicating that neutrophil recruitment and transmigration can also lead to host-tissue injury and subsequently inflammation-related diseases. Neutrophil-induced tissue injury is highly regulated by the microenvironment of the infiltrated tissue, which includes cytokines, chemokines, and the provisional extracellular matrix, remodeled through increased vascular permeability and other cellular infiltrates. Thus, investigation of the effects of matrix proteins on neutrophil-EC interaction and neutrophil transmigration may help identify the proteins that induce pro- or anti-inflammatory responses. This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases. This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. For each disease model, inflammatory molecules released by neutrophils, important regulatory matrix proteins, current anti-inflammatory treatments, and the scope for further research will be summarized.

  View details for PubMedID 22737047

  View details for PubMedCentralID PMC3375712