Jagannath (Jagan) Padmanabhan, Ph.D. is an Instructor in the Department of Surgery at Stanford University. He is a bioengineer by training (M.Eng., Cornell University, 2011; Ph.D., Yale University, 2016) and works as a project lead for translational and clinical research projects with Dr. Geoffrey C. Gurtner, the Inaugural Vice Chairman of Surgery for Innovation at Stanford University. Jagan's research expertise spans the fields of wound care, medical devices & MedTech. His research work has led to 29 published manuscripts and multiple patent applications (US10213144B2; PCT/US2021/053992). Over the past five years, Jagan has been invited to critically evaluate scientific manuscripts by 30 different journals.
Jagan is passionate about biomedical innovation and Industry-Academia collaborations. He recently coordinated a department-wide effort and partnered with Silicon Valley MedTech experts for a unique summer program on biomedical innovation. He also runs a blog for scientists, seekers, and skeptics at www.sciencers.org.
Quick fact: Four languages and counting.
Casual - Other Teaching Staff, Continuing Studies and Summer Session
Ignite Fellow, Stanford Graduate School of Business, Business / Innovation (Part-time) (2021)
Postdoctoral Research Fellow, Stanford University, Plastic and Reconstructive Surgery (2021)
Ph.D., Yale University, Biomedical Engineering (2016)
M.Phil., Yale University, Engineering and Applied Science (2013)
M.S., Yale University, Engineering and Applied Science (2013)
M.Eng., Cornell University, Biomedical Engineering (2011)
B.Tech, Anna University, Industrial Biotechnology (2010)
Emily R. Kinser, Themis Kyriakides, Jagannath Padmanabhan. "United States Patent US10213144B2 Nanopatterned biosensor electrode for enhanced sensor signal and sensitivity", International Business Machines Corporation, Yale University, Feb 26, 2019
Allometric Tissue-Scale Forces Activate Mechanoresponsive Immune Cells To Drive Pathological Foreign Body Response To Biomedical Implants
WILEY. 2022: A19-A20
View details for Web of Science ID 000763583000048
IQGAP1-mediated mechanical signaling promotes the foreign body response to biomedical implants.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2022; 36 (2): e22007
The aim of this study was to further elucidate the molecular mechanisms that mediate pathologic foreign body response (FBR) to biomedical implants. The longevity of biomedical implants is limited by the FBR, which leads to implant failure and patient morbidity. Since the specific molecular mechanisms underlying fibrotic responses to biomedical implants have yet to be fully described, there are currently no targeted approaches to reduce pathologic FBR. We utilized proteomics analysis of human FBR samples to identify potential molecular targets for therapeutic inhibition of FBR. We then employed a murine model of FBR to further evaluate the role of this potential target. We performed histological and immunohistochemical analysis on the murine FBR capsule tissue, as well as single-cell RNA sequencing (scRNA-seq) on cells isolated from the capsules. We identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most promising of several targets, serving as a central molecular mediator in human and murine FBR compared to control subcutaneous tissue. IQGAP1-deficient mice displayed a significantly reduced FBR compared to wild-type mice as evidenced by lower levels of collagen deposition and maturity. Our scRNA-seq analysis revealed that decreasing IQGAP1 resulted in diminished transcription of mechanotransduction, inflammation, and fibrosis-related genes, which was confirmed on the protein level with immunofluorescent staining. The deficiency of IQGAP1 significantly attenuates FBR by deactivating downstream mechanotransduction signaling, inflammation, and fibrotic pathways. IQGAP1 may be a promising target for rational therapeutic design to mitigate pathologic FBR around biomedical implants.
View details for DOI 10.1096/fj.202101354
View details for PubMedID 35051300
Disrupting biological sensors of force promotes tissue regeneration in large organisms.
2021; 12 (1): 5256
Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.
View details for DOI 10.1038/s41467-021-25410-z
View details for PubMedID 34489407
In Vivo Models for the Study of Fibrosis.
Advances in wound care
2019; 8 (12): 645-654
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
- In Vivo Models for the Study of Fibrosis ADVANCES IN WOUND CARE 2019
Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation.
The Journal of investigative dermatology
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
Nanopatterned Bulk Metallic Glass Biosensors.
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
Disease models: Method in the madness of fibrosis.
2017; 16 (12): 1176–77
View details for PubMedID 29170546
Regulation of cell-cell fusion by nanotopography.
2016; 6: 33277
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
2015; 7 (3): 355-370
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
2014; 8 (5): 4366-4375
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
Galvanotactic Smart Bandage for Chronic Wound Management and Tissue Regeneration
WILEY. 2022: A36
View details for Web of Science ID 000763583000080
Mechanical Signaling Mediated by IQGAP1 Promotes Pathologic Foreign Body Response
WILEY. 2022: A21
View details for Web of Science ID 000763583000050
Application of No Releasing Gel Increases Fibronectin, TGF-beta 1, and Accelerates Wound Healing in Diabetic Mice
WILEY. 2022: A8
View details for Web of Science ID 000763583000028
Interactions Of Fibroblasts Versus Macrophages In An In Vitro Model Of Scar Formation And Wound Healing
WILEY. 2022: A53-A54
View details for Web of Science ID 000763583000115
Pullulan-Collagen Hydrogel Wound Dressing Promotes Dermal Remodeling and Healing in an Excisional Wound Model
WILEY. 2022: A24
View details for Web of Science ID 000763583000056
Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing
WILEY. 2022: A31-A32
View details for Web of Science ID 000763583000072
Inhibiting Fibroblast Mechanotransduction Modulates Severity of Idiopathic Pulmonary Fibrosis.
Advances in wound care
OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF.INNOVATION: Mechanotransduction pathways have not been thoroughly examined in the context of lung disease and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remain incompletely understood.APPROACH: In this study, we used conditional KO mice to block mechanotransduction by knocking out FAK (Focal Adhesion Kinase) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, qRT-PCR, and Western Blot to evaluate the effects of FAK inhibition (FAKI) on modulating fibrotic and inflammatory genes.RESULTS: Our data indicate that deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. FAK inhibition decreases these signals but has less effect on IPF fibroblasts as compared to normal human fibroblasts.CONCLUSION: Administering FAKI at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.
View details for DOI 10.1089/wound.2021.0077
View details for PubMedID 34544267
Mechanical Strain Drives Myeloid Cell Differentiation Toward Pro-Inflammatory Subpopulations.
Advances in wound care
OBJECTIVE: After injury, humans and other mammals heal by forming fibrotic scar tissue with diminished function, and this healing process involves the dynamic interplay between resident cells within the skin and cells recruited from the circulation. Recent studies have provided mounting evidence that external mechanical forces stimulate intracellular signaling pathways to drive fibrotic processes.INNOVATION: While most studies have focused on studying mechanotransduction in fibroblasts, recent data suggest that mechanical stimulation may also shape the behavior of immune cells, referred to as "mechano-immunomodulation". However, the effect of mechanical strain on myeloid cell recruitment and differentiation remains poorly understood and has never been investigated at the single cell level.APPROACH: In this study, we utilized a three-dimensional (3D) in vitro culture system that permits the precise manipulation of mechanical strain applied to cells. We cultured myeloid cells and used single cell RNA-sequencing to interrogate the effects of strain on myeloid differentiation and transcriptional programming.RESULTS: Our data indicate that myeloid cells are indeed mechanoresponsive, with mechanical stress influencing myeloid differentiation. Mechanical strain also upregulated a cascade of inflammatory chemokines, most notably from the Ccl family.CONCLUSION: Further understanding of how mechanical stress affects myeloid cells in conjunction with other cell types in the complicated, multicellular milieu of wound healing may lead to novel insights and therapies for the treatment of fibrosis.
View details for DOI 10.1089/wound.2021.0036
View details for PubMedID 34278820
Mechanical Activation Of Inflammation At The Implant-tissue Interface Underlies Pathological Foreign Body Response
WILEY. 2021: A9
View details for Web of Science ID 000650720500032
CRISPR/Cas9 Editing Of Autologous Dendritic Cells To Enhance Angiogenesis And Wound Healing
WILEY. 2021: A31-A32
View details for Web of Science ID 000650720500079
Disrupting Mechanotransduction Reduces Scar Formation And Restores Cellular Subpopulations In A Large Animal Model Of Skin Grafting
WILEY. 2021: A12-A13
View details for Web of Science ID 000650720500039
Adipose-derived stromal cells seeded in pullulan-collagen hydrogels improve healing in murine burns.
Tissue engineering. Part A
Burn scars and scar contractures cause significant morbidity for patients. Recently, cell-based therapies have been proposed as an option for improving healing and reducing scarring after burn injury, through their known pro-angiogenic and immunomodulatory paracrine effects. Our lab has developed a pullulan-collagen hydrogel that, when seeded with mesenchymal stem cells (MSCs), improves cell viability and augments their pro-angiogenic capacity in vivo. Concurrently, recent research suggests that prospective isolation of cell subpopulations with desirable transcriptional profiles can be used to further improve cell-based therapies. In this study, we examined whether adipose-derived stem cell-seeded hydrogels could improve wound healing following thermal injury using a murine contact burn model. Partial thickness contact burns were created on the dorsum of mice. On days 5 and 10 following injury, burns were debrided and received either ASC-hydrogel, ASC injection alone, hydrogel alone, or no treatment. On days 10 and 25, burns were harvested for histologic and molecular analysis. This experiment was repeated using CD26+/CD55+ FACS-enriched ASCs to further evaluate the regenerative potential of ASCs in wound healing. ASC-hydrogel-treated burns demonstrated accelerated time to re-epithelialization, greater vascularity, and increased expression of the pro-angiogenic genes MCP-1, VEGF, and SDF-1 at both the mRNA and protein level. Expression of the pro-fibrotic gene Timp1 and pro-inflammatory gene Tnfa were down-regulated in ASC-hydrogel treated burns. ASC-hydrogel treated burns exhibited reduced scar area compared to hydrogel-treated and control wounds, with equivalent scar density. CD26+/CD55+ ASC-hydrogel treatment resulted in accelerated healing, increased dermal appendage count, and improved scar quality with a more reticular collagen pattern. Here we find that ASC-hydrogel therapy is effective for treating burns, with demonstrated pro-angiogenic, fibro-modulatory and immunomodulatory effects. Enrichment for CD26+/CD55+ ASCs has additive benefits for tissue architecture and collagen remodeling post-burn injury. Research is ongoing to further facilitate clinical translation of this promising therapeutic approach.
View details for DOI 10.1089/ten.TEA.2020.0320
View details for PubMedID 33789446
Epidermal-Derived Hedgehog Signaling Drives Mesenchymal Proliferation during Digit Tip Regeneration.
Journal of clinical medicine
2021; 10 (18)
Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.
View details for DOI 10.3390/jcm10184261
View details for PubMedID 34575372
Hydrogel Scaffolds to Deliver Cell Therapies for Wound Healing.
Frontiers in bioengineering and biotechnology
2021; 9: 660145
Cutaneous wounds are a growing global health burden as a result of an aging population coupled with increasing incidence of diabetes, obesity, and cancer. Cell-based approaches have been used to treat wounds due to their secretory, immunomodulatory, and regenerative effects, and recent studies have highlighted that delivery of stem cells may provide the most benefits. Delivering these cells to wounds with direct injection has been associated with low viability, transient retention, and overall poor efficacy. The use of bioactive scaffolds provides a promising method to improve cell therapy delivery. Specifically, hydrogels provide a physiologic microenvironment for transplanted cells, including mechanical support and protection from native immune cells, and cell-hydrogel interactions may be tailored based on specific tissue properties. In this review, we describe the current and future directions of various cell therapies and usage of hydrogels to deliver these cells for wound healing applications.
View details for DOI 10.3389/fbioe.2021.660145
View details for PubMedID 34012956
First reported case of Wohlfahrtiimonas chitiniclastica infection in California JAAD Case Reports
Journal of the American Academy of Dermatology Case Reports
View details for DOI 10.1016/j.jdcr.2021.09.022
- Xenogeneic skin transplantation promotes angiogenesis and tissue regeneration through activated Trem2+ macrophages. Science advances 2021; 7 (49): eabi4528
Inhibiting mechanotransduction signaling changes fibroblast heterogeneity and promotes tissue regeneration in healing wounds
WILEY. 2020: S12–S13
View details for Web of Science ID 000548418300023
Flexible smart bandage for wireless wound healing
WILEY. 2020: S24
View details for Web of Science ID 000548418300050
Digit tip regeneration relies on germ layer restricted Wnt and Hedgehog signaling
WILEY. 2020: S5
View details for Web of Science ID 000548418300006
Inhibiting mechanotransduction signaling changes fibroblast heterogeneity and promotes tissue regeneration in healing wounds
WILEY. 2020: S13–S14
View details for Web of Science ID 000548418300026
Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model.
International wound journal
Cryopreserved human skin allografts (CHSAs) are used for the coverage of major burns when donor sites for autografts are insufficiently available and have clinically shown beneficial effects on chronic non-healing wounds. However, the biologic mechanisms behind the regenerative properties of CHSA remain elusive. Furthermore, the impact of cryopreservation on the immunogenicity of CHSA has not been thoroughly investigated and raised concerns with regard to their clinical application. To investigate the importance and fate of living cells, we compared cryopreserved CHSA with human acellular dermal matrix (ADM) grafts in which living cells had been removed by chemical processing. Both grafts were subcutaneously implanted into C57BL/6 mice and explanted after 1, 3, 7, and 28 days (n = 5 per group). A sham surgery where no graft was implanted served as a control. Transmission electron microscopy (TEM) and flow cytometry were used to characterise the ultrastructure and cells within CHSA before implantation. Immunofluorescent staining of tissue sections was used to determine the immune reaction against the implanted grafts, the rate of apoptotic cells, and vascularisation as well as collagen content of the overlaying murine dermis. Digital quantification of collagen fibre alignment on tissue sections was used to quantify the degree of fibrosis within the murine dermis. A substantial population of live human cells with intact organelles was identified in CHSA prior to implantation. Subcutaneous pockets with implanted xenografts or ADMs healed without clinically apparent rejection and with a similar cellular immune response. CHSA implantation largely preserved the cellularity of the overlying murine dermis, whereas ADM was associated with a significantly higher rate of cellular apoptosis, identified by cleaved caspase-3 staining, and a stronger dendritic cell infiltration of the murine dermis. CHSA was found to induce a local angiogenic response, leading to significantly more vascularisation of the murine dermis compared with ADM and sham surgery on day 7. By day 28, aggregate collagen-1 content within the murine dermis was greater following CHSA implantation compared with ADM. Collagen fibre alignment of the murine dermis, correlating with the degree of fibrosis, was significantly greater in the ADM group, whereas CHSA maintained the characteristic basket weave pattern of the native murine dermis. Our data indicate that CHSAs promote angiogenesis and collagen-1 production without eliciting a significant fibrotic response in a xenograft model. These findings may provide insight into the beneficial effects clinically observed after treatment of chronic wounds and burns with CHSA.
View details for DOI 10.1111/iwj.13349
View details for PubMedID 32227459
- Age-associated intracellular superoxide dismutase deficiency potentiates dermal fibroblast dysfunction during wound healing EXPERIMENTAL DERMATOLOGY 2019; 28 (4): 485–92
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
2019; 144 (1): 58e–67e
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
WILEY. 2018: A13
View details for Web of Science ID 000451464000057
Nanopatterned bulk metallic glass-based biomaterials modulate macrophage polarization.
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
WILEY. 2018: A33
View details for Web of Science ID 000430308600139
Age-Associated Intracellular Superoxide Dismutase Deficiency Potentiates Dermal Fibroblast Dysfunction During Wound Healing.
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
2017; 18 (9)
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.
2016; 6: 26950
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 2013; 86 (4): 525-?
The effects of extracellular matrix proteins on neutrophil-endothelial interaction--a roadway to multiple therapeutic opportunities.
Yale journal of biology and medicine
2012; 85 (2): 167-185
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