Chandan K Sen

Indiana University School of Medicine | IUSOM · Department of Surgery

ABSTRACT In the United States, chronic wounds affect 6.5 million patients. An estimated excess of US$25 billion is spent annually on treatment of chronic wounds and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. The annual wound care product...

Although cellular therapies represent a promising strategy for a number of conditions, current approaches face major translational hurdles, including limited cell sources and the need for cumbersome pre-processing steps (for example, isolation, induced pluripotency). In vivo cell reprogramming has the potential to enable more-effective cell-based t...

Objective: This study was designed to employ electroceutical principles, as an alternative to pharmacological intervention, to manage wound biofilm infection. Mechanism of action of a United States Food and Drug Administration-cleared wireless electroceutical dressing (WED) was tested in an established porcine chronic wound polymicrobial biofilm i...

Inflammation, following injury, induces cellular plasticity as an inherent component of physiological tissue repair. The dominant fate of wound macrophages is unclear and debated. Here we show that two-thirds of all granulation tissue fibroblasts, otherwise known to be of mesenchymal origin, are derived from myeloid cells which are likely to be wou...

The purpose of this study was to characterize the effects of tocotrienol form of vitamin E (TCT) on platelet function in patients with stroke or transient ischemic attack (TIA). A double blind, randomized, single center phase II clinical trial was conducted comparing placebo (PBO) and 400 and 800 mg TCT daily for a year in 150 patients with a senti...

Introduction Between 5% and 20% of all combat-related casualties are attributed to burn wounds. A decrease in the mortality rate of burns by about 36% can be achieved with early treatment, but this is contingent upon accurate characterization of the burn. Precise burn injury classification is recognized as a crucial aspect of the medical artificial...

Sweating and heat buildup at the skin-liner interface is a major challenge for persons with limb loss. Liners made of heat-non-conducting materials may cause sweating of the residual limb and may result in liners slipping off the skin surface especially on a warm day or during high activity, causing skin breakdown and affecting limb health. To addr...

Chronic wounds like diabetic foot ulcers (DFU) can result in significant medical issues like limb amputation, infection, sepsis, and even death. In those with DFU, 65% recur within 5 years after wound closure. Infection is a common complication of DFU. Biofilm infection of wound may result in a state where the wound appears closed (visually, standa...

Unlabelled: Hydrolyzed collagen-based matrices are widely used as wound care dressings. Information on the mechanism of action of such dressings is scanty. Objective: The objective of this study was to test the effect of a specific hydrolyzed collagen powder (HCP) which is extensively used for wound care management in the United States. Approac...

Fetal skin achieves scarless wound repair. Dermal fibroblasts play a central role in extracellular matrix deposition and scarring outcomes. Both fetal and gingival wound repair share minimal scarring outcomes. We tested the hypothesis that compared to adult skin fibroblasts, human fetal skin fibroblast diversity is unique and partly overlaps with g...

This work sought to develop a robust and clinically relevant swine model of critical limb ischemia (CLI) involving the onset of ischemic muscle necrosis. CLI carries about 25–40% risk of major amputation with 20% annual mortality. Currently, there is no specific treatment that targets the ischemic myopathy characteristic of CLI. Current swine model...

Injury-induced transient downregulation of endothelial miR-200b is required to jump-start wound angiogenesis, but the underlying mechanisms remain unclear. Single cell RNA sequencing was performed on ~15000 human endothelial cells under high (mimic treated) miR-200b conditions. Unsupervised clustering using CellRanger identified five cell clusters,...

Our recent work reported on the identification of the vasculogenic fibroblast (VF) that is capable of generating new blood vessels during tissue repair (Pal et al. Nat Com, 2023). While these cells are physiologic and injury-inducible, the generation of VF is blunted under conditions of diabetes. Such barrier may be overcome by the inhibition of fi...

Our previous work (PMID: 35192691) has identified that genetically silenced phospholipase Cγ2 (PLCγ2) hinders VEGF therapy of the diabetic ischemic limb. Hyperglycemia caused hypermethylation of endothelial specific gene promoter. Given that epigenetic changes are reversible, this work tests the significance of gene-targeted therapeutic DNA demethy...

Human death marks the end of organismal life under conditions such that the components of the human body continue to be alive. Such postmortem cellular survival depends on the nature (Hardy scale of slow-fast death) of human death. Slow and expected death typically results from terminal illnesses and includes a prolonged terminal phase of life. As...

Sweating and heat buildup at the skin-liner interface is a major challenge for amputees. Liners made of heat-non-conducting materials cause sweating of the residual limb and may result in liners slipping off the skin surface, causing skin breakdown and affecting limb health. To address this, we evaluated the efficacy of the vented liner-socket syst...

Repair of epithelial defect is complicated by infection and related metabolites. Pyocyanin is one such metabolite which is secreted during Pseudomonas aeruginosa infection. Keratinocyte migration is required for the closure of skin epithelial defects. The current work sought to understand pyocyanin-keratinocyte interaction and its significance in t...

Background/Objective: 8.2 million US patients are affected with chronic wounds, with costs ranging from $28.1-$96.8 billion. Increasing healthcare costs, population age, and chronic condition incidences pose immense threats to the healthcare system and patients struck with the burden of chronic wounds. A sociogenomic approach to investigating mecha...

Introduction Patients with sepsis exhibit significant, persistent immunologic dysfunction. Evidence supports the hypothesis that epigenetic regulation of key cytokines plays an important role in this dysfunction. In sepsis, circulating microvesicles (MVs) containing elevated levels of DNA methyltransferase (DNMT) mRNA cause gene methylation and sil...

Tissue injury to skin diminishes miR-200b in dermal fibroblasts. Fibroblasts are widely reported to directly reprogram into endothelial-like cells and we hypothesized that miR-200b inhibition may cause such changes. We transfected human dermal fibroblasts with anti-miR-200b oligonucleotide, then using single cell RNA sequencing, identified emergenc...

Objective: Despite advances in the use of topical and parenteral antimicrobial therapy and the practice of early tangential burn-wound excision to manage bacterial load, 60% of the mortality from burns is attributed to bacterial biofilm infection. A low electric field (~1V) generated by the novel FDA-cleared wireless electroceutical dressing (WED)...

Electroceutical Suture Microstructured fiber, reported in article number 2201854 by Louis A. van der Elst, Merve Gokce, and co‐workers, autonomously induces an electric field to a wound, suppressing the proliferation of multiresistant bacteria. The fiber, weaved into gauze, spooled into a sponge, or used as a surgical suture, provides a non‐drug, e...

Background/Objective: Chronic wound (CW) represents a major burden on the individual patients who are typically challenged with many underlying health related complications. Stress is now recognized as a universal premorbid factor associated with many risk factors of various chronic diseases. This study utilized socio-demographic data of CW patient...

Background: Lymphedema is limb swelling caused by lymphatic dysfunction. It occurs in 30% of patients that undergo axillary lymph node dissection in the treatment of breast cancer. It can cause pain, impair function, and decrease quality of life. Lymphedema is treated with compression, excisional procedures and microsurgical physiologic procedures....

Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotyp...

α-Tocotrienol (TCT) form of natural vitamin E is more potent than better known α-tocopherol against stroke. Angiographic studies of canine stroke revealed beneficial cerebrovascular effects of TCT. This work sought to understand the molecular basis of such effect. In mice, TCT supplementation improved perfusion at the stroke-affected site by induci...

Antibiotic‐resistant infections caused by bacterial pathogens pose a serious threat to public health, hampering wound healing and causing significant morbidities worldwide. A biomedical fiber‐device that functions as a drugless antiseptic is introduced as a solution to this problem. Through stitching, piercing, or topical application to the wound,...

Type 2 diabetes mellitus (T2DM) causes peripheral vascular disease because of which several blood-borne factors, including vital nutrients fail to reach the affected tissue. Tissue epigenome is sensitive to chronic hyperglycemia and is known to cause pathogenesis of micro- and macrovascular complications. These vascular complications of T2DM may pe...

Extracellular vesicles (EV) are nanovesicles released by all eukaryotic cells. This work reports the first nanoscale fluorescent visualization of tumor-originating vesicles bearing an angiogenic miR-126 cargo. In a validated experimental model of lethal murine vascular neoplasm, tumor-originating EV delivered its miR-126 cargo to tumor-associated m...

Approximately 1.25 million people in the United States are treated each year for burn injuries. Precise burn injury classification is an important aspect of the medical AI field. In this work, we propose an explainable human-in-the-loop framework for improving burn ultrasound classification models. Our framework leverages an explanation system base...

This work rests on our non-viral tissue nanotransfection (TNT) platform to deliver MyoD (TNT MyoD ) to injured tissue in vivo. TNT MyoD was performed on skin and successfully induced expression of myogenic factors. TNT MyoD was then used as a therapy 7 days following volumetric muscle loss (VML) of rat tibialis anterior and rescued muscle function....

Fetal cutaneous wound closure and repair differ from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure), though not in adult epidermis, but...

Multidrug resistant persister bacterial biofilm infections are difficult to treat. GelATA is a novel wound care dressing that disrupts polymicrobial persister biofilm and promotes functional wound closure in vivo

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Foot Consortium (DFC) was established in September 2018 by the NIDDK to build an organization to facilitate the highest quality of clinical research on diabetic foot ulcers (DFUs) that will answer clinically significant questions to improve DFU healing and prevent...

Fetal cutaneous wound closure and repair differs from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure) though not in adult epidermis but, i...

Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic r...

Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids. In the blood of LAL deficient (lal-/-) mice, increased CD11c+ cells were accompanied by up-regulated PD-L1 expression. Single cell RNA sequencing of lal-/- CD11c+ cells identified two distinctive clusters with a major metabolic shift towards glucose utilization...

Significance: Diabetic peripheral neuropathy (DPN) associated with a diabetic foot ulcer (DFU) is likely to be complicated with critical factors such as biofilm infection and compromised skin barrier function of the diabetic skin. Repaired skin with a history of biofilm infection is known to be compromised in barrier function. Loss of barrier func...

An extreme chronic wound tissue microenvironment causes epigenetic gene silencing. Unbiased whole-genome methylome was studied in the wound-edge (WE) tissue of chronic wound patients. A total of 4689 differentially methylated regions (DMRs) were identified in chronic WE compared to unwounded (UW) human skin. Hypermethylation was more frequently obs...

Unresolved inflammation compromises diabetic wound healing. Recently, we reported that inadequate RNA packaging in murine wound-edge keratinocyte-originated exosomes (Exoκ) leads to persistent inflammation [Zhou, X. ACS Nano 2020, 14(10), 12732-12748]. Herein, we use charge detection mass spectrometry (CDMS) to analyze intact Exoκ isolated from a 5...

Chronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa...

Introduction: Survivors of sepsis exhibit persistent immunosuppression. Epigenetic events may be responsible for some of these immunosuppressive changes. During sepsis circulating exosomes contain large quantities of DNA methyltransferase (DNMT) mRNAs. We hypothesized that exosomes directly transfer DNMT mRNAs to recipient monocytes with resultant...

Objective: To conduct a systematic review and meta-analysis of recently published randomized controlled trials (RCTs) that employed the use of topical oxygen therapy as an adjunct therapy in the treatment of Wagner 1 and 2 diabetic foot ulcers Approach: Following a literature search of eligible studies from 2010 onward, 4 RCTs were included. Studi...

Mol. Nutr. Food Res. 2022, 66, 202100852 DOI: 10.1002/mnfr.202100852 Fermented Papaya Preparation (FPP) treatment increases macrophage intracellular myo‐inositol. FPP and myo‐inositol bolsters human macrophage ROS production and phagocytosis. Myo‐inositol transporters SMIT1and HMIT are involved in FPP and myo‐inositol induced macrophage functions....

Introduction Burn injuries are common to all military conflicts. In combat, eradication and prevention of burn wound infection is complicated by high rates of soft tissue contamination and prolonged delays to definitive stateside care. Furthermore, in the battlefield setting the salvage rate for infected burned extremities is low. Therefore, a simp...

Therapeutic VEGF replenishment has met with limited success for the management of critical limb threatening ischemia (CLTI). To improve outcomes of VEGF therapy we applied single-cell RNA sequencing technology to study the endothelial cells of the human diabetic skin. Single-cell suspensions were generated from the human skin followed by cDNA prepa...

Each cell in the body contains an intricate regulation for the expression of its relevant DNA. While every cell in a multicellular organism contains identical DNA, each tissue-specific cell expresses a different set of active genes. This organizational property exists in a paradigm that is largely controlled by forces external to the DNA sequence v...

Scope: Reactive oxygen species production by innate immune cells plays a central role in host defense against invading pathogens at wound-site. A weakened hos-defense results in persistent infection leading to wound chronicity. Fermented Papaya Preparation (FPP), a complex sugar matrix, bolstered respiratory burst activity and improved wound heali...

Hollow needle array-based tissue nanotransfection (TNT) presents an in vivo transfection approach that directly translocate exogeneous genes to target tissues by using electric pulses. In this work, the gene delivery process of TNT was simulated and experimentally validated. We adopted the asymptotic method and cell-array-based model to investigate...

Objective To incorporate chronic vascular adaptations into a mathematical model of the rat hindlimb to simulate flow restoration following total occlusion of the femoral artery. Methods A vascular wall mechanics model is used to simulate acute and chronic vascular adaptations in the collateral arteries and collateral-dependent arterioles of the ra...

Coronavirus with intact infectivity attached to PPE surfaces pose significant threat to the spread of COVID-19. We tested the hypothesis that an electroceutical fabric, generating weak potential difference of 0.5 V, disrupts the infectivity of coronavirus upon contact by destabilizing the electrokinetic properties of the virion. Porcine respiratory...

Background Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged st...

Tissue nanotransfection (TNT) is an electromotive gene transfer technology that was developed to achieve tissue reprogramming in vivo. This protocol describes how to fabricate the required hardware, commonly referred to as a TNT chip, and use it for in vivo TNT. Silicon hollow-needle arrays for TNT applications are fabricated in a standardized and...

Significance: Lymphedema is chronic limb swelling from lymphatic dysfunction. The condition affects up to 250 million people worldwide. In breast cancer patients, lymphedema occurs in 30% who undergo axillary lymph node dissection (ALND). Recent Advances: Immediate lymphatic reconstruction (ILR), also termed Lymphatic Microsurgical Preventing Heal...

Objective: This work addressing complexities in wound infection, seeks to test the reliance of bacterial pathogen Pseudomonas aeruginosa (PA) on host skin lipids to form biofilm with pathological consequences. Background: PA biofilm causes wound chronicity. Both CDC as well as NIH recognizes biofilm infection as a threat leading to wound chronic...

Impaired re-epithelialization characterized by hyperkeratotic non-migratory wound epithelium is a hallmark of non-healing diabetic wounds. In chronic wounds, copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte activator. This work sought to understand the signal transduction pathway responsible for...

Wireless electroceutical dressing (WED) fabric kills bacteria and disrupts bacterial biofilm. This work tested, comparing with standard of care topical antibiotic ketoconazole, whether the weak electric field generated by WED is effective to manage infection caused by ketoconazole-resistant yeast Candida albicans. WED inhibited Candida albicans bio...

Learning objectives: After studying this article, the participant should be able to: 1. Understand the basics of biofilm infection and be able to distinguish between planktonic and biofilm modes of growth. 2. Have a working knowledge of conventional and emerging antibiofilm therapies and their modes of action as they pertain to wound care. 3. Unde...

Purpose: Breast Implant Illness (BII) is patient-described constellation of symptoms that are believed to be related to their breast implant. The symptoms described include fibromyalgia, chronic fatigue and a host of other symptoms that are often associated with autoimmune illnesses. In this work, we report that bacterial biofilm associated with br...

Iterative cycles of epithelial‒mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are responsible for epithelial plasticity necessary to achieve functional wound closure. Restoration of the barrier function of the repaired skin is a hallmark of functional wound closure. Both EMT and MET are subject to control by glycemic st...

Normal wound healing progresses through inflammatory, proliferative and remodeling phases in response to tissue injury. Collagen, a key component of the extracellular matrix, plays critical roles in the regulation of the phases of wound healing either in its native, fibrillar conformation or as soluble components in the wound milieu. Impairments in...

In WOUND REPAIR AND REGENERATION (Vol. 29, No. 3, pp. A47-A48). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.

The global prevalence of antibiotic-resistant bacteria has increased the risk of dangerous infections, requiring rapid diagnosis and treatment. The standard method for diagnosis of bacterial infections remains dependent on slow culture-based methods, carried out in central laboratories, not easily extensible to rapid identification of organisms, an...

Significance: Chronic wounds impact the quality of life of nearly 2.5% of the total population of the United States and the management of wounds has a significant economic impact on healthcare. Given the aging population, the continued threat of diabetes and obesity worldwide, and the persistent problem of infection, it is expected that chronic wo...

Ischemic stroke causes vascular and neuronal tissue deficiencies that could lead to substantial functional impairment and/or death. Although progenitor-based vasculogenic cell therapies have shown promise as a potential rescue strategy following ischemic stroke, current approaches face major hurdles. Here, we used fibroblasts nanotransfected with E...