Rajeshwar Nitiyanandan’s research while affiliated with Arizona State University and other places

Surgical-site infections occur in 2-5% patients undergoing surgery in the US alone, impacting 300,000-500,000 lives each year, and presenting up to 11 times greater risk of death compared to patients...

Copper ions play an important role in several physiological processes, including angiogenesis, growth factor induction and extracellular matrix remodeling, that modulate wound healing and tissue repair. In this work, copper-loaded alginate fibers were generated and used as surgical sutures for repair of incisional wounds in live mice. Approximately 95% of initially loaded copper ions were released from the sutures within the first 24 hours following an initial burst release. This localized delivery of copper at the incision site resulted in significantly higher recovery in tissue biomechanical strengths compared to conventional nylon and calcium-alginate sutures at early times following surgery. Irradiation of copper-alginate sutures with near infrared light resulted in a robust photothermal response and led to efficacies similar to those seen with non-irradiated sutures. Histopathology and immunohistological analyses indicated significantly reduced epithelial gap and higher number of CD31+ cells, which is indicative of increased angiogenesis around the incision site. Delivery of copper ions did not result in toxicity under the conditions employed. Our findings demonstrate that delivery of ionic copper from sutures resulted in efficacious approximation and healing of incisional wounds, and copper-eluting fibers may have translational potential for accelerating repair in surgical and trauma wounds.

Sutures are typically the primary means of soft tissue repair in surgery and trauma. Despite their widespread use, sutures do not result in immediate sealing of approximated tissues, which can result in bacterial infection and leakage. Nonabsorbable sutures and staples can be traumatic to tissue, and the trauma can be exacerbated by their subsequent removal. Use of cyanoacrylate glues is limited because of their brittleness and toxicity. In this work, laser‐activated tissue‐integrating sutures (LATIS) are described as novel nanodevices for soft tissue approximation and repair. Incorporation of gold nanorods within fibers generated from collagen result in LATIS fibers which demonstrate robust photothermal responses following irradiation with near infrared laser light. Compared to conventional sutures, LATIS fibers result in greater biomechanical recovery of incised skin in a mouse model of skin closure after spine surgeries. Histopathology analyses show improved repair of the epidermal gap in skin, which indicate faster tissue recovery using LATIS. The studies indicate that LATIS‐facilitated approximation of skin in live mice synergizes the benefits of conventional suturing and laser‐activated tissue integration, resulting in new approaches for faster sealing, tissue repair, and healing.

Effective transgene expression in mammalian cells relies on successful delivery, cytoplasmic trafficking, and nuclear translocation of the delivered vector, but delivery is impeded by several formidable physicochemical barriers on the surface of and within the target cell. Although methods to overcome cellular exclusion and endosomal entrapment have been studied extensively, strategies to overcome inefficient nuclear entry and subsequent intranuclear barriers to effective transient gene expression have only been sparsely explored. In particular, the role of nuclear packaging of DNA with histone proteins, which governs endogenous gene expression, has not been extensively elucidated in the case of exogenously delivered plasmids. In this work, a parallel screen of small molecule inhibitors of chromatin-modifying enzymes resulted in the identification of class I/II HDACs, sirtuins, LSD1, HATs, and the methyltransferases EZH2 and MLL as targets whose inhibition led to the enhancement of transgene expression following polymer-mediated delivery of plasmid DNA. Quantitative PCR studies revealed that HDAC inhibition enhances the amount of plasmid DNA delivered to the nucleus in UMUC3 human bladder cancer cells. Native chromatin immunoprecipitation (N-ChIP)-qPCR experiments in CHO-K1 cells indicated that plasmids indeed interact with intracellular core Histone H3, and inhibitors of HDAC and LSD1 proteins are able to modulate this interaction. Pair-wise treatments of effective inhibitors led to synergistic enhancement of transgene expression to varying extents in both cell types. Our results demonstrate that the ability to modulate enzymes that play a role in epigenetic processes can enhance the efficacy of non-viral gene delivery, resulting in significant implications for gene therapy and industrial biotechnology.

Exosomes are nanoscale extracellular vesicles (EVs) that are shed from different cells in the body. Exosomes encapsulate several biomolecules including lipids, proteins, and nucleic acids, and can therefore play a key role in cellular communication. These vesicles can be isolated from different body fluids and their small sizes make them attractive in various biomedical applications. Here, we review state-of-the art approaches in exosome isolation and purification, and describe their potential use in cancer vaccines, drug delivery, and diagnostics. This article is protected by copyright. All rights reserved.

Targeted delivery of anticancer therapeutics can potentially overcome limitations of poor drug bioavailability, drug resistance, and off-target side-effects that are associated with current chemotherapeutic regimens. Folate receptors are overexpressed on several types of cancer cells including, ovarian, non-small cell lung, triple-negative breast and bladder cancers, and are therefore attractive for the targeted delivery of small-molecule or nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid-conjugated, aminoglycoside-derived polymers for targeted delivery of transgenes to triple-negative breast cancer and bladder cancer cells. Transgene expression was significantly higher with folic acid-conjugated paramomycin- and neomycin-derived polymers compared to lipofectamine, and folate-targeted polymers demonstrated minimal cytotoxicty by themselves. Competitive inhibition using free folic acid significantly reduced transgene expression efficacy of folate-targeted polymers compared to parental polymers, suggesting a role for folate receptor-mediated uptake. Folic-acid targeted polymers that displayed high efficacies of transgene expression were employed to deliver a plasmid that expresses the TRAIL (Tumor Necrosis Factor-alpha Related Apoptosis-Inducing Ligand) protein, in order to induce death in cancer cells. Taken together, these results indicate that folic acid-conjugated, aminoglycoside-derived polymers are promising materials for targeted delivery of nucleic acids to cancer cells that overexpress the folate receptor. This article is protected by copyright. All rights reserved.