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Chetna Dhand,1,2,* Yamini Balakrishnan,3,* Seow Theng Ong,4,* Neeraj Dwivedi,5 Jayarama R Venugopal,6 Sriram Harini,1 Chak Ming Leung,3 Kenny Zhi Wei Low,7 Xian Jun Loh,7 Roger W Beuerman,1,2 Seeram Ramakrishna,8 Navin Kumar Verma,1,4 Rajamani Lakshminarayanan1,2 1Anti-Infectives Research Group, Singapore Eye Research Institute, The Academia, Discovery Tower, Singapore; 2Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore; 3Department of Bioengineering, National University of Singapore, Singapore; 4Dermatology and Skin Biology, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 5Department of Electrical and Computer Engineering, National University of Singapore, Singapore; 6Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Gambang, Malaysia; 7Department of Mechanical Engineering, Faculty of Engineering, Center for Nanofibers and Nanotechnology, National University of Singapore, Singapore; 8Soft Materials Department, Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research, Singapore *These authors contributed equally to this work Introduction: In search for cross-linkers with multifunctional characteristics, the present work investigated the utility of quaternary ammonium organosilane (QOS) as a potential cross-linker for electrospun collagen nanofibers. We hypothesized that the quaternary ammonium ions improve the electrospinnability by reducing the surface tension and confer antimicrobial properties, while the formation of siloxane after alkaline hydrolysis could cross-link collagen and stimulate cell proliferation. Materials and methods: QOS collagen nanofibers were electrospun by incorporating various concentrations of QOS (0.1%–10% w/w) and were cross-linked in situ after exposure to ammonium carbonate. The QOS cross-linked scaffolds were characterized and their biological properties were evaluated in terms of their biocompatibility, cellular adhesion and metabolic activity for primary human dermal fibroblasts and human fetal osteoblasts. Results and discussion: The study revealed that 1) QOS cross-linking increased the flexibility of otherwise rigid collagen nanofibers and improved the thermal stability; 2) QOS cross-linked mats displayed potent antibacterial activity and 3) the biocompatibility of the composite mats depended on the amount of QOS present in dope solution – at low QOS concentrations (0.1% w/w), the mats promoted mammalian cell proliferation and growth, whereas at higher QOS concentrations, cytotoxic effect was observed. Conclusion: This study demonstrates that QOS cross-linked mats possess anti-infective properties and confer niches for cellular growth and proliferation, thus offering a useful approach, which is important for hard and soft tissue engineering and regenerative medicine. Keywords: anti-infective wound dressing, cyto-compatible nanofibre, electrospinning, cost-effective cross-linker, tissue regeneration, antimicrobial

Rajamani Lakshminarayanan,1,2 Radhakrishnan Sridhar,3,4 Xian Jun Loh,5 Muruganantham Nandhakumar,1 Veluchamy Amutha Barathi,1,6 Madhaiyan Kalaipriya,3,4 Jia Lin Kwan,1 Shou Ping Liu,1,2 Roger Wilmer Beuerman,1,2 Seeram Ramakrishna3,4,7 1Singapore Eye Research Institute, 2Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, 3Department of Mechanical Engineering, National University of Singapore, 4Center for Nanofibers and Nanotechnology, National University of Singapore, 5Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), 3 Research Link, Singapore, 6Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 7NUS Nanoscience and Nanotechnology Initiative, Singapore Abstract: Topical application of antifungals does not have predictable or well-controlled release characteristics and requires reapplication to achieve therapeutic local concentration in a reasonable time period. In this article, the efficacy of five different US Food and Drug Administration-approved antifungal-loaded (amphotericin B, natamycin, terbinafine, fluconazole, and itraconazole) electrospun gelatin fiber mats were compared. Morphological studies show that incorporation of polyenes resulted in a two-fold increase in fiber diameter and the mats inhibit the growth of yeasts and filamentous fungal pathogens. Terbinafine-loaded mats were effective against three filamentous fungal species. Among the two azole antifungals compared, the itraconazole-loaded mat was potent against Aspergillus strains. However, activity loss was observed for fluconazole-loaded mats against all of the test organisms. The polyene-loaded mats displayed rapid candidacidal activities as well. Biophysical and rheological measurements indicate strong interactions between polyene antifungals and gelatin matrix. As a result, the polyenes stabilized the triple helical conformation of gelatin and the presence of gelatin decreased the hemolytic activity of polyenes. The polyene-loaded fiber mats were noncytotoxic to primary human corneal and sclera fibroblasts. The reduction of toxicity with complete retention of activity of the polyene antifungal-loaded gelatin fiber mats can provide new opportunities in the management of superficial skin infections. Keywords: fungal infections, electrospinning, antifungals, controlled release, drug–matrix interactions