Multiscale multifactorial approaches for engineering tendon substitutes

The physiology of tendons and the continuous strains experienced daily make tendons very prone to injury. Excessive and prolonged loading forces and aging also contribute to the onset and progression of tendon injuries, and conventional treatments have limited efficacy in restoring tendon biomechanics. Tissue engineering and regenerative medicine (TERM) approaches hold the promise to provide therapeutic solutions for injured or damaged tendons despite the challenging cues of tendon niche and the lack of tendon-specific factors to guide cellular responses and tackle regeneration. The roots of engineering tendon substitutes lay in multifactorial approaches from adequate stem cells sources and environmental stimuli to the construction of multiscale 3D scaffolding systems. To achieve such advanced tendon substitutes, incremental strategies have been pursued to more closely recreate the native tendon requirements providing structural as well as physical and chemical cues combined with biochemical and mechanical stimuli to instruct cell behavior in 3D architectures, pursuing mechanically competent constructs with adequate maturation before implantation.Authors acknowledge the project “Accelerating tissue engineering and personalized medicine discoveries by the integration of key enabling nanotechnologies, marinederived biomaterials and stem cells,” supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Authors acknowledge the H2020 Achilles Twinning Project No. 810850, and also the European Research Council CoG MagTendon No. 772817, and the FCT Project MagTT PTDC/CTM-CTM/ 29930/2017 (POCI-01-0145-FEDER-29930

Biodistribution of gold nanoparticles in BBN-induced muscle-invasive bladder cancer in mice

Henry M Smilowitz,1 Lauren J Tarmu,1–3 Mary Melinda Sanders,4 John A Taylor III,5 Dharamainder Choudhary,6 Crystal Xue,7 Nathaniel A Dyment,8 Dan Sasso,1 Xiaomeng Deng,9 James F Hainfeld10 1Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, 2Department of Human Behavior, College of Southern Nevada, North Las Vegas, 3Department of Anthropology, University of Nevada, Las Vegas, NV, 4Department of Anatomic Pathology, University of Connecticut Health Center, Farmington, CT, 5Department of Urology, University of Kansas Medical Center, Kansas City, KS, 6Department of Surgery, University of Connecticut Health Center, Farmington, CT, 7George Washington University School of Medicine, Washington, DC, 8Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA, 9David Geffen School of Medicine at UCLA, Los Angeles, CA, 10Nanoprobes, Inc, Yaphank, NY, USA Abstract: Bladder-sparing options are being developed for muscle-invasive bladder cancer in place of radical cystectomy, including the combination of chemotherapy and radiation therapy. We reasoned that improving the radiotherapy component of chemoradiation could improve the control of locally advanced disease. Previously, we showed that gold nanoparticles (AuNPs) are potent enhancers of radiation therapy. We hypothesized that if AuNPs were to preferentially localize to bladder tumors, they may be used to enhance the radiation component of muscle-invasive bladder tumor therapy. Mice were treated with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 17, 20, and 22 weeks – long enough to induce muscle-invasive tumors. Mice were then anesthetized and injected intravenously with 1.9 nm AuNPs of which most were rapidly cleared from the blood and excreted after a 30–50 minute residence time in the bladder. We found AuNPs distributed throughout the bladder wall, but most of the AuNPs were associated with the stroma surrounding the tumor cells or extracellular keratin produced by the tumor cells. There were relatively few AuNPs in the tumor cells themselves. The AuNPs therefore localized to tumor-associated stroma and this tumor specificity might be useful for specific X-ray dose enhancement therapy of muscle-invasive bladder carcinomas. Keywords: N-butyl-N-(4-hydroxybutyl)nitrosamine, BBN, muscle-invasive bladder cancer, gold nanoparticles, mouse mode