Micro/Nano-Structured implants for controlled Drug/protein delivery in chemo/anti-angiogenic therapy of malignant glioma

Ph.DDOCTOR OF PHILOSOPH

Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering

Mesenchymal stromal cells (MSCs) are promising therapeutic candidates given their potent immunomodulatory and anti-inflammatory secretome. However, controlling the MSC secretome post-transplantation is considered a major challenge that hinders their clinical efficacy. To address this, we used a microparticle-based engineering approach to non-genetically modulate pro-inflammatory pathways in human MSCs (hMSCs) under simulated inflammatory conditions. Here we show that microparticles loaded with TPCA-1, a small-molecule NF-κB inhibitor, when delivered to hMSCs can attenuate secretion of pro-inflammatory factors for at least 6 days in vitro. Conditioned medium (CM) derived from TPCA-1-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared with CM from untreated or TPCA-1-preconditioned hMSCs. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction.United States. National Institutes of Health (HL097172)United States. National Institutes of Health (HL095722

Engineering multifunctional adhesive hydrogel patches for biomedical applications

Traditional patches, such as sticking plaster or acrylic adhesives used for over a hundred years, lack functionality. To address this issue of poor functionality, adhesive hydrogel patches have emerged as an efficient bioactive multifunctional alternative. Hydrogels are three-dimensional, water-swellable, and polymeric materials closely resembling the native tissue architecture. The physicochemical properties of hydrogels can be modified easily, allowing them to be suitable for various biomedical applications. Moreover, adhesive properties can be imparted to hydrogels through physicochemical manipulations, making them ideal candidates for supplementing or replacing traditional sticking plaster. As a result, sticky hydrogel patches are widely used for transdermal drug delivery and have even found commercial purposes. Beyond transdermal delivery, such hydrogel patches have also found applications in cardiac therapy, cancer research, and biosensing, among other applications. In this mini-review, we critically discuss the challenges of fabricating multifunctional adhesive hydrogel patches. Furthermore, we introduce some of the chemical strategies involved with fabricating the patches. We also review their emerging biomedical applications. Finally, we explore their potential future in the flourishing field of tissue engineering and drug delivery

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model

Funding: The authors acknowledge the funding support from Biomedical Research Council (BMRC), A*STAR under the grant numbers BMRC/07/1/21/19/508. CHW and WZ acknowledge the support from the National Research Foundation (NRF), Prime Minister’s Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme. Grant Number R-706-001-101-281, National University of Singapore.Peer reviewedPublisher PD

Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease

The broad repertoire of secreted trophic and immunomodulatory cytokines produced by mesenchymal stem cells (MSCs), generally referred to as the MSC secretome, has considerable potential for the treatment of cardiovascular disease. However, harnessing this MSC secretome for meaningful therapeutic outcomes is challenging due to the limited control of cytokine production following their transplantation. This review outlines the current understanding of the MSC secretome as a therapeutic for treatment of ischemic heart disease. We discuss ongoing investigative directions aimed at improving cellular activity and characterizing the secretome and its regulation in greater detail. Finally, we provide insights on and perspectives for future development of the MSC secretome as a therapeutic tool

Inter-subject variability of fluorescein clearance after the probe drop in two subjects.

<p>The excitation slit was focused on the tear film and the fluorescence <i>vs</i>. time profile was obtained for 10 min. F⁰_dP and k_d are the intercept and slope, respectively, of the fluorescence decay in the tear film as per the exponential decay curve (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198831#pone.0198831.e004" target="_blank">Eq 4</a>) using non-linear least squares. Half-lives t^d_1/2 indicated in the inset were calculated from k_d. <b>Panels A and B</b>: Data from a subject showing rapid clearance of fluorescein with half-lives of only 88 and 96 seconds in the left and right eyes, respectively. <b>Panels C and D</b>: Data from a different subject showing a relatively slower clearance with half-lives of 208 and 210 seconds in the left and right eyes, respectively.</p

Schematic of the multi-drop protocol for the measurement of epithelial permeability.

<p>At t = 0, a 0.35% fluorescein drop (0.35 gm of fluorescein/100 mL PBS buffer) is instilled on the bulbar conjunctiva and the tear fluorescence is measured (shown by red unfilled circles). After clearance of the dye (usually < 15 min), two drops of 2% fluorescein (2 gm of fluorescein/100 mL PBS buffer) are instilled 10 min apart (T₁ and T₂). About fifteen minutes after the second drop, the ocular surface is washed with CMC solution (carboxymethyl cellulose solution; Blue arrow). Next, stromal fluorescence is measured 3–4 times at time T_s (usually within 5–10 min after T₃). AUC_dL1 and AUC_dL2, which are assumed to be equal, are estimated based on the area under the curve calculated for the 0.35% drop (AUC*). The tear fluorescence in response to the probe drop is fitted to a single-exponential decay to determine F⁰_dp and k_d. F⁰_dp is then used to estimate F⁰_dL1 and F⁰_dL2. k_d for the 2% drops is assumed to be the same as that for the 0.35% drop. Hence, the first 0.35% drop is referred to as the probe drop. The 2% drops have been employed to load the stroma with measurable levels of fluorescein so that noise-free measurements of the stromal accumulation can be obtained. Therefore, the 2% drops are referred to as the loading drops.</p

Estimated fluorescein elimination rate constant (k_d) following instillation of the probe drop.

<p>k_d was obtained as the slope of the fluorescence decay by fitting to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198831#pone.0198831.e004" target="_blank">Eq 4</a> according to ln F_dP (t) = ln F⁰dP—k_d t. The mean and SD values are 0.0142 and 0.0107 sec^-1, respectively (n = 49 eyes and 29 subjects).</p

Estimated tear fluorescence at time t = 0 after instillation of the probe drop (F⁰_dP,).

<p>The Y intercept (tear fluorescence at t = 0, F⁰_dP) of the fluorescence <i>vs</i>. time plot was obtained by fitting data to the exponential decay as per <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198831#pone.0198831.e004" target="_blank">Eq 4</a>: ln F_dP (t) = ln F⁰dP—k_d t. The mean and SD values are 206.51 and 113.89 mV, respectively (n = 49 eyes and 29 subjects).</p

Mathematical notations.

<p>Mathematical notations.</p