Nano‐/microfiber scaffold for tissue engineering: Physical and biological properties

Alginate hydrogel (AH) has intrinsic physical and biological limitations that hinder its broader application in tissue engineering. We hypothesized that the inclusion of nanofibers in the hydrogel and the use of a biotemplate that mimics nature would enhance the translational potential of alginate hydrogels. In this study, we have shown a method to obtain nano‐/microfibers of titanium (nfTD) and hydroxyapatite (nfHY) using cotton as a biotemplate. These fibers were incorporated in the alginate hydrogel and the mechanical characteristics and biological response to these reinforced materials were evaluated. We observed that these nanofibers resembled the structure of natural collagen and did not mediate cell toxicity. The incorporation of nfTD or nfHY to the AH has not increased the viscosity of the hydrogel. Therefore, this is a feasible method to produce a scaffold with improved physical characteristics, while at the same time generating an enhanced environment for cell adhesion and proliferation. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3051–3058, 2012.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93772/1/34242_ftp.pd

A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment

<div><p>Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth.</p></div

Impact of the amplification factor, <i>A</i>_<i>in</i> and the differentiated cell death rate, <i>δ</i>_<i>D</i> on tumor growth.

<p>Model predictions of the tumor volume vs. time for the control cases as well as for treatment with 1 or 5 mg/kg TCZ when A: the amplification factor, <i>A</i>_<i>in</i>, is slightly increased from its baseline value and when C: the differentiated cell death rate, <i>δ</i>_<i>D</i> is slightly decreased from baseline. Model predictions of the CSC percentage vs time for the control cases as well as for treatment with 1 or 5 mg/kg TCZ when B: the amplification factor, <i>A</i>_<i>in</i>, is slightly increased and when D: the differentiated cell death rate, <i>δ</i>_<i>D</i> is slightly decreased (D).</p

Impact of dose frequency.

<p>Model predictions of the tumor volume vs. time for the control case (no treatment) as well as for treatment with 1 mg/kg TCZ administered every 7, 14, 21 and 28 days. The line shows the first day of the final dose for each treatment schedule.</p

Variables related to anti-IL-6R treatment model.

<p>Variables related to anti-IL-6R treatment model.</p

Numerical simulations of TCZ treatment.

<p>A: The amount of TCZ within the tumor during 7 weeks of treatment. B: Model predictions of tumor volume vs. time after treatment with TCZ. 1mg/kg or 5 mg/kg of TCZ is administered weekly when tumor reaches 125 mm³.</p

Parameter values obtained using IL-6+/+ data for primary tumor cells.

<p>Parameter values obtained using IL-6+/+ data for primary tumor cells.</p

Experimental data.

<p>A: Data for tumor growth. B: Data for stem cell percentage. This data plot was redrawn from Figs 1B and 1C in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005920#pcbi.1005920.ref008" target="_blank">8</a>], where they generated tumor xenografts by transplanting primary human cancer stem-like cells in SCID mice without human endothelial cells.</p

Schematic diagram of the cellular and molecular processes considered in the mathematical model.

<p>A: stem cell division (this figure was adapted from Fig. 1 in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005920#pcbi.1005920.ref024" target="_blank">24</a>] B: IL-6 binding dynamics.</p