A prosurvival and proangiogenic stem cell delivery system to promote ischemic limb regeneration
Graphical abstract
Section snippets
Introductions
Atherosclerotic peripheral artery disease (PAD) affects more than 27 million people in North America and Europe [1], [2] PAD decreases blood perfusion in the tissues and causes tissue ischemia. Critical limb ischemia (CLI) represents the most severe form of PAD. It is characterized by low blood perfusion, severe tissue ischemia, and degenerated skeletal muscle. Quick restoration of blood perfusion to salvage existing cells and promotion of muscle repair represent the optimal goals for CLI
Materials
All chemicals were purchased from Sigma–Aldrich unless otherwise stated. 2-hydroxyethyl methylmethacrylate (HEMA) was purchased from TCI and passed through an inhibitor remover column to eliminate inhibitor. N-isopropylacrylamide (NIPAAm, Alfa Aesar) was purified by recrystallization for 3 times using hexane. 3,6-Dimethyl-1,4-dioxane-2,5-dione, acryloyl chloride, sodium methoxide and chondroitin sulfate were used as received.
Hydrogel synthesis
The hydrogel was synthesized from NIPAAm, HEMA and a macromer based on
Bioactive bFGF can be gradually released from the hydrogel
The bFGF was able to continuously release from the hydrogel during the 28-day release period. The release exhibited a two-phase profile, i.e., an initial burst release in the first 5 days followed by a slower release until day 28 (Fig. 1A). The bioactivity of the released bFGF was evaluated in terms of its stimulatory effect on fibroblast growth. 1 ng/mL bFGF solution was used as a control as this concentration significantly stimulated fibroblast growth. The cells cultured in the release medium
Discussion
The objective of this work was to develop a stem cell delivery system that augments cell survival under ischemic conditions, thus enhancing ischemic limb regeneration. Ischemic limbs are characterized by a low nutrient and oxygen, and poorly vascularized environment. Inferior cell survival in this environment is one of the key causes that are responsible for the low therapeutic efficacy of stem cell therapy. Augmentation of cell survival under these harsh conditions represents a critical need
Conclusions
In this work, a stem cell delivery system capable of augmenting cell survival in ischemic limbs was created for quick recovery of blood perfusion and enhancing skeletal muscle regeneration. The delivery system was based on an injectable, biodegradable, and thermosensitive hydrogel, bFGF, and MSCs. When tested under low nutrient and oxygen conditions in vitro, the system significantly increased cell survival and paracrine effects. When transplanted in the ischemic limbs, the system not only
Acknowledgments
The assistance of Dr. Jianjie Ma’s group and Dr. Matthew Joseph is greatly appreciated. This work was supported by US National Science Foundation (1006734 and 1160122), American Heart Association (15GRNT25830058 and 13GRNT17150041), US National Institutes for Health (R01HL124122), National Science Foundation of China (81471788), and Institute for Materials Research seed grant at The Ohio State University.
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These authors contributed equally to this work.