Abstract
Cell therapies to treat critical limb ischaemia have demonstrated only modest results in clinical trials, and this has been partly attributed to poor cell retention following their delivery directly into the ischaemic limb. The aim of this study was to determine whether alginate encapsulation of therapeutic pro-angio/arteriogenic macrophages enhances their retention and ultimately improves limb perfusion. A reproducible GMP-compliant method for generating 300 µm alginate capsules was developed to encapsulate pro-angio/arteriogenic macrophages. Longitudinal analysis revealed no detrimental effect of encapsulation on cell number or viability in vitro, and macrophages retained their pro-angio/arteriogenic phenotype. Intramuscular delivery of encapsulated macrophages into the murine ischaemic hindlimb demonstrated increased cell retention compared with injection of naked cells (P = 0.0001), and that this was associated both enhanced angiogenesis (P = 0.02) and arteriogenesis (P = 0.03), and an overall improvement in limb perfusion (P = 0.0001). Alginate encapsulation of pro-angio/arteriogenic macrophages enhances cell retention and subsequent limb reperfusion in vivo. Encapsulation may therefore represent a means of improving the efficacy of cell-based therapies currently under investigation for the treatment of limb ischaemia.
Highlights
Critical limb ischaemia (CLI) is a severe manifestation of peripheral arterial disease (PAD) that is characterised by pain and gangrene.[1]
Clinical trials of cell therapy to date have only shown a modest benefit with disappointing results attributed to the lack of potency of cells injected, including a functional impairment of autologous cells harvested from patients with multiple co-morbidities.[3,4,5,6,7,8,9,10]
There are currently no studies to assess retention of cells injected into the ischaemic limb in man, but clinical studies of therapeutic cell injection into the heart reveal a similar precipitous loss, with only ~12% of cells retained after 1 h
Summary
Critical limb ischaemia (CLI) is a severe manifestation of peripheral arterial disease (PAD) that is characterised by pain and gangrene.[1] The limb salvage rate for patients with CLI remains poor,[2] with a significant proportion of patients not amenable to standard treatments, including surgical bypass and angioplasty. This has been the driver for the development of angiogenic cell-based therapies aimed at limb salvage in these no option patients. There are currently no studies to assess retention of cells injected into the ischaemic limb in man, but clinical studies of therapeutic cell injection into the heart reveal a similar precipitous loss, with only ~12% of cells retained after 1 h.13
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