Biomedical Engineering Reference
In-Depth Information
Stem Cells in Cardiac Repair and Revascularization
(Engineering Damaged Heart Tissue)
Sources of cells for cardiac repair, and routes of their administration
: Cells in
current human trials include skeletal muscle myoblasts, unfractionated bone mar-
row, and circulating (endothelial) progenitor cells [
13-
15
]. Cells in preclinical stud-
ies include bone marrow MSCs, multipotent cells from other sources, and novel
progenitor or stem cells discovered in the adult myocardium [
16-
20
] . Existing trials
use intracoronary delivery routes (over-the-wire balloon catheters), intramuscular
delivery via catheters (e.g., the NOGA system for electromechanical mapping), or
direct injection during cardiac surgery. Not represented here is the theoretical poten-
tial for systemic delivery, suggested by the homing of some cell types to infarcted
myocardium and strategies to mobilize endogenous cells from other tissue sites to
the heart. Thus far, progenitor cells for cardiac repair have been delivered in three
ways: via an intracoronary arterial route or by injection of the ventricular wall via a
percutaneous endocardial or surgical epicardial approach [
21-
27
] .
The advantage of intracoronary infusion—using standard balloon catheters—is
that cells can travel directly into myocardial regions where nutrient blood flow and
oxygen supply are preserved, which hence ensures a favorable environment for
cells' survival, a prerequisite for stable engraftment. Conversely, homing of intra-
arterially applied progenitor cells requires migration out of the vessel into the sur-
rounding tissue, so that unperfused regions of the myocardium are targeted far less
efficiently, if at all. Moreover, whereas bone marrow-derived and blood-derived
progenitor cells are known to extravasate and migrate to ischemic areas [
28-
31
] ,
skeletal myoblasts do not, and furthermore may even obstruct the microcirculation
after intra-arterial administration, leading to embolic myocardial damage. By con-
trast, direct delivery of progenitor cells into scar tissue or areas of hibernating myo-
cardium by catheter-based needle injection, direct injection during open-heart
surgery and minimally invasive thoracoscopic procedures are not limited by cell
uptake from the circulation or by embolic risk. An offsetting consideration is the
risk of ventricular perforation, which may limit the use of direct needle injection
into freshly infracted hearts. In addition, it is hard to envisage that progenitor cells
injected into uniformly necrotic tissue—lacking the syncytium of live muscle cells
that may furnish instructive signals and lacking blood flow for the delivery of oxy-
gen and nutrients—would receive the necessary cues and environment to engraft
and differentiate. Most cells, if injected directly, simply die [
32
] . For this reason,
electromechanical mapping of viable but “hibernating” myocardium may be useful
to pinpoint the preferred regions for injection [
33
]. Finally, in diffuse diseases such
as dilated nonischemic cardiomyopathy, focal deposits of directly injected cells
might be poorly matched to the underlying anatomy and physiology.
More complex and challenging is a series of pathobiological concerns, which
have sent the scientific community from bedside to bench and back again. Certain
patients' cells may be unsatisfactory, in their naive and unmanipulated state, which
is now prompting systematic dissection of each step in progenitor cell function,
