Biomedical Engineering Reference
In-Depth Information
Previous research focused on enhancement of efficiency, production of growth factors,
and survival of MSCs. For MSC spheroids, however, the therapeutic efficacy of this
approach is restricted by the number of MSCs that can be included in the spheroids. When
the size of the spheroid increased beyond a certain value, a large number of MSCs in the
core underwent hypoxia and eventually died. Therefore, a strategy that enhanced their
efficiency seemed essential. The strategy developed by Shim
et al
. [44] included increasing
the survival rate of MSCs in a spheroid to inhibit their apoptosis activated by interactions
between Fas and its ligand (FasL). They synthesized B-PDA nanocarriers for efficient intra-
cellular delivery of Fas-silencing siRNA into hMSCs to improve the treatment of ischemic
disease. The enlarged hMSC spheroids remarkably enhanced angiogenesis in mouse ischemic
hind limbs. These researchers introduced an interdisciplinary approach of integrating
sequence-specific RNAi, nonviral gene delivery, and spheroid-based stem cell delivery as a
powerful therapeutic tool for the efficient treatment of ischemic disease.
Diblock Copolymer
Designing a new block copolymer that can be assembled into nanocarriers improves hydro-
philicity, degradation rate, and crystallization, and shows tremendous potential for
development in protein and gene delivery [45]. This copolymerization can increase loading,
reduce the burst effect, prolong the
in vivo
residence time of bioactive agents, and prevent
them from being engulfed by macrophages.
Benoit
et al
. [11] have synthesized diblock copolymers for siRNA complexation, protec-
tion, and uptake in addition to pH-responsive blocks for endosomal escape. The designed
copolymer consists of two blocks where the first block is composed of cationic dimethyl-
aminoethyl methacrylate (DMAEMA), which complexes with negatively charged molecules
(siRNA). The second block consists of relative amounts of DMAEMA/poly(propylacrylic
acid) (PAA)/poly(butyl methacrylate) (BMA) essential for the endosomal escape of siRNA.
This nanocarrier is cytocompatible and does not cause any negative effect on MSC surviv-
ability. The siRNA delivered via this copolymer does not alter MSC phenotype or MSC
differentiation capacity. Thus, this polymer delivery system has been proven to be capable of
siRNA delivery for controlling stem-cell behaviors for a variety of applications in regenera-
tive medicine.
Polyethylene Glycol
Conjugation PEI with nonionic and hydrophilic polymers (such as polyethylene glycol
(PEG)) minimizes toxicity. Polyethylene glycol improves the solubility of PEG-grafted PEI
(PEG-g-PEI) complexes, minimizes aggregation, and reduces nonspecific interactions with
proteins. This complex, PEG-g-PEI, holds promise in gene delivery due to ease of its prep-
aration and potential targeting modification.
Chen
et al
. [15] showed that a PEG-PEI graft copolymer had better gene delivery efficiency
than cationic liposomes and did not affect the bionomics, proliferation, and differentiation
potential of MSCs into adipocytes and osteoblasts (Figure 13.5). This copolymer completely
NH
2
O
H
O
N
NH
2
O
N
H
3
C
O
11
N
m
2
m
1
H
O
Figure 13.5
Synthesized PEG-PEI copolymer by conjugating PEG onto polyethylenimine (PEI) [15].
