Page 464 - IJB-9-2

International Journal of Bioprinting Bioprinting of exosomes

or bind with cellular integrin receptors to promote adamantine and β-cyclodextrin-modified hydroxyapatite,
directional cell migration via focal adhesion formation . improved angiogenesis and functionality following MI .
[59]
[44]
Additionally, the binding of FN-coated EXOs with laminin Shi et al. showed that gingival MSC-derived EXOs loaded
or Col fibrils in the ECM offers enhanced cell adhesion into a silk/chitosan hydrogel were found to improve
dynamics for augmenting cell adhesion and migration [46,47] . wound healing in a diabetic skin defect rat model . These
[60]
Likewise, HSPGs have been demonstrated to facilitate the studies demonstrated that the controlled release of EXOs
uptake of EXOs by recipient cells . Exofacially bound from biomaterial scaffolds could serve as novel therapeutic
[48]
HA, secreted by BMMSCs, has been shown to contribute platforms for inducing and promoting tissue injury repair
toward ECM reorganization, tissue regeneration, and and regeneration in vivo.
the regulation of EXO interactions with target cells .
[49]
Furthermore, EXO surface-associated enzymes, such as 3. Three-dimensional bioprinting
matrix metalloproteases (MMPs), have been implicated to Recently, three-dimensional bioprinting (3DBP), an
facilitate EXO mobility, release immobilized growth factors additive manufacturing technique, has emerged as
and signaling mediators, as well as influence cell migration a promising strategy for engineering intricate tissue
within the ECM matrix via regulated matrix degradation . scaffolds for various biomedical applications [61,62] . Indeed,
[50]
With regard to their tissue regenerative potential, BMMSC cell-laden gelatin- or fibrin-based bioinks printed
EXOs have been demonstrated to negate proteolytic activity alongside an embedded vasculature, and subsequently
by attenuating MMP2 expression coupled with elevated functionalized with endothelial cells to create a perfusable
expression of tissue inhibitors of MMP1/2 and imparting vascular network within a 3D perfusion chip have been
elastic matrix regenerative benefits in an abdominal shown to yield soft heterogeneous tissues at centimeter
aorta aneurysm rat model in vivo . In another study, scale that can be maintained for long periods of time [63,64] .
[51]
adipose MSC (AdMSC) EXOs reduced MMP1, MMP13, In this transformative approach, it is quite eminent that
and ADAMTS-5 (a disintegrin and metalloproteinase scaffolds can be fabricated through precise layer-by-layer
with thrombospondin motif 5) expressions in human deposition of materials to yield biologically relevant
chondrocytes, thereby preserving chondrocyte-rich ECM constructs with intricate geometries . More importantly,
[61]
and preventing cartilage degeneration [52,53] . As another the fine spatiotemporal control and high submicron scale
exemplar, weekly intra-articular injections of EXOs derived resolution offered by 3DBP allow for the incorporation and
from immortalized human embryonic MSCs promoted directional gradient release of single or multiple biomimetic
cartilage repair and regeneration through the upregulation cues over a sustained period of time, which is amenable
of Col II deposition and GAGs in an osteochondral defect for tissue engineering and the applications of regenerative
rat model in vivo . medicine . This is particularly advantageous, as tissues
[54]
[61]
biofabricated using this methodology can closely mimic
Despite the favorable effects in different pathological
conditions, one of the main challenges associated with the the physical, biochemical, and complex developmental
profiles of native heterogeneous tissues in vivo .
[62]
systemic delivery of EXOs is their rapid clearance from
the circulation (plasma half-life of 2–4 min) by virtue of Therefore, biomaterial scaffolds fabricated with
their accumulation in parenchymal organs, such as liver, specific growth factor patterns and gradients conducive
lung, and spleen . Hence, efforts have been made to for tissue development have been employed through
[55]
[65]
facilitate the sustained release of EXOs from implantable various bioprinting approaches . These approaches have
biomaterial scaffolds to improve the bioavailability of been investigated for the development of bone, cartilage,
EXOs and enhance their therapeutic outcomes. With nervous, and vascular tissues [66-68] . For example, in order to
regard to this, Shafei et al. loaded EXOs into alginate mimic the bone and cartilage layers at the osteochondral
(Alg)-based hydrogel scaffolds to enhance angiogenesis interface, a highly porous nanocomposite scaffold
and Col synthesis as well as to improve wound closure in with defined microarchitecture and spatiotemporal
a full-thickness wound excision rat model . In another patterning of growth factors has been engineered through
[56]
[66]
study, Alg scaffolds loaded with human umbilical cord stereolithography technique . Results have shown that
MSC EXOs were employed to repair bone defects in rats the fabricated osteochondral scaffold promotes human
in vivo . EXOs secreted from cardiomyocyte-derived bone marrow-derived MSC attachment and proliferation,
[57]
induced pluripotent stem cells, which have been loaded but more importantly, induces chondrogenic and
into engineered hydrogel foam that is composed of type I osteogenic differentiation of seeded MSCs in vitro. In
Col, facilitated cardiac regeneration in infarcted hearts . addition, the differentiated cells significantly upregulated
[58]
Chen et al. discovered that endothelial progenitor cell- glycosaminoglycan production, Col II synthesis, and
derived EXOs from a shear thinning hydrogel, composed of calcium deposition compared to the control samples.

Volume 9 Issue 2 (2023) 456 https://doi.org/10.18063/ijb.690