Page 229 - IJB-9-3

International Journal of Bioprinting Biomaterials for vascularized and innervated tissue regeneration

In situ printing technique provides a potential approach skin defects, owing to the positive effect of bioactive
for overcoming these problems. Briefly, in situ printing elements (Mg, Si, Sr, Fe, Mn, P, etc.) on angiogenesis,
strategy allows the biomaterials to be directly deposited immunomodulation, collagen deposition and wound
onto the wound site during surgery, which significantly healing [5,75-81] . Until now, various inorganic materials have
simplifies the preparation process and avoids preservation been prepared and incorporated into wound dressings
and transportation of growth factors-laden scaffolds before to improve its biological activity. For example, Ma et al.
surgery [67,68] . Therefore, this strategy obviously saved the developed a 3D-printed inorganic/organic composite
cost of preservation and transportation of scaffolds. For wound dressing for the treatment of deep skin burns .
[82]
example, Nuutila et al. developed in situ 3D-printed VEGF- Diatomite (DE, SiO ·nH O), the natural siliceous skeleton,
2
2
gelatin methacryloyl (GelMA) hydrogel scaffold for wound was incorporated into GelMA matrix to serve as a bioactive
healing via a custom-made handheld printer (Figure 3B) . agent to sustainably release Si ions, which is beneficial
[69]
Briefly, VEGF-GelMA precursor was directly deposited to cell proliferation and vascularization. As a result,
onto wound beds and then integrated with host tissues 3D-printed composite wound dressings could promote
after in situ crosslinked by blue light. The strategy of the angiogenesis-related genes expression of HUVECs
in situ printing can greatly shorten the preparation time of in vitro and the formation of new blood vessels in vivo.
scaffolds, which is beneficial to maintaining the biological Hence, the incorporation of inorganic biomaterials has
activity of VEGF. Moreover, in situ crosslinking strategy been regarded as an effective and inexpensive strategy to
could enhance the adhesion strength of scaffolds to wound endow the 3D-printed scaffolds with enhanced angiogenic
beds, which further simplified the procedures of surgery. bioactivities.
As a result, the developed VEGF-GelMA scaffolds had In addition to acellular wound dressings, 3D
a great performance in stimulating angiogenesis and bioprinting of cellular living system with biomimetic
enhancing the quality of skin regeneration in skin defects dermal-epidermal physiological structures for use in skin
model (Figure 3C). regeneration has gained huge attention [83,84] . However, the
Exosomes, one of the most important secretory products low cell viability and differentiation capacities have limited
of cells, are collectively a type of emerging bioactive agent its further application. To overcome these shortcomings,
for regulating cell–cell communications . Many studies our group developed a strontium silicate (SS)-containing
[70]
have shown that exosomes can promote tissue repair, multicellular system with vascularization-induced
due to its immune regulation and angiogenesis ability . properties (Figure 4) . SS microparticles were integrated
[71]
[85]
For example, Hu et al. fabricated a cryogenic 3D-printed into bioinks to act as stable biological agent to promote the
hydrogel wound dressing with the incorporation of differentiation of encapsulated endothelial cells through
BMSCs-derived exosomes for diabetic wound healing . continuous release of Sr and Si ions. As a result, the SS-
[72]
Exosomes could be sustainably released from the containing biomimetic skin constructs can rapidly integrate
3D-printed hydrogel scaffolds and capable to promote with host tissues and induce vascularization, resulting in
the differentiation activities of human umbilical vein accelerated skin regeneration in vivo. In another work of
endothelial cells (HUVECs). Furthermore, the developed our group, inspired by the immune modulation effects on
scaffolds possessed the ability of stimulating the process of angiogenesis, Wu et al. developed manganese silicate (MS)-
angiogenesis and increasing the blood flow of wound beds, containing bioinks with immunomodulatory properties .
[86]
resulting in accelerated wound healing. The Mn and Si ions could provide a beneficial immune
Peptides, formed by amino acid sequences with the microenvironment for stimulating angiogenesis through
connection of peptide bond, have been confirmed to modulating macrophages into anti-inflammatory M2
be beneficial to angiogenesis and wound healing . For phenotype.
[73]
instance, Chu et al., prepared proangiogenic peptide 3.3. 3D-printed biomaterials for innervated skin
nanofiber-integrated GelMA hydrogel scaffolds via 3D regeneration
printing technology for vascularized skin regeneration . Skin is an electroactive tissue with conductivity values
[74]
The pro-angiogenesis ability of peptide nanofiber was ranging from 0.1 to 2.6 mS cm −1[61,87] . It is reported that skin
similar to growth factors. Besides, the interconnected defects can trigger the formation of endogenous electric
macroporous structure of scaffolds could provide physical fields, and these electric fields have been confirmed to
cues for the proliferation and migration of endothelial cells, promote cell migration and wound contraction . Besides,
[88]
and induce the ingrowth of host blood vessels, resulting in neural cells are known to be sensitive to electrical signals.
early vascularization. For example, Sebastian et al. had confirmed that electrical
Apart from biological factors, inorganic materials signals stimulation can accelerate wound healing by
have attracted great attention for the regeneration of promoting re-innervation [89,90] . Therefore, the incorporation

Volume 9 Issue 3 (2023) 221 https://doi.org/10.18063/ijb.706