Page 27 - IJB-3-1

William Whitford and James B. Hoying

ing materials, accommodating (or ameliorating) heig- tion or topology of the microvessels in the perfusion
htened leachables contamination as well as sorption of network impacts overall performance [27] . Thus, the
lipophilic vitamins or lipids may be considered. incorporation of a vascular supply into a manufactured
tissue construct must address the formation of each of
4.4 Application-specific Factors the numerous, complex individual microvessels and

Depending upon the application, a number of addi- their integration into a perfusion circuit [28] matched to
tional manufacturing aspects may need to be consi- the needs of the tissue parenchyma.
dered. For tissues, tissue-mimics or other structures 4.6 Angiogenesis and Vasculogenesis
related to either cell and tissue therapies or in IVD
applications, the quality and regulatory implications of New microvessels arise from either angiogenic sprouts
the bioink must be examined, as has been begun for of existing, parent microvessels or the de novo assem-
printed medical devices [24] . For these applications es- bly of vascular cells into the microvessels called vas-
pecially, the nature and number of particulates from culogenesis [27] . A variety of cell types and strategies
the disposable components of the printing path cou- have been employed to derive microvessels. These
ld be significant. The composition of biopapers, or a include the use of endothelial cells, both macrovascu-
matrix upon which the ink is applied during printing, lar and microvascular, endothelial progenitor cells
is another consideration in some applications. An in- (EPCs), perivascular cell precursors, mesenchymal
teresting new development for applications employing and hematopoietic stem cells (MSCs and HSCs), and
human pluripotent stem cells is the announcement by smooth muscle cells incorporated into the construct
GE Healthcare that a serum-derived protein supple- either alone or in combination. Adipose stromal vas-
ment in a completely defined, xeno-free medium can cular fraction (SVF) cells show particularly robust
support stable culture of human pluripotent stem cells vasculogenic activity, perhaps because all of the cell
on untreated matrix [25] . types necessary to forming microvasculatures are
present within the isolate [20,29] . Angiogenesis-based
4.5 Vascularization strategies include pre-packaging endothelial cells in
clusters or aggregates, from which neovessels
The importance of including a vascular component in [30]
digitally biomanufactured tissue constructs as both a sprout , or the use of intact microvessel fragments as
a source of parent microvessels from which neoves-
means to provide perfusion to a tissue and impart re- sels arise via angiogenesis [28] .
levant functionality (as the vasculature also contri-
butes to tissue function) is well appreciated. The abil- 4.7 Post Printing Cues
ity to establish and maintain a functional microcircu-
lation in vitro significantly impacts a broad array In all cases, the newly formed microvessels (or neo-
of biomedical arenas [21,22] . In virtually every discus- vessels) are immature in form and function, requiring
[31]
sion concerning the building of tissue replacements, hemodynamic cues to drive subsequent maturation .
the critical importance of having a microvasculature This vascular maturation, of both the individual neo-
integrated into the tissue construct is stressed [23–25] . In vessels and network, depends on substantial remode-
cellular assay platforms, the presence of a perfused ling and adaptation activities, as the neovessels speci-
vasculature in combination with the target parenchy- fy into arterioles, capillaries, and venules and integrate
ma cell is considered to improve the utility of the as- into a contiguous network. Therefore, consideration
say beyond having just parenchyma cells [26] . Signifi- of bioinks amenable to successful fabrication of vas-
cantly, the smaller elements of the vasculature, the culatures in a digital biomanufacturing process should
microvasculature, pose unique challenges in a bioma- support not only vascular cell viability, but also pro-
nufacturing process. A stereotypical microvessel is mote individual neovessel assembly and permit adap-
comprised of multiple cell types (endothelial cells, tation to a mature microvasculature.
smooth muscle/contractile cells, perivascular mesen- 5. Vascular Compatible Bioinks
chymal cells, and immune cells) assembled in a very
structured way critical to the microvessel’s function [26] . Nearly all the bioinks used with non-vascular cells
In addition, many individual microvessels are needed will also support vascular cells. Furthermore, leverag-
(perhaps thousands in some applications) to assemble ing the potent self-assembly capabilities intrinsic to
and effective perfusion circuit. Finally, the organiza- vascular cells, these bioinks readily enable formation

International Journal of Bioprinting (2017)–Volume 3, Issue 1 23