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William Whitford and James B. Hoying

enterprise control, and verification [3,4] . Digital bioma- inks), fluids to be removed after leaving a void (sa-
nufacturing (DB) is part of an evolution, one further crificial or fugitive bioinks) and even cell-free matrix
step in the application of Industrial Internet of Things solutions intended to be immediately populated with
(IIoT). It refers to instruments becoming intercon- cells post-printing (printed scaffold bioinks). Also,
nected, but more than that — it denotes high levels of there are printing technologies that either employ op-
data analysis, information management and process timized de-cellularized natural matrices [10,11] , print
control being implemented into a “process network”. into polymerization-initiation chemical baths (di-
DB promises such value as real-time optimization of rect-writing) [12] or whose cell-laden bioinks do not
the manufacturing process based on such highly valu- require a scaffold component at all [13] .
able criteria as projected product quality and batch
profitability. 2.3 Supported Printing Parameters
2.1 Terminology Therefore, depending upon the specific reference,
a bioink must variously support the mechanical and
It is desirable to use a distinct term here to distinguish chemical aspects of the particular printing technolo-
it because, as in the terms bioproduction and bioph- gy(s) employed, structure of the printed assembly,
armacology, DB addresses the many unique aspects health of the particular cell types employed and post-
of biologically-based activities. For example, the term printing functions [14] . Their specific design and for-
digital biomanufacturing may be used to describe the mulation is becoming even more important as the in-
advanced manufacturing practices of many biophar- dustry is adopting such advances as multi-comp-
maceutical entities or vaccines. It is not to be confused onent bioinks in multi-step 3D printing process and
with direct digital biomanufacturing processes, such anisotropic matrices [15] . Currently, researchers and
as employed in, e.g., some synthetic biology and printed construct sponsors in 3DBP must develop their
[5]
3D bioprinting applications . 3-dimensional biopri- own inks. Until quite recently, all the structural ma-
nting (3DBP) can therefore be conceived of as one terial components of bioinks were adopted from other
implementation of direct digital biomanufacturing or applications. However, some characterized products
additive biomanufacturing. 3DBP and bioplotting are and bioprinting qualified materials are now becoming
also now employing other elements of DB. One ex- commercially available [16,17] . The cell-culture compo-
ample of this is software to support the management nents have been supplied by commercialized culture
of imported digital analytics and imaging files, as well media formulations and most-often include serum. As
as programs to design, visualize, simulate, and analyze applications mature, demand is growing for optimized,
[6]
3D computer models of printed structures . Others serum-free bioinks, and 3DBP-related cell culture me-
include the emerging applications of distributed, clo- dia, of consistent quality manufactured in regulated
sed loop and supervisory control technology to bio- facilities.
printing. As 3DBP operations move towards the
promise of therapeutic applications, these factors will 2.4 Tunable Fluid Characteristics
enable more efficient, reproducible and self-adaptive Bioinks must provide many distinct features that
processes. can be considered as elements of tunable solutions
enabling a digital biomanufacturing technology. In
2.2 Bioinks
3DBP, this is accomplished by (i) specifically sup-
As fluids are deposited during 3DBP, the composition porting a particular printing technology; (ii) providing
of bioinks are very important to the outcome of the a matrix, scaffold or extra-cellular matrix (ECM) for
printing [7,8] . Precise and universal definitions of most the immediate structural integrity of the printed con-
terms in biomedical applications of additive manufac- struct; (iii) supporting the immediate stable culture
[9]
turing are rare . Generally, the term “bioink” refers to and robust performance of the living cells within the
a fluid containing living cells (or cell assemblies) and printed construct (e.g., nutrition, factor and
many low and high molecular weight components mass-transfer); (iv) enabling required scaffold assem-
to be employed in 3DBP. However, there are other bly or polymerization; (v) supporting post-printing
usages — some refer to cell-free fluids as a type cell-attachment, migration or phenotypic progression;
of bioink. For example, bioinks deposited for ancil- (vi) accommodating any required subsequent matrix
lary buttressing of the primary product (support bio- remodeling, interaction or absorption; and (vii) pro-

International Journal of Bioprinting (2017)–Volume 3, Issue 1 19