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International Journal of Bioprinting Bioprinting of β-islet-like constructs

Mostly, it is not the bioprinting technology, but the cells, be solved with special designs containing directed pores.
materials, and the design of the constructs, which determine Hwang et al. [158] have shown that the viability and function
the functionality of the artificial pancreas. The shortage of printed β islet-like cells in porous hybrid scaffold
of primary pancreatic cells leads to the use of allogeneic systems were better than that in nonporous type (Table 3).
and autogenic stem cell-derived β-cells. Biologists have Many of the published bioprinted pancreas models have
differentiated MSCs isolated from several tissues into a lack of vasculature, which is a limitation. The lack of
functional β-cells or even differentiated somatic cells proper vascular formation after transplantation causes the
through reprogramming (iPSC) approaches into insulin- loss of transplanted islets because immediate cell death
producing cells to resolve these challenges (Figure 1C). occurs due to insufficient oxygen and nutrients. Idaszek
When printing cellular structures, the cells used are et al. [159] have demonstrated that using human MSCs and
frequently not well-differentiated. Instead, precursors are human umbilical vein endothelial cells (HUVEC) in the
given the appropriate stimulation to differentiate into the bioprinting of porcine pancreatic islets preserved insulin
required lineage for the graft. One problem that might secretion in response to glucose stimulation. Moreover,
occur in these grafts is faulty differentiation, meaning evidence of CD31 cells in that bioprinted construct has
+
that the precursor can yield many different types of cells. confirmed potential vessel-like formation (Table 3) [159] .
Since stem cells can differentiate into many endocrine or Coaxial bioprinting has provided an opportunity to fabricate
exocrine pancreas lineages and hypertrophic α- or β-cells, the artificial pancreatic islets using endothelial cells and
this can prove challenging in artificial environments to other supporting cells (Treg, endothelial progenitor cells
obtain pure differentiated cell lines. Another problem [EPCs]) to enhance vasculogenesis and regulate immune
could be that the differentiation process in the stem activity around the transplanted islets (Figure 2C and
and progenitor cells is not complete and no terminally Table 3) [154,155] . Hybrid bioprinting is another direction
differentiated β-cells are produced (partial differentiation). that combines natural and synthetic materials. This hybrid
FDA approval for clinical trials and the encouraging system can use functionalized biodegradable polymer as
results of PEC-Encap device (Figure 2A), which contains a supportive network and bioactive hydrogel containing
hESCs-derived pancreatic endoderm progenitor cells, have living cells to create the 3D scaffolds [148] . The modification
spawned new avenues in this field to treat diabetes using of the PCL scaffold surface by VEGF and heparin due
bioartificial pancreas, but more time should be spent in to the reduction of hydrophobic properties leads to the
studying and validating their utilization [172] . Last but not improvement of angiogenesis, cell adhesion, and protein
least, from a clinical therapeutic point of view, it is very binding capacity (Table 3) [112,148] .
important whether the cells are derived from autologous
or allogeneic (possibly xenograft) donors, which has not The majority of the three bioprinted pancreases were
been decided to date. in vitro models; no transplantation was performed and
therefore, the survival and full functionality of the constructs
In mature normal pancreatic islets, ECM components is not known. Commonly, most of the studies investigated
and ECM-associated growth factors are involved in β-cell bioprinted pancreases for only a few weeks (short term)
survival, proliferation, and insulin secretion (Table 1). or 12 weeks (long term) [146] . From the clinical perspective,
The encapsulation of pancreatic islets prevents rejection these are not considered long-term observations. This
by separating the transplanted islets from the host is important as in the long term, such an artificial tissue
immune system and diminishes toxic immunosuppression should not induce an immune response and should be
administration. Natural polymers and their derivatives, fully functional. Short-term studies and animal models
such as collagen, gelatin, GelMA, and alginate, have been have shown no immunological adverse reactions, but no
widely used for pancreatic islet encapsulation, as they one has investigated long-term immunological processes.
can provide an ECM environment and immune isolation The same applies to functionality. Determination of insulin
(Table 3). Synthetic scaffolds (PCL, PLA) have also been used production in 3D-bioprinted constructs in vitro, peripheral
to create functional bioprinted pancreas, but as it is a soft blood insulin, C-peptide level, sugar content in animal
tissue, hydrogels are more likely to approximate the natural models, and administration of body weight are considered
environment. Nevertheless, the ordinary encapsulation standard. In the long term, however, routine measurements
approach has significant restrictions. Hypoxia, which are not always feasible, and the measurement of other
occurs in the core of capsules, reduces the viability of islets biomarkers (cytokines, inflammatory factors, metabolites,
and increases apoptosis, thereby reducing the efficiency of etc.) has not been implemented. Immunological responses
transplantation significantly and limiting the enlargement and functionality are strongly influenced by tissue
of capsules to hold more β-cells. This obstacle has made integration. Pericapsular fibrotic overgrowth with islet
this method inefficient for clinical application. This could necrosis has been observed in grafted alginate-encapsulated

Volume 9 Issue 2 (2023) 269 http://doi.org/10.18063/ijb.v9i2.665