Raoufinia et al.

Journal of Translational Medicine (2024) 22:435 Journal of Translational

https://doi.org/10.1186/s12967-024-05226-3
Medicine

REVIEW Open Access

Advances and challenges of the cell-based

therapies among diabetic patients
Ramin Raoufinia1,2, Hamid Reza Rahimi2, Ehsan Saburi2 and Meysam Moghbeli2*

Abstract
Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity
and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present
review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet
and stem cell transplantation technologies used in clinical settings, highlighting their strengths and limitations.
We also discussed immunomodulatory strategies employed in cell therapies. Therefore, this review highlights
key progresses that pave the way to design transformative treatments to improve the life quality among diabetic
patients.
Keywords Diabetes, Cell therapy, Translplantation, Islet, Immunosuppression

Background insulin resistance along with diminished compensatory

Diabetes mellitus poses a formidable global public health insulin secretion from pancreatic beta cell dysfunction
challenge due to its rapid growing prevalence and asso- [7]. Diabetes is associated with macrovascular complica-
ciated morbidity, disability, and mortality [1]. According tions such as heart disease and stroke, as well as micro-
to the International Diabetes Federation, over 537 million vascular issues in eyes, kidneys, and nervous system [8].
adults aged 20–79 had diabetes worldwide in 2021 that Cancer is also a leading cause of diabetes-related death,
is expected to rise to around 783 million cases by 2045 and dementia-associated mortality has risen in recent
[2]. Obesity, unhealthy diets, physical inactivity as well as decades [9–12]. Cell therapy involves transferring autolo-
genetic and epigenetic predispositions are important risk gous or allogenic cellular material into patients [13]. The
factors of diabetes [3–5]. Diabetes is typically classified global market size of cell therapy is estimated to grow
into type 1 diabetes mellitus (T1DM), gestational diabe- from $9.5 billion in 2021 to $23 billion by 2028 [14]. It
tes mellitus (GDM), and type 2 diabetes mellitus (T2DM) combines stem and non-stem cell therapies consisting of
[2]. T1DM primarily arises from autoimmune-related unicellular or multicellular preparations. Cell therapies
damage of insulin-secreting beta cells, resulting in severe typically use autologous or allogenic cells via injection
hyperglycemia and ketoacidosis [6]. In contrast, T2DM and infusion [15]. In the present review, we discussed the
generally has a more gradual onset characterized by recent advances in cell-based therapy of diabetes, from
foundational islet transplantation to regenerative strat-
egies to highlight key developments that improve the
*Correspondence: effective treatments for diabetic patients.
Meysam Moghbeli
[email protected]; [email protected]
1
Noncommunicable Diseases Research Center, Neyshabur University of Cell replacement therapy for diabetes
Medical Sciences, Neyshabur, Iran Pancreatic transplantation was firstly used in 1966 to
2
Department of Medical Genetics and Molecular Medicine, School of
Medicine, Mashhad University of Medical Sciences, Mashhad, Iran treat type 1 diabetes using whole organ transplants.

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Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 2 of 15

During the 1970s–80s, segmental pancreatic grafts were barium-alginate capsules that sustained insulin produc-
combined with techniques to divert digestive secretions tion for up to 2.5 years [23]. It has been reported that the
away from transplanted cells. Three main techniques microneedle, comprising a calcium alginate frame with
emerged; simultaneous pancreas-kidney transplants, polydopamine-coated poly-lactic-co-glycolic acid micro-
pancreas transplants following kidney transplants, and spheres encapsulating insulin, enables light-triggered
pancreatic transplants. International collaboration on insulin release. Microneedle provided a suitable insulin
tracking outcomes began in 1980 with the formation of dose to maintain blood glucose levels in line with daily
several pancreatic transplant registries and associations. fluctuations. These results established the efficacy and
However, whole organ transplantation was faced with safety of the developed microneedle for diabetes treat-
several challenges including organ rejection, vascular ment [24]. Another therapeutic approach explored the
complications, limited organ availability, and the effects encapsulation of pancreatic islets with mesenchymal
of lifelong immunosuppression [16, 17]. Islet cell trans- stem cells (MSCs) and decellularized pancreatic extra-
plantation was explored as an alternative, however iso- cellular matrix (ECM). ECM derived from the pancreas
lating and transplanting pancreatic islets proved difficult supported islet cell growth and maintenance to enhance
due to donor availability, rejection, and immunosuppres- insulin expression [25]. Sodium alginate and hyaluronic
sion side effects. Recent research has focused on stem cell acid were incorporated due to their roles in collagen pro-
sources that could reconstitute immune tolerance and duction, wound healing, and physical crosslinking. The
preserve beta cell function such as mesenchymal stem 3D porous membranes allowed optimal water and oxy-
cells, bone marrow cells, and embryonic stem cells [18]. gen transfer while diverting excess exudate from diabetic
A novel stem cell therapy called VX-880 was developed wounds. Hydrogel accelerated re-epithelization, while
using proprietary technology to grow insulin-producing decreased inflammation, indicating potential as the dia-
beta cells from allogeneic stem cells. Clinical trials began betic wound dressings [26]. Additionally, the incorpora-
in 2021 after FDA approval to deliver the cells intrahe- tion of specific ECM components, such as collagen IV
patically under immune suppression. A second approach and RGD, into alginate-based microcapsules significantly
called VX-264 encapsulates the same cells, avoiding improved the survival, insulin secretion, and longevity of
immunosuppression but requiring surgical implantation microencapsulated islets [27].
[17]. In 2023, FDA approved the first allogeneic pancre-
atic islet cell therapy called Lantidra for adults with type Encaptra® device from ViaCyte
1 diabetes experiencing severe hypoglycemia. Approval In contrast to microencapsulation techniques, Via-
was based on two studies where 21–30% of participants Cyte developed a semipermeable pouch method named
no longer required insulin one year post-treatment, with Encaptra, which contains pancreatic precursor cells
benefits lasting over five years in some cases. However, derived from the embryonic stem cells [28]. In the ini-
this treatment have mild and serious adverse events that tial trial conducted in 2014, the “VC-01” device was
are associated with treatment dose and the methods of implanted in T1D individuals without the use of immu-
islet cell infusion [19, 20]. nosuppression [29]. The trial confirmed the safety of
the device; however, the occurrence of hypoxia induced
Emerging strategies for cell delivery via cellular necrosis [30]. The device was modified as “VC-
microencapsulation and biological devices in clinical trials 02” with larger pores, and two trials (NCT03162926,
Alginate capsules as cell delivery systems NCT03163511) demonstrated promising outcomes,
A seminal investigation conducted in 1994 demonstrated including increased fasting C-peptide levels and a 20%
the successful transplantation of alginate-encapsulated reduction in insulin requirements during one year in the
islets into the peritoneum of kidney transplant patients majority of participants [31]. In order to eliminate the
who were receiving immunosuppression therapy. necessity for immunosuppressants, ViaCyte collaborated
Remarkably, these patients achieved insulin indepen- with Gore to develop an expanded polytetrafluoroethyl-
dence for up to nine months [21]. However, subsequent ene (ePTFE) device with both immuno-isolating and pro-
trials conducted without immunosuppression yielded angiogenic properties [32]. This device (NCT04678557)
inconsistent outcomes. In a study conducted in 2006, aimed to prevent immune cell attachment and T-cell
islets were encapsulated in triple-layer alginate capsules activation [33]. Additionally, ViaCyte is exploring the
and implanted intraperitoneally in type 1 diabetes (T1D) integration of CRISPR technology to modify stem cells,
patients. There was a positive correlation between the specifically by eliminating β2-microglobulin expression
encapsulation and insulin production that reduced exog- and PD-L1 up regulation. It is hypothesized that these
enous insulin requirements during one year. Despite this genetic modifications will further hinder immune cell
progress, the entry of cytokines remained a potential attachment and T-cell activation [30, 34].
concern [22]. Another study employed the single-layer
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 3 of 15

Semipermeable device from Semma therapeutics of six months [45]. In a 2020 trial conducted for hemo-
Semma Therapeutics, which has been acquired by Ver- philia (NCT04541628), the spheres were evaluated for
tex, pioneered the utilization of differentiated stem cell- their ability to express Factor VIII [46]. However, the trial
derived islet cell clusters in clinical trials. Semma houses was paused due to the development of antibodies in the
these cells between two semipermeable polyvinylidene third recipient receiving the highest cell doses. While,
fluoride membranes and is designed for subcutaneous preclinical studies have shown promising efficacy, there
implantation (NCT04786262) [31, 35]. Vertex reported are safety concerns regarding the TMTD coating that
a significant breakthrough by infusing differentiated beta need to be addressed before these spheres can be used
cells via the portal vein in a participant who was receiv- for human islet transplantation as a treatment for diabe-
ing immunosuppressants. This approach led to substan- tes [31]. Emerging technologies have been investigated
tial C-peptide production and improved glycemic control in clinical trials for delivering insulin-producing islets
during 90 days [36]. or stem cell-derived beta cells via microencapsulation or
use of implantable biological devices (Table 1). Optimiz-
βAir device from Beta O2 ing encapsulation and developing alternative implant-
Beta O2’s innovative βAir device utilizes an alginate- able devices moves the field toward delivering safe and
PTFE membrane complex to encapsulate islets, provid- effective islet replacement without chronic immunosup-
ing partial immunoisolation while ensuring a continuous pression dependency that represented an important new
supply of oxygen, which is crucial for optimal islet func- frontier for the cell-based treatment of diabetes. How-
tion [37, 38]. The βAir device that was seeded with ever, continued refining will be required to fully realize
human islets was subcutaneously implanted in T1D indi- this promising vision and using these preclinical con-
viduals (NCT02064309). Although, low insulin levels cepts in clinic.
were produced for up to eight weeks, there was not any
reduction in the required exogenous insulin [37]. While, Immunoengineering strategies: biomaterials for
increasing the number of islets could potentially enhance modulating immune responses
their function, it is important to note that the continu- Islet encapsulation aims to prevent immune responses
ous reliance on oxygen poses a risk of infection, despite toward transplant antigens. However, foreign body
efforts to optimize the survival of encapsulated islets [39, response (FBR) against biomaterials induces inflamma-
40]. tion around encapsulated islets that obstructs oxygen/
nutrient access and causes graft failure [31]. Extensive
Cell pouch™ device from Sernova research revealed biomaterial properties profoundly
Sernova has developed the Cell Pouch device, which influence FBR severity, with high purity/biocompatibil-
offers pre-vascularized polypropylene chambers for islet ity moderating inflammation [47]. Deeper understand-
transplantation without the need for immunoprotec- ing of biomaterial immunobiology enabled developing
tion. The device consists of multiple cylindrical cham- immune-modulating constructs to steer host interac-
bers that are prefilled with PTFE plugs, which are then tions. By altering topology/chemistry to hinder nonspe-
removed after implantation to create the empty space cific binding and cell adhesion, these “immune-evasive
[41]. In a 2012 trial (NCT01652911), islets were placed biomaterials” intended to attenuate xenograft rejection
in the vascularized pouches of three recipients who at inception [44]. Both innate and adaptive immune
were also receiving immunosuppression that resulted in responses have crucial roles in the context of pancre-
a transient increase in C-peptide levels [41]. In a 2018 atic islet transplantation. These responses encompass
trial (NCT03513939), immunosuppression was adminis- the activation of tissue macrophages and neutrophils
tered after implantation and islet introduction. This trial following injury, leading to the release of inflammatory
reported sustained C-peptide production for up to nine cytokines that subsequently activate antigen-presenting
months in two recipients, along with improved glycemic cells (APCs), CD8 + T cells, CD4 + T cells, and cytotoxic
control [42]. Regarding the limitations of immunosup- T lymphocytes (Fig. 1). Zwitterionic polymers conferred
pression, Sernova is exploring the possibility of encapsu- anti-fouling attributes but crosslinking limitations con-
lating islets in hydrogel as an alternative approach [43]. strained their application [48]. Novel mild zwitterioniza-
tion introduced alginate modifications that prolonged
Shielded living therapeutics™ from Sigilon Therapeutics prevention of fibrotic overgrowth by mitigating initial
Sigilon has developed the Shielded Living Therapeutics responses [49–51]. The prevention of graft rejection fol-
sphere, which consists of cell clusters enclosed within an lowing islet cell transplantation necessitates the systemic
alginate-TMTD coating [44]. Preclinical studies demon- administration of immunosuppressive agents. While,
strated that murine islet transplants encapsulated within these agents effectively suppress immune responses,
these spheres maintained normoglycemia for a period their continuous use exposes patients to an increased
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 4 of 15

Fig. 1 Immune Responses toward pancreatic islets following transplantation. This figure illustrates the immune responses, including the innate and
adaptive immunity that are triggered upon pancreatic islet transplantation. Immune response begins with the activation of tissue macrophages and
neutrophils in response to injury. Subsequent, release of inflammatory cytokines stimulates antigen-presenting cells (APCs), CD4 + T cells, CD8 + T cells,
and cytotoxic T lymphocytes to orchestrate the immune response

risk of infection and cancer. To mitigate these concerns, glycol encapsulation alone by inducing regulatory T-cell
an alternative approach involving the localized delivery lineages [62]. Silk scaffolds facilitated IL-4/dexametha-
of immunosuppressants at the transplantation site has sone emancipation that meaningfully decreased immune
emerged. This localized delivery system offers several reactions to grafts [63]. Therefore, the localized delivery
advantages, including targeted drug delivery, reduced of immunosuppressants at the transplantation site rep-
systemic exposure, and potentially reduces the immu- resents a promising strategy for islet cell transplantation.
nosuppressants doses [52]. Polymeric carriers dispersed Compared to systemic administration, local delivery can
cyclosporine A continuously at the graft site to dynami- achieve targeted immune modulation only at the graft
cally tamp down proinflammatory cascades and T-cell location while reducing drug exposure throughout the
activation [53, 54]. TGF-β/IL-10 co-delivery at the micro- body. This localized approach aims to sufficiently sup-
encapsulation interface hindered innate antigen presen- press the immune response to prevent rejection, while
tation, obstructing adaptive response priming [55, 56]. limiting negative side effects that may occur from sys-
Regulatory T-cells emerged as the potent immunomodu- temic immunosuppression. A variety of biomaterials and
lators when coated on islets to improve insulin produc- surface modification strategies have been developed and
tion in vitro [57]. Similarly, recombinant Jagged-1 surface investigated for the local delivery of immunosuppres-
patterning increased regulatory lymphocytes in vitro sive agents and immunomodulatory cytokines [64–66].
while enhancing glycemic oversight in vivo [58]. Target- Understanding how biomaterial properties influence the
ing proinflammatory effector T-cells or presenting their immune response is critical to design biomaterials that
Fas ligand death receptor improved long-term viability can modulate inflammation and improve islet graft sur-
when combined with rapamycin prophylaxis [52, 59]. vival through localized immunomodulation.
Immobilizing thrombomodulin or urokinase mitigated
local inflammation, with the latter conferring lifelong Cell-based therapy through the integration of additive
xenotransplant survival [60]. Peptides recognizing IL-1 manufacturing techniques
receptors provided robust protection from destabiliz- Additive manufacturing utilizes computer modeling to
ing proinflammatory cytokines [61]. Leukemia inhibit- fabricate complex 3D structures on-site with minimal
ing factor improved islet performance over polyethylene post-processing. Common methods for the biomedical
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 5 of 15

application are fused filament fabrication (FFF), stereo- the geometries of encapsulation devices using conven-
lithography (SLA), and bioprinting [67]. FFF is a layer- tional methods to enhance oxygen delivery has proven
by-layer technique that extrudes heated thermoplastics to be inconsistently challenging [67], so that novel
[68]. Commonly used feedstocks include acrylonitrile approaches are required to address these challenges.
butadiene styrene (ABS) and polylactic acid (PLA). Other Additive manufacturing allows customizing biomaterial
thermoplastics that have been utilized with FDM include scaffolds with defined geometries and micropore sizes
thermoplastic polyurethane (TPU), polycarbonate (PC), to improve transport [75–79]. The 3D printed PLA scaf-
polystyrene (PS), polyetherimide (PEI), polycaprolactone folds with islets have successful vascularization and cel-
(PCL), polyaryletherketone (PAEK), and polyetherether- lular survival after subcutaneous transplantation [80, 81].
ketone (PEEK), with the latter demonstrating high Interlocking toroidal hydrogel-elastomer constructs also
strength and heat tolerance. A major advantage of FDM increased surface area and cell viability [82–84].
is its ability to fabricate multi-material objects through
continuous printing and alteration of the build material. Enhancing vascularization and engraftment
In addition to typical polymers like PC and polystyrene Rich host vascularization of transplant devices is essen-
(PS), FDM can print composites reinforced with glass, tial to support long-term islet survival through efficient
metals, ceramics, and bioresorbable polymers via inte- nutrient delivery and insulin kinetics. Early platforms
gration of the constituent powders with a binding matrix. modified bulk material properties to promote vessel infil-
This enables enhanced control over the experimental tration and anastomoses [85–89]. Additive manufactur-
component fabrication. While, ceramic and metal fila- ing can further optimize microscale geometry to both
ments traditionally contain the corresponding powder accelerate host vessel connections and control intra-
mixed with a binder, FDM provides versatility in the device vasculature homogeneity beyond traditional fab-
functional prototype construction from a wide range of rication. Initial work reproduced macroscale vessels but
thermoplastic feedstocks using precise and additive layer scales were diverged from cell-based therapies [73, 90–
manufacture [68–72]. It provides geometric reproducibil- 92]. Leveraging Additive manufacturing designed struc-
ity and reduced variability compared to traditional tech- tures guided vessel formation in vitro and in vivo [80, 89,
niques. FFF prints served as scaffolds for the transplanted 93]. Shifting to bioprinting complex branching conduits
cells [67]. However, minimum feature size is limited to in supportive hydrogels facilitated clinical translation for
?∼ 250 μm by nozzle diameter [68]. SLA employs light- diverse cell therapies [94–98]. Researchers focused on
curable liquid resins and achieves higher 50–150 μm developing a 3D scaffold platform to improve the trans-
resolution than FFF but with restricted material choices. plantation outcomes of islet cells in T1D. The scaffold
Bone grafts and surgical guides are common applications featured a heparinized surface and immobilized vascular
[67]. Incorporating biomaterials like hydroxyapatite has endothelial growth factor (VEGF) to enhance vascular-
expanded utility, though processing is required to miti- ization. Scaffold effectively promoted angiogenesis and
gate cytotoxicity. Additive manufacturing can address facilitated the growth of new blood vessels. Addition-
limitations in oxygen transport, cell/material placement ally, encapsulated islets within the scaffold had functional
control and vasculature formation, and clinically trans- responses to glucose stimuli. These findings suggested
latable insulin-secreting implants [67]. Therefore, addi- that the developed scaffold platform holds potential for
tive manufacturing technologies have the potential to successful extra-hepatic islet transplantation, offering
enhance various aspects of the cell-based transplant new possibilities for T1D treatment [99]. Research on
design, from improving nutrient transport through opti- vascularization of islets via additive manufacturing tech-
mized implant geometry to achieving precision integra- niques has primarily focused on the fundamental discov-
tion of therapeutic agents (Table 2). eries. In one study, engineered pseudo islets (EPIs) were
created by combining the mouse insulin-secreting beta
Enhancing nutrient transport through optimization of cells with rat heart microvascular endothelial cells. EPIs
implant geometry demonstrated extensive outgrowth of capillaries into the
Tissue engineering for the islet transplantation requires surrounding matrix. Although, EPIs containing both cell
maximizing nutrient transport [73, 74]. Traditional scaf- types that underwent capillarization maintained viabil-
fold fabrication introduces macroporosity but lacks ity and function over time in culture, non-vascularized
precision that results in inflammation [67]. Cell encap- EPIs lacking endothelial cells could not sustain viability
sulation provides immunoprotection by limiting inter- or functionality long-term. This supported the poten-
actions between transplanted cells and the host immune tial for inducing angiogenesis within bioengineered islet
system. However, this protective barrier also poses chal- constructs. Future work may combine patient-specific
lenges for the efficient transport of essential nutrients, stem cell-derived human beta cells with endothelial cells
including oxygen, to the encapsulated cells. Modifying using this approach to promote long-term graft survival
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 6 of 15

for treating type 1 diabetes [98]. While, large-scale 3D manipulate the insulin gene in various tissues. Viral
printed vascularized structures are currently limited for methods, such as lentivirus, adenovirus, and adeno-asso-
the islet transplantation, advancements in leveraging ciated virus (AAV), along with non-viral techniques like
additive manufacturing for the optimization vascular- liposomes and naked DNA, have been utilized to deliver
ization conditions through the pore sizes and material the insulin gene to target tissues [115]. This section aims
choices, may facilitate translation to β-cell therapy in to provide an overview of important studies in the field
type 1 diabetes. of gene therapy for diabetes management, emphasizing
advancements in insulin gene delivery and manipulation
Precision placement of cells and matrix for enhanced (Table 3).
control
Beyond distributing biomaterials, additive manufactur- Enteroendocrine K-cells and pancreatic β-cells
ing enables micro-level cell and protein control. For islet Enteroendocrine K-cells in the intestines and pancreatic
transplantation, optimal cellular distribution and sup- β-cells share similarities in their production of glucose-
portive extracellular matrix niche reduce rapid dysfunc- dependent insulinotropic polypeptide (GIP) and their
tion and apoptosis [100–102]. Traditional techniques regulatory mechanisms. Understanding these similari-
heterogeneously load cells after fabrication or struggle ties offers insights into T2D management and improv-
with incomplete encapsulation [103, 104]. Bioprinting ing glucose homeostasis. However, attempts to reverse
allows in situ encapsulation and printing of multiple cell diabetes effectively through K-cell transplantation have
types and matrix components while dictating 3D place- been unsuccessful. Nevertheless, research on gene edit-
ment and dimensions [105, 106]. Islet transplant research ing techniques has shown promising results in manage-
prints hydrogel-encapsulated clusters surrounded by ment of the diabetes mellitus [116, 117]. AAV vectors
supportive cells and doped with immune modulators have been employed to co-express insulin and glucoki-
to improve the transplant environment [107]. Progress nase genes in skeletal muscles, demonstrating long-term
in bioprinting offers consistency and defines physical/ effectiveness in achieving normo-glycemia without exog-
chemical graft properties beyond traditional fabrication. enous insulin [118, 119].

Achieving controlled integration of therapeutic agents for Gene editing techniques

enhanced efficacy Gene editing techniques using AAV vectors effec-
In addition to the cell and matrix placement, additive tively improved normo-glycemia in animal models. Co-
manufacturing enables precision therapeutic integration. expression of insulin and glucokinase in transgenic mice
Incorporating therapeutics aims to recapitulate the in increased glucose absorption and regulated insulin pro-
vivo environment through angiogenesis, islet health pro- duction. Duodenal homeobox 1 (PDX1) gene transfer
motion, and immunomodulation [67, 108]. Growth fac- via AAV2 in a humanized liver mouse model also led to
tors promote vessel formation and insulin secretion while insulin secretion and glycemic control [120]. Adenovirus-
decrease apoptosis [108–111]. Local immunomodulators mediated transfection of hepatic cells with neurogenin 3
regulate the immune system in a specific site of the body. (NGN3) resulted in insulin production and trans-differ-
They decrease inflammation and promote the successful entiation of oval cell populations [121, 122]. Targeting
integration of transplanted cells or tissues by minimizing specific promoters in liver cells such as phosphoenol-
the need for widespread immune suppression in whole pyruvate carboxykinase (PEPCK), glucose 6-phospha-
body [67]. Traditional homogeneous delivery meth- tase (G6Pase), albumin, and insulin-like growth factor
ods restrict the ability to customize the spatial distribu- binding protein-1 (IGFBP-1) enhanced hepatic insulin
tion of substances and pose a risk of harmful effects on gene therapy [123, 124]. AAV-mediated overexpression
transplants or hosts [112]. The use of discreet gradients of SIRT1 reduced inflammation, hypoxia, apoptosis and
in bioprinting can offer precise physiological signals. By improved neural function in the retina of diabetic db/db
combining traditional drug release methods with AM, it mice [125]. Another study developed a plasmid express-
becomes possible to create tissues that exhibit distinct ing a single-strand insulin analogue for intramuscular
therapeutic localization. Bioprinted composites have the injection using a specialized gene delivery technique. A
ability to release factors with gradients throughout the single administration provided sustained insulin expres-
entire construct that enables a more comprehensive and sion for 1.5 months and effectively regulated blood glu-
targeted approach in tissue engineering [112–114]. cose levels without immune responses or tissue damage
in diabetic mice.
Cell based gene therapy
Gene therapy holds great promise for diabetes manage-
ment, offering innovative approaches to deliver and
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 7 of 15

Non-viral gene delivery methods seek alternative unlimited cellular sources to address
Non-viral approaches have also key roles in achieving limited islet availability. Mesenchymal stem cells pos-
glycemic control. The combination of insulin fragments sess immunomodulatory properties and their adjuvant
with DNA plasmid, administered via intravenous injec- delivery, either early in disease onset or simultaneously
tion improved normo-glycemia for extended periods. with islet transplantation, has shown promising signs
DNA transposon facilitated gene integration into the of improving outcomes in preclinical investigations. By
host chromosome that addressed the short-term liver dampening inflammatory responses and favoring regen-
expression. Additionally, the co-injection of DNA plas- erative processes, stem cells may help to establish a more
mid containing insulin with furin significantly enhanced tolerogenic transplant environment. These bioengineer-
insulin production within muscles [126]. Non-viral plas- ing and cell therapy approaches offer potential pathways
mids were engineered to carry proinsulin and pancreatic towards eliminating the exogenous insulin requirement
regenerating genes to ameliorate streptozotocin-induced [144, 145]. A variety of stem cell types have therapeu-
T1DM [127]. The pVAX plasmid vectors prolonged ther- tic potential for diabetes (Fig. 2). Pluripotent stem cells
apeutic effects in achieving normo-glycemia without possess immense promise for overcoming the limita-
the need for further treatment [127]. Bioreducible cat- tions of islet transplantation. Human embryonic stem
ionic polymers, such as poly-(cystamine bisacrylamide- cells and induced pluripotent stem cells are especially
diamino hexane) (p(CBA-DAH)), have been employed to attractive candidates due to their unique ability to both
deliver RAE-1 to pancreatic islets, resulting in improved self-renew indefinitely and differentiate into any cell type.
insulin levels [128]. Furthermore, ex vivo gene transfer This makes them an ideal source of replacement pan-
and autologous grafts have shown promising outcomes creatic beta cells. Significant research effort across aca-
in animal models. The introduction of the human insu- demic and industrial laboratories has led to advancement
lin gene into pancreatic or liver cells followed by autolo- in differentiation protocols that can convert pluripotent
gous grafts improved insulin secretion, glycemic control, stem cells into functional beta-like cells in vitro. How-
and alleviated the diabetic complications in pigs. How- ever, establishing consistent, well-characterized cellular
ever, gene silencing eventually occurred, necessitating production methods that comply with stringent safety
a deeper understanding of the underlying mechanisms and efficacy standards remains a priority for clinical
[128, 129]. translation. Ongoing work aims to generate therapeu-
tic stem cell-derived beta cell replacements exhibiting
Stem cell based therapy in diabetes stable, glucose-responsive insulin secretion comparable
Efforts are ongoing to develop standardized processes to primary islets. Although, technological and regula-
for donor and recipient selection/allocation to increase tory hurdles still must be cleared, pluripotent stem cells
pancreas utilization [130–133]. Techniques for isolat- have the greatest potential to finally solve the prob-
ing pancreatic islets are being optimized to become lem of limited cell availability and provide an unlimited
more standardized and consistent. Noninvasive imaging source of transplantable tissue suitable for widespread
technologies allow the monitoring of the transplanted treatment of diabetes [145–148]. There are currently
islets without surgery [134, 135]. Biomarkers could also six registered clinical trials evaluating the use of human
evaluate how immunomodulation strategies are work- pluripotent stem cells for the T1D treatment. All trials
ing [136–138]. Researchers are also exploring alternative except one use PEC-01 cells, which consist of a mixture
transplant sites in the body beyond just the liver, to see if of pancreatic endoderm and polyhormonal cell popula-
the other locations may better support islet graft survival tion derived from CyT49 stem cells that are fully com-
and function. Together, these areas of refinement aim mitted to endocrine differentiation upon implantation
to improve the safety and reliability of islet transplanta- [149]. The initial trial implanted PEC-01 cells within an
tion procedures as a potential therapy for diabetes [139]. encapsulation device, hypothesizing no need for immu-
Bioengineering approaches are being developed to opti- nosuppression. While, well-tolerated with minor adverse
mize the islet transplantation microenvironment using effects, insufficient engraftment occurred due to for-
biomaterials which enhance islet engraftment and func- eign body responses that eliminated the cells [150]. The
tion through engineered extracellular niches [140, 141]. trial transitioned in 2017 to use an open encapsulation
For example, encapsulation techniques aim to protect device that required immunosuppression. Subcutane-
pancreatic islets against immune reponse by enclosing ous engraftment, differentiation of cells into islet-like
them within semipermeable hydrogel polymer capsules clusters, and glucose-responsive insulin production pro-
[142, 143]. This localized immunoisolation strategy uti- vided the first evidence that pancreatic progenitor cells
lizes biomaterials like alginate to create a physical bar- can survive, mature, and function as the endocrine cells
rier preventing immune cell contact while still allowing in humans. Potential benefits on stimulated C-peptide
nutrient and oxygen diffusion. Researchers concurrently levels and glycemic control were observed in one patient
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 8 of 15

Fig. 2 Potential stem cell sources for the treatment of diabetes

Table 1 Summary of clinical trials evaluating various encapsulation and cellular delivery devices for the islet and stem cell
transplantation in diabetic cases
Delivery system Developer Clinical trial ID Description Results
Encaptra device ViaCyte NCT02239354 Semipermeable pouch containing The trial confirmed safety but hypoxia led
NCT03163511 pancreatic progenitor cells to necrosis. Subsequent trials demonstrated
NCT03162926 increased C-peptide and 20% reduced required
NCT04678557 insulin for one year.
Semipermeable Semma/Vertex NCT04786262 Houses differentiated stem cell- The trial improved glycemic control via portal
device derived islet clusters vein infusion.
βAir device Beta O2 NCT02064309 Alginate-PTFE membrane encapsu- The trial showed small insulin amounts for up to
lating islets 8 weeks but no insulin reduction, Oxygen reli-
ance risks infection despite optimization efforts.
Cell Pouch device Sernova NCT03513939 Pre-vascularized polypropylene One trial showed transient C-peptide increase,
NCT01652911 chambers for islet transplantation Other trial reported sustained C-peptide for up
to nine months.
Shielded Living Sigilon NCT04541628 Cell clusters within alginate-TMTD The hemophilia trial paused due to antibodies
Therapeutics coating in highest doses, Safety concerns regarding
spheres TMTD coating remain.

[151, 152]. Two reports in late 2021 described results months. Explanted tissues contained heterogeneous pan-
in 17 patients receiving PEC-01 cells in an open device. creatic compositions including mature beta cells, with
Engraftment and insulin expression occurred in the no teratoma formation and mild adverse effects related
majority, glucose-responsive secretion in over one-third, to surgery/immunosuppression. VX-880 uses fully dif-
and various glycemic improvements were observed at six ferentiated insulin-producing stem cell-derived islet cells
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 9 of 15

Table 2 Summary of potential applications of additive manufacturing techniques for improving islet transplantation
Application Objective Approach Benefits Challenges
Implant Geometry Enhance nutrient transport 3D printing scaffolds with Increased surface area to volume Material restrictions of early
defined Pore architecture ratio, precise microstructure control am methods
Vascularization Accelerate formation of Bioprinting of vascular Faster endothelial cell integration, Scaling construct size for
vasculature conduits and guides optimized intra-device networks clinical translation
Cell/Matrix Maintain optimal In Situ bioprinting of mul- Uniform composition, consistent Refining multiple material
Placement microenvironment tiple components presentation of signals deposition
Therapeutic Modulate Host/Graft Printing of drug-loaded Spatial control over cues, reduced Characterizing release kinet-
Integration responses depots/gradients toxicity risks ics from complex designs

Table 3 Summary of gene therapy and cell therapy approaches studied for diabetes
Cell source Gene/Protein Delivered Vector Study model Outcomes Refer-
ences
Liver cells Insulin and glucokinase Adeno-associat- Dog with STZ- Achieved normoglycemia without exogenous insulin [119]
ed virus (AAV) induced diabetes long-term.
Liver Pancreatic and duodenal AAV2 Humanized liver Liver cells secreted insulin leading to glycemic control. [120]
homeobox 1 (PDX1) mouse model
Hepatic cells Neurogenin 3 (NGN3) Adenovirus Mice Produced insulin and trans-differentiation of oval cells. [121,
122]

in phase 1/2 trial evaluating portal infusion and differ- Following treatment, HbAc1 levels decreased by an aver-
ent doses requiring immunosuppression. Preliminary age of 32%, fasting blood glucose levels decreased by an
results suggest early engraftment and insulin secretion. average of 45%, and C-peptide levels showed a decrease
The manin challenge was controlling immune rejection of 38% in two trials and an increase of 36% in four trials.
without systemic immunosuppression [149]. Several Notably, no severe adverse events were reported across
strategies are being explored to address the challenges of all trials. Therefore, it can be concluded that MSC ther-
immune rejection in stem cell therapies for diabetes. They apy for type 2 diabetes is safe and effective [157].
include generating stem cell lines that are universally
compatible through HLA silencing, developing milder Advances in islet transplantation and stem cell-derived
regimens of immunosuppression, and refining encapsula- Beta cells
tion and containment approaches to protect transplanted Limited number of the islet transplantation donors
cells toward immune response. Establishing standardized highlights the importance of cell therapy in diabetes.
stem cell banks is also an area of investigation [153, 154]. Although, higher islet numbers from multiple donors
Xenotransplantation using gene-edited porcine islets increase the success, limited pancreas availability
remains an exciting avenue of research given advances restricts widespread use [158]. Using multiple donors
to improve engraftment and reduce immunogenicity in also increases rejection risk, while isolation of the islets
preclinical studies [155]. Novel approaches continue to can cause tissue damage [159]. To overcome these chal-
emerge as well, such as decellularization techniques, 3D lenges, researchers have explored the differentiation of
bioprinting of tissue constructs, and creating interspe- stem cells into beta cells in vitro to generate an unlimited
cies chimeras. Rapid evolution of cell-based therapies supply of insulin-producing cells with standardized and
across both academic and commercial sectors is promis- characterized products. Genetic engineering techniques
ing to restore normoglycemic control in diabetic cases. have also been investigated to confer advantages such
Refinement of existing methods and development of new as stress resistance or immune evasion [158]. ViaCyte
strategies hold potential to perform a safe and effective has developed a stem cell-derived pancreatic progeni-
cell replacement without reliance on systemic immuno- tor called PEC-01, which has the ability to mature into
suppression. Stem cell and regenerative therapies may endocrine cells in rodent models. To protect the trans-
ultimately manage diabetes through restored endoge- planted cells from immune response, retrieval encapsu-
nous insulin production [156]. Recently a meta analysis lation devices were also created [160–162]. In an initial
evaluated the safety and efficacy of MSC-based therapy human clinical trial conducted in 2014 (NCT02239354),
for diabetes in humans. This comprehensive analysis was the Encaptra device was utilized with the aim of pro-
conducted on 262 patients across six trials that met the viding complete immunoprotection of transplanted
inclusion criteria within the last five years. The results cells through the use of a cell-impermeable membrane.
reveal that treatment with MSCs significantly reduced Although, the PEC-Encap product showed reliable toler-
the dosage of anti-diabetic drugs over a 12-months. ance and minimal adverse effects, the trial was stopped
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 10 of 15

due to the inadequate engraftment of functional prod- blood glucose levels without exogenous insulin remains
ucts. While, a few endocrine cells were observed, fibro- a challenge in human studies. In the field of gene therapy
sis around the capsule led to graft loss and supression of and stem cell differentiation, research focuses on genet-
the insulin secretion. To address this challenge, a more ically-modified or progenitor-derived insulin-secreting
recent development called the PEC-Direct device was β-like cells to optimize protocols that ensure safety and
introduced, which featured openings in the membrane functionality. The main challenge is to establish stable and
to facilitate vascularization, thereby improving nutrient functional cells capable of permanently restoring normo-
exchange and supporting cell viability. However, since glycemia without the need for external intervention. One
host cells could infiltrate the device, immunosuppression major barrier is the immune response, which targets allo-
was necessary following the transplantation [163–165]. geneic and xenogeneic islet grafts. Although, local immu-
Protocols were developed to generate clusters of stem notherapy minimizes the systemic effects, evading graft
cell-derived beta cells that secreted glucose-responsive destruction through biomaterials without the require-
insulin. These clusters, referred to SC-islets, also con- ment of immune suppression remains a significant chal-
tained other endocrine cells, including glucagon-produc- lenge. The translation of precision 3D islet constructs and
ing cells. SC-islets improved glycemic control in diabetic genetically reprogrammed cells also necessitates scal-
mice and nonhuman primates [146, 166–168]. In a trial able manufacturing processes to ensure consistent func-
conducted in 2017 (NCT03163511), the transplantation tion and long-term safety across batches. When critically
of progenitor cells resulted in the maturation of endo- appraising progress in the field of cell-based diabetes
crine cells, and glucose-responsive C-peptide secretion treatments, it is imperative to consider the regulatory,
was observed 6–9 months post-transplantation. Notably, ethical, economic, and safety factors that shape transla-
the majority of these mature endocrine cells exhibited tional applications. At the regulatory level, oversight bod-
glucagon-positive characteristics. The porous regions ies play a pivotal role in establishing standards to ensure
housing the endocrine cells allowed for the infiltration patient welfare while enabling therapeutic innovation.
of host vessels to facilitate vascularization. However, FDA oversees clinical trials and product approvals in the
non-cellular regions were isolated by the presence of United States (US), while in Europe the EMA provides
fibrosis [164, 165]. Although, there was not a sufficient parallel regulatory guidance. Within the US, organiza-
levels of circulating C-peptide in these trials, the find- tions like the United Network for Organ Sharing (UNOS)
ings underscored the significance of promoting vascu- and Organ Procurement and Transplantation Network
larization and minimizing fibrotic reactions [164, 169]. (OPTN) govern organ and cell allocation protocols [17,
Vertex conducted a human trial in 2021 (NCT04786262) 170]. However, as regenerative approaches diverge from
involving the transplantation of half-dose VX-880 cells traditional organ transplantation, regulatory pathways
(SC-islets) without a device to avoid previous problems, require ongoing harmonization between the agencies
which necessitated immunosuppression. Preliminary and jurisdictions. Continual dialogue between research-
results reported improved glycemic control, although it ers, oversight boards, and policymakers will be crucial
took longer to achieve the same outcome compared to to streamline guidelines in a patient-centric manner that
rodent models [158]. Overall, progresses in islet trans- balances safety, efficacy, and timely access to cutting-edge
plantation and stem cell-derived beta cells pave the way therapies. For instance, as stem cell-derived beta cells
for overcoming the limitations of traditional approaches. and 3D bioprinted tissue constructs emerge, traditional
Further research and refinements are also required to drug and device frameworks may not adequately address
achieve consistent and clinically significant outcomes in product characterization and manufacturing complexi-
the treatment of diabetes. ties for these advanced therapeutic products [67]. Within
clinics, maintaining compliance with evolving regula-
Chalenges and limitations tions impacts research directives and ultimately patients’
Cell-based therapies have been significantly progressed access to the novel treatments. Addressing informed
for diabetes; however, there are still several challenges consent, clinical trial design, and privacy protections for
that need to be overcome. Clinical trials investigating sensitive health data are also paramount from an ethical
encapsulation devices and islet transplantation tech- perspective [128, 129]. Autonomy and agency of research
niques have provided valuable insights but face several participants in decision-making related to experimental
obstacles including oxygenation, host immune responses, therapies demand prudency. Equitable accessibility of
and insufficient long-term engraftment success. Immu- new treatment options also warrants attention to avoid
noengineering of biomaterials and additive manufac- certain populations facing undue barriers. Cell sourc-
turing for the development of 3D islet structures aim to ing presents ethical issues depending on derivation from
modulate inflammation and promote graft revasculariza- embryonic, fetal or adult tissues. Logistical matters like
tion. Nevertheless, achieving consistent normalization of shipping and processing stem cell-derived islets prior to
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 11 of 15

transplantation necessitate scrutiny. Tumorigenic poten- microencapsulation design, immunomodulation, tissue

tial of the undifferentiated pluripotent stem cells should constructs, genetic and cellular reprogramming tech-
be optimized through rigorous preclinical testing. Tran- niques, as well as initial clinical translation. However,
sitioning therapies between animal and early human the complete restoration of normoglycemia without the
investigations necessitates well-characterized cellular need for lifelong immunosuppression is still considered
products showing consistent safety and glucose-respon- as a significant therapeutic challenge. Therefore, address-
sive insulin secretion profiles comparable to pancreatic ing the transplant environment of the hostile nature,
islets. Long-term animal model data substantiating lack developing minimally invasive delivery methods, and
of malignant transformation following transplantation overcoming limitations in engraftment efficiency and
aids allaying ethical safety concerns as the therapies longevity are crucial issues for the future researches.
progress clinically. Researchers carefully screen new con- Through the sustained multidisciplinary efforts for the
cepts to prevent side effects in participants while pursu- improvement of existing strategies and establishing novel
ing curative goals. In terms of economic costs, islet and paradigms, achieving durable insulin independence can
stem cell transplant procedures remain prohibitively be a realistic goal for all diabetic cases through the per-
expensive for broad applicability despite promising clini- sonalized cell replacement or regeneration.
cal signals. The field requires sustained study to validate
Abbreviations
techniques, track long-term outcomes, assess healthcare ABS Acrylonitrile butadiene styrene
costs offsets from mitigating diabetes’ debilitating com- APCs Activate antigen-presenting cells
plications, and establish cost-benefit ratios for national AAV Adeno-associated virus
PDX1 Duodenal homeobox 1
reimbursement paradigms. Public-private partnerships EPIs Engineered pseudo islets
may accelerate large, interventional trials and longitudi- ePTFE Expanded polytetrafluoroethylene
nal research to precisely quantify the cellular therapies’ ECM Extracellular matrix
FBR Foreign body response
safety profiles and real-world efficacies compared to FFF Fused filament fabrication
intensive management versus costs of intensive diabetes GDM Gestational diabetes mellitus
care. Ongoing developments like 3D bioprinting offer G6Pase Glucose 6-phosphatase
IGFBP-1 Insulin-like growth factor binding protein-1
catalytic manufacturing potential fundamentally reca- MSCs Mesenchymal stem cells
librating economics by enhancing yields, standardizing NGN3 Neurogenin 3
procedures, and reducing costs through scale. By thor- OPTN Organ Procurement and Transplantation Network
PEPCK Phosphoenolpyruvate carboxykinase
oughly and sensitively examining regulatory frameworks, PAEK Polyaryletherketone
informed consent processes, risks and benefits, as well as PCL Polycaprolactone
financial considerations at both micro and macro levels, PC Polycarbonate
PEEK Polyetheretherketone
researchers, oversight boards and broader stakeholder PEI Polyetherimide
networks can advance cell-based therapies towards deliv- PLA Poly-lactic acid
ering life-changing benefits for all communities. A mul- PS Polystyrene
SLA Stereolithography
tidisciplinary, conscientious approach balances progress TPU Thermoplastic polyurethane
against patient welfare. A combination of multiple strate- T1D Type 1 diabetes
gies may help to overcome these limitations. For instance, T1DM Type 1 diabetes mellitus
T2DM Type 2 diabetes mellitus
gene-modified islets integrated within vascularized bio- UNOS United Network for Organ Sharing
material implants or sequenced therapies have promising US United States
results to prime grafts in pro-regenerative environments VEGF Vascular endothelial growth factor

before transplantation. Collaboration across disciplines Acknowledgements

offers hope that refined individualized therapies may None.
eventually achieve durable insulin independence through
Author contributions
functional pancreatic cell or tissue engraftment, not only RR, HRR, and ES were involved in search strategy and drafting. MM revised,
for diabetes but also for chronic pancreatitis. Regard- designed, and supervised the manuscript. All authors read and approved the
ing, ongoing progresses in unraveling these barriers, cell final manuscript.

replacement approaches have the potential to improve Funding

diabetes management. None.

Data availability
Conclusions The datasets used and/or analyzed during the current study are available from
This review provides a comprehensive overview of the the corresponding author on reasonable request.
advances, challenges, and future directions in various
cell-based therapeutic approaches for the treatment of
diabetes. Significant progresses have been achieved in
Raoufinia et al. Journal of Translational Medicine (2024) 22:435 Page 12 of 15

Declarations 22. Calafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, et al.
Microencapsulated pancreatic islet allografts into nonimmunosuppressed
Ethics approval and consent to participate patients with type 1 diabetes: first two cases. Diabetes Care. 2006;29(1):137–8.
Not applicable. 23. Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, et al. Safety
and viability of microencapsulated human islets transplanted into diabetic
Consent for publication humans. Diabetes Care. 2009;32(10):1887–9.
Not applicable. 24. Weng L, Wang X, Liu H, Yu Z, Liu S. Light-responsive microneedle array with
tunable insulin release function for painless and on-demand anti-diabetic
Competing interests therapy. Mater Lett. 2023:135684.
The authors declare that they have no competing interests. 25. Okcu A, Yazir Y, Şimşek T, Mert S, Duruksu G, Öztürk A, et al. Investigation
of the effect of pancreatic decellularized matrix on encapsulated islets of
Received: 14 February 2024 / Accepted: 22 April 2024 Langerhans with mesenchymal stem cells. Tissue Cell. 2023;82:102110.
26. Khaliq T, Sohail M, Minhas MU, Mahmood A, Munir A, Qalawlus AHM, et al.
Hyaluronic acid/alginate-based biomimetic hydrogel membranes for acceler-
ated diabetic wound repair. Int J Pharm. 2023;643:123244.
27. Kuwabara R, Qin T, Llacua LA, Hu S, Boekschoten MV, de Haan BJ, et al. Extra-
cellular matrix inclusion in immunoisolating alginate-based microcapsules
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