Hydrogel-Based Vascularized Organ Tissue Engineering: A Systematized Review on Abdominal Organs
Abstract
1. Introduction
1.1. Health Necessity of Manufacturing Organs and Organ Shortage
1.2. Hydrogels in Tissue Engineering
1.3. Scope of This Review
2. Materials and Methods
2.1. Study Design
2.2. Search Strategy
2.3. Data Extraction
2.4. Data Presentation
3. Results of Recent Advances
3.1. Study Selection
3.2. Study Characteristics
4. Discussion
4.1. Summary of the Results
4.2. State-of-the-Art Applications
4.3. Comparison of Findings from the Literature
4.4. Limitations of the Review
5. Conclusions
6. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | Year Published * | Authors | Type of Study | Used Simulation Tools | Organs/ Tissues Created | Method Used for Hydrogel Preparation/Gelation | Material Used for Hydrogel | In Vivo Experiment Duration |
---|---|---|---|---|---|---|---|---|
Liver/hepatic tissue-related applications | ||||||||
1 | 2010 | Zhao Y. et al. [11] | In vivo (rats) | − | Hepatic tissue | Gel was prepared in a syringe | Collagen | − |
2 | 2013 | Leong M.F. [12] | In vitro/in vivo (mice) | − | Hepatic tissue | After polyionic droplets were arranged on a template, individual fibers were drawn in parallel and assembled into higher-order structures. Cells were encapsulated in the fiber. | Alginate | Animals were sacrificed on day 14 |
3 | 2018 | Agarwal T. et al. [13] | In vitro | − | Liver tissue | After the pH of the solution was adjusted, the pre-gel solutions were prepared on ice to prevent the gelation of the matrix. Thereafter, it was briefly centrifuged, added to the culture dish and incubated at 37 °C for 20 min to facilitate gelation. Cells were entrapped into hydrogels post-neutralization | Caprine liver extracellular matrix (CLECM) and collagen | − |
4 | 2018 | Zhang B. et al. [14] | In vitro | − | Hepatic tissue | Collagen–Matrigel hydrogel mixture was prepared. Then, the cells were suspended in the mixture. The bioreactor was placed in an incubator with a built-in humidified chamber for 30 min to achieve the gelation of collagen–Matrigel. | Collagen–Matrigel | − |
5 | 2018 | Jin Y. et al. [15] | In vitro | + | Hepatic tissue and multiorgan model (3D liver organoids; 3D gastric and small intestinal organoids) | The decellularized liver extracellular matrix (LEM) was used to form a 3D hydrogel by inducing the self-assembly of extracellular matrix (ECM) components by adjusting the temperature. The cells were resuspended in the LEM pre-gel solution and incubated at 37 °C for 30 min to induce gelation. In addition, gastric organoids and intestinal organoids were encapsulated in Matrigel. | Liver extracellular matrix (LEM) as main ingredient for liver, with Matrigel for gastric and intestinal tissue | − |
6 | 2019 | Carpenter R. et al. [16] | In vivo (mice) | − | Liver tissue | Interconnected porous hydrogel scaffolds were created. For their fabrication, glass beads were utilized, and the precursor solution was composed of an acrylamide monomer, bisacrylamide crosslinker, N,N,N′,N′-tetramethylethylenediamine accelerator and 2-hydroxy-2-methylpropiophenone photoinitiator in nitrogen-purged DI water. The precursor solution was immediately polymerized under a UV light source for 15 min. Glass beads were selectively dissolved. Stromal cells were seeded in the scaffolds. And tissue pieces were inserted in a hole in the scaffold or on top of the scaffold. | Acrylamide monomer was the main ingredient of the hydrogel | 2 weeks for liver tissue/organ |
7 | 2020 | Cui J. et al. [17] | In vitro | + | Liver lobule-like tissue | Each of the two pre-polymer solutions (i.e., PEGDA and GelMA) were fully mixed with cell-laden solutions. Then, photo-crosslinking took place to form the hydrogels. | Poly(ethylene glycol) diacrylate (PEGDA) and gelatin methacrylate (GelMA) | − |
8 | 2022 | Rajasekar S. et al. [18] | In vitro | − | Vascularized liver tissue | The authors developed a subtractive manufacturing technique. Using this technique, a 2D surface can be patterned using a flexible sacrificial material that changes its shape and swells when it is exposed to an aqueous hydrogel. It then subsequently degrades to create perfusable networks in a natural hydrogel matrix that can be populated with cells. | Alginate, collagen, Matrigel and fibrin | − |
9 | 2024 | Fritschen A. et al. [19] | In vitro | − | Liver carcinoma | Microfluidic chip in combination with the automated 3D-bioprint process and robotic handling. | Agarose and fibrin | − |
10 | 2024 | Jiang Z. et al. [20] | In vitro/in vivo (mice) | − | Liver | Cells from a C166 suspension or from a hepatocyte suspension were mixed with GelMA solution and LAP solution at 37 °C to bioprint cell-laden hepato-spheroid-encapsulated artificial livers with veins. Syringes loaded with inks were stored at 4 °C for 20 min until complete physical gelation. Then, the syringes were mounted into the extruders on the 3D printer with a temperature at 20 °C. Finally, they were UV irradiated for 30 s to crosslink the printed constructs. | Gelatin methacrylate (GelMA) | 2 weeks after transplantation |
Pancreatic tissue-related applications | ||||||||
11 | 2018 | Jung et al. [21] | In vivo (mice) | − | Pancreatic cancer tissue | Disc-shaped fibrin samples were fabricated by casting a mixture of fibrinogen and thrombin (specifically thrombin and aprotinin) solutions in PDMS wells. During mixing, cell culture medium containing cells was added to the fibrinogen solution. | Fibrin | Up to 8 weeks |
12 | 2018 | Weaver J.D. et al. [22] | In vivo (rats) | + | Islet transplantation with vascularization | A hydrogel core crosslinked with a non-degradable PEG dithiol and a vasculogenic outer layer crosslinked with a peptide that is susceptible to proteases to facilitate degradation comprise a two-component synthetic PEG hydrogel macro-device system. | Poly(ethylene glycol) (PEG) as the major ingredient | 4 weeks after transplantation for glucose monitoring; up to 14 weeks after transplantation for stability |
13 | 2022 | Hsu Y.-J. et al. [23] | In vitro/in vivo (mice) | + | Islet transplantation | Pre-polymer GelPhMA solutions were gently mixed with mesenchymal stem cells alone or a mixture of mesenchymal stem cells and human umbilical endothelial cells. Then, photo-crosslinking with UV light occurred. | Gelatin–phenolic hydroxyl-methacrylic anhydride (GelPhMA) | Up to 1 week |
14 | 2022 | Kinney S.M. et al. [24] | In vivo (mice were recipients; donors were rats) | − | Subcutaneous islet transplantation | The injectable hydrogels were prepared as follows: Precursor solutions were quickly drawn up in a syringe capped with an 18-gauge needle and were then used to quickly draw islet-equivalent units into the needle. The mixture of islets and hydrogel was injected into the mice approximately 30 s prior to the gelation time of the hydrogels. | Methacrylic acid-polyethylene glycol (MAA-PEG) | Up to 70 days |
15 | 2022 | Perugini et al. [25] | In vitro | − | Vascularized pancreatic β-cell islets | In a gelatin-containing medium, β-cells and endothelial cells were suspended. After putting the cell suspension in sterile tubes, it was then left at 37 °C for 20 min on a tissue culture rotator. Then, the cells, after a 2 h incubation, were treated with fetal bovine serum and incubated for another 24 and 48 h under continuous, gentle agitation at 37 °C, 5% CO2 and 95% humidity, which was sufficient to improve media flow around the formed 3D constructs. | Gelatin | − |
Renal tissue-related applications | ||||||||
16 | 2019 | Huling J. et al. [26] | In vitro (rats) | − | Vascularized functional renal tissues | The MS1-coated scaffolds were embedded in collagen type 1 hydrogel in 48-well plates. Human renal cells were mixed in the collagen hydrogel before they were neutralized with NaOH. | Polycaprolactone (PCL) and collagen were used in the application | − |
17 | 2022 | Rajasekar S. et al. [18] | In vitro | − | Vascularized kidney proximal tubules | The authors developed a subtractive manufacturing technique. Using this technique, a 2D surface can be patterned using a flexible sacrificial material that changes its shape and swells when it is exposed to an aqueous hydrogel. It then subsequently degrades to create perfusable networks in a natural hydrogel matrix that can be populated with cells. | Alginate, collagen, Matrigel and fibrin | − |
18 | 2023 | Zhang Y. et al. [27] | In vitro/in vivo (rats) | − | Renal tissue | Photo-crosslinking (UV light) for hydrogel preparation and then cell seeding in vitro and photo-crosslinking (UV light) for hydrogel preparation in vivo. | Gelatin methacrylate (GelMA) | Up to 12 weeks |
Intestinal tissue-related applications | ||||||||
19 | 2024 | Orge I.D. et al. [28] | In vitro | − | Vascularized intestinal organoids | A fibrinogen solution mixed with aprotinin was used. For hydrogel embedding, intestinal organoids combined with vascular units, these were added to the fibrinogen solution and then mixed with thrombin and allowed to crosslink for 30 min at 37 °C. | Fibrin-based hydrogels were mainly used | − |
Stomach tissue-related applications | ||||||||
20 | 2019 | Carpenter R. et al. [16] | In vivo (mice) | − | Gastric cancer tissue | Interconnected porous hydrogel scaffolds were created. For their fabrication, glass beads were utilized, and the precursor solution was composed of an acrylamide monomer, bisacrylamide crosslinker, N,N,N′,N′-tetramethylethylenediamine accelerator and 2-hydroxy-2-methylpropiophenone photoinitiator in nitrogen-purged DI water. The precursor solution was immediately polymerized under a UV light source for 15 min. Glass beads were selectively dissolved. Stromal cells were seeded in the scaffolds. And tissue pieces were inserted in a hole in the scaffold or on top of the scaffold. | Acrylamide monomer was the main ingredient of the hydrogel | 6 weeks for gastric tissue/organ |
No. | Year Published * | Authors | Outcome Summary |
---|---|---|---|
Liver/hepatic tissue-related applications | |||
1 | 2010 | Zhao Y. et al. [11] | Type I collagen hydrogel was used as a matrix for the growth and differentiation of hepatocytes to create engineered hepatic units to reconstitute 3D, vascularized hepatic tissue in vivo. The hepatocytes were transplanted in vivo in small hepatic units. Large hepatic tissue (more than 0.5 cm thick) containing blood vessels could be engineered in vivo by merging small hepatic units |
2 | 2013 | Leong M.F. [12] | Patterned constructs of endothelial cells with anastomosing hepatocytes with the host vasculature in a mouse model, leading to vascularized tissue. |
3 | 2018 | Agarwal T. et al. [13] | The co-culture of HepG2 cells and endothelial cells in decellularized caprine liver extracellular matrix-derived hydrogel showed functionality and differentiation for both cell types. It also showed that these hydrogels supported the development of the microvasculature in vitro. This renders it a suitable candidate for development of a pre-vascularized liver tissue construct |
4 | 2018 | Zhang B. et al. [14] | A detailed protocol is provided for fabricating the AngioChip scaffold, populating it with endothelial cells and parenchymal tissues. The functionality of AngioChip-vascularized hepatic tissue was demonstrated. |
5 | 2018 | Jin Y. et al. [15] | Vascularized liver organoid-like tissue constructs were generated via the 3D co-culture of induced hepatic (iHep) cells and endothelial cells in a 3D decellularized liver extracellular matrix (LEM) hydrogel reconstituted in a microfluidic device. The resulting 3D vascularized liver organoids showed enhanced drug responses, metabolic activity, biosynthetic activity and hepatic functionality under this physiologically relevant culture microenvironment. In addition, the 3D liver organoids were also placed in a tripartite culture along with 3D gastric and small intestinal organoids. The feasibility of using the iHep-based 3D liver organoid is proven. It can be used as a high-throughput drug screening platform, and it can also be used in a multiorgan model consisting of multiple internal organoids. |
6 | 2019 | Carpenter R. et al. [16] | It was found that the human bone marrow stromal cell scaffold improved the preservation of intrinsic hepatic sinusoids and assisted in reaching stably reconnected vasculature compared to scaffold-free and blank-scaffold results. Blank-scaffold and human bone marrow stromal cell scaffold-transplanted hepatic tissues retained morphological features present in the native liver (e.g., portal veins). The characterization of albumin secretion via immunohistochemistry revealed the maintenance of liver function in all transplanted tissues. |
7 | 2020 | Cui J. et al. [17] | A ten-layered liver lobule-like construct with an embedded lumen, containing an inner radial-like poly(ethylene glycol) diacrylate structure with hepatocytes and outer hexagonal gelatin methacrylate structure with endothelial cells, was assembled. The 3D liver lobule-like constructs demonstrated high cell activity throughout long-term co-culture. They also maintained tissue-like morphology and the vascular lumen. The 3D liver lobule-like constructs allowed for perfusion culture through its lumen, which promoted albumin secretion of the embedded cells. |
8 | 2022 | Rajasekar S. et al. [18] | The developed technique was applied to fabricate organ-specific vascular networks and then further scaled to a 24-well plate format to make a large vascular network, vascularized liver tissues and for integration with ultrasound imaging. |
9 | 2024 | Fritschen A. et al. [19] | The functionality of the developed microfluidic chip in combination with the automated 3D-bioprint process and robotic handling is demonstrated. A liver carcinoma model based on HepG2 cells is presented, and a stable microvascular network is developed around the islets of the HepG2 cells. The HepG2 cells proliferate strongly and form spheroidal agglomerates |
10 | 2024 | Jiang Z. et al. [20] | By combining with compatible bioink a bulk gel support medium called omnidirectional printing embedded network, the researchers were able to generate hepato-spheroid-encapsulated artificial liver constructs that maintain liver function in vitro and promote neovascularization in vivo. |
Pancreatic tissue-related applications | |||
11 | 2018 | Jung et al. [21] | Endothelial cells and pancreatic carcinoma cells were encapsulated in fibrin gel and subcutaneously implanted into nude mice. It was shown that 3D cancer xenograft tissue formation may be achieved in vivo by using fibrin hydrogel as a scaffold and endothelial cells to support vasculogenesis. |
12 | 2018 | Weaver J.D. et al. [22] | A synthetic, non-degradable hydrogel microdevice designed to encapsulate and deliver islets to the omentum was presented. The vasculogenic and degradable hydrogel layer that was applied to the macro-device’s exterior interface improved the vascular density in the rat omentum transplant site in vivo. This resulted in improved encapsulated islet viability in a syngeneic diabetic rat model. |
13 | 2022 | Hsu Y.-J. et al. [23] | Using an animal model that is clinically relevant, a cell-based approach for rapidly generating large, functional vasculature was developed and shown to possess advantages over existing techniques. The hydrogel structures’ geometry was optimized by the utilization of diffusion-based computational simulations. Furthermore, transplanted islets were rapidly integrated subcutaneously in this developed functional vascular bed, which significantly improved islet viability and insulin secretion. |
14 | 2022 | Kinney S.M. et al. [24] | It was demonstrated that islets engraft in the subcutaneous space when injected in an inherently vascularizing, degradable methacrylic acid–polyethylene glycol (MAA-PEG) hydrogel. Note that no vascularizing cells or growth factors were required. In diabetic mice, the injection of 600 rodent islet equivalents in MAA-PEG hydrogels was sufficient to reverse diabetes for 70 days. Additionally, a PEG gel without MAA had no benefit. Over the course of a week, the MAA-PEG hydrogel scaffolds degraded and were replaced by a host-derived, vascularized, innervated matrix that supported subcutaneous islets. Islets delivered in degradable hydrogels were incorporated into a host-derived, vascularized, collagen-rich subcutaneous matrix by the 21st day. |
15 | 2022 | Perugini V. et al. [25] | The formation of bioengineered pancreatic islets through cell anchoring to a gelatin-based biomaterial, PhenoDrive-Y, which can mimic the basement membrane of tissues, was demonstrated. This contrasts with the majority of studies published till this date, where pancreatic islets of pancreatic β-cells are encapsulated in hydrogels. Gelatin was used as control. The cultures with PhenoDrive-Y exhibited a greater degree of organization in tissue-like structures, more pronounced endothelial sprouting and stronger expression of characteristic/typical cell markers in comparison to gelatin. In addition, the two constructs were incubated in normo-glycemic conditions and hyperglycemic conditions. |
Renal tissue-related applications | |||
16 | 2019 | Huling J.et al. [26] | In a rat renal cortical defect model, a biomimetic collagen vascular scaffold achieved by means of a vascular corrosion casting technique can improve vascularization within the collagen hydrogel implant. The created scaffolds were coated with endothelial cells to pre-vascularize them. They were then integrated into three-dimensional renal constructs and implanted in the renal cortexes of nude rats, either with or without human renal cells. The collagen-based vascular scaffold that was implanted was easily identified and integrated into native kidney tissue. When combined with human renal cells, the biomimetic collagen vascular scaffolds coated with endothelial cells can improve vascularization and assist the formation of renal tubules after 14 days. |
17 | 2022 | Rajasekar S. et al. [18] | The developed technique was applied to fabricate organ-specific vascular networks, vascularized kidney proximal tubules, in a customized 384-well plate. |
18 | 2023 | Zhang Y. et al. [27] | A novel, biocompatible, 3D, porous gelatin methacrylate (GelMA) hydrogel (DFO-gel) with sustained releasing of deferoxamine (DFO) and a prolonged hypoxia-mimicking environment was developed using a facile and feasible photo-crosslinking method (using UV light) for in situ renal injury repair. This hydrogel can also improve the injured renal microenvironment by alleviating oxidative and inflammatory stresses, accelerating neovascularization and promoting efficient anti-synechia |
Intestinal tissue-related applications | |||
19 | 2024 | Orge I.D. et al. [28] | By integrating vascularized microtissues or vascular units with intestinal organoids within the “vessel-on-chip”, it is illustrated how vascular units can act as “vascularization bridges”, extending a microvascular network throughout the hydrogel bulk and supporting the formation of a vascularized stroma around multiple organoids within a single microfluidic device. |
Stomach tissue-related applications | |||
20 | 2019 | Carpenter R. et al. [16] | Regarding gastric cancer, it was found that tumor morphology appeared to be conserved following transplantation in successfully engrafted tissue. In addition, scaffold-assisted transplantation did not negatively affect the tumor phenotype compared to the control. Also, immuno-histostaining results demonstrate higher mitogenic and human immune cell activities in human tumors co-implanted with biomaterials compared to that of scaffold-free controls. |
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Karageorgos, F.F.; Alexiou, M.; Tsoulfas, G.; Alexopoulos, A.H. Hydrogel-Based Vascularized Organ Tissue Engineering: A Systematized Review on Abdominal Organs. Gels 2024, 10, 653. https://doi.org/10.3390/gels10100653
Karageorgos FF, Alexiou M, Tsoulfas G, Alexopoulos AH. Hydrogel-Based Vascularized Organ Tissue Engineering: A Systematized Review on Abdominal Organs. Gels. 2024; 10(10):653. https://doi.org/10.3390/gels10100653
Chicago/Turabian StyleKarageorgos, Filippos F., Maria Alexiou, Georgios Tsoulfas, and Aleck H. Alexopoulos. 2024. "Hydrogel-Based Vascularized Organ Tissue Engineering: A Systematized Review on Abdominal Organs" Gels 10, no. 10: 653. https://doi.org/10.3390/gels10100653
APA StyleKarageorgos, F. F., Alexiou, M., Tsoulfas, G., & Alexopoulos, A. H. (2024). Hydrogel-Based Vascularized Organ Tissue Engineering: A Systematized Review on Abdominal Organs. Gels, 10(10), 653. https://doi.org/10.3390/gels10100653