Available online 5 May 2023

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Islet transplantation is regarded as the most promising therapy for type 1 diabetes. However, both hypoxia and immune attack impair the grafted islets after transplantation, eventually failing the islet graft. Although many studies showed that biomaterials with nanoscale pores, like hydrogels, could protect islets from immune cells, the pores on biomaterials inhibited vascular endothelial cells (VECs) to creep in, which resulted in poor revascularization. Thus, a hydrogel device that can facilitate in situ immune modulations without the cost of poor revascularization should be put forward. Accordingly, we designed a spA-modified hydrogel capturing anti-HMGB1 mAB (mAB-spA Gel): the Staphylococcus aureus protein A (spA) was conjugated on the network of hydrogel to capture anti-HMGB1mAB which can inactivate immune cells, while the pore sizes of the hydrogel were more than 100μm which allows vascular endothelial cells (VECs) to creep in. In this study, we screened the optimal spA concentration in mAB-spA Gel according to the physical properties and antibody binding capability, then demonstrated that it could facilitate in situ immunomodulation without decreasing the vessel reconstruction in vitro. Further, we transplanted islet graft in vivo and showed that the survival of islets was elongated. In conclusion, mAB-spA Gel provided an alternative islet encapsulation strategy for type 1 diabetes.

Statement of Significance

: Although various studies have shown that the backbone of the hydrogels can isolate islets grafts from immune cells and the survival of the islets can be prolonged by this way, it is also reported that when the pore size of the backbone is too small the revascularization will be adversely affected. According to this point, it is hard to adjust hydrogel's pore size to protect the islets from the immune attack while allowing endothelial vascular cells to creep in. To solve this dilemma, we designed an immunomodulatory hydrogel inhibiting the activation of T cells by immunosuppressive IgGs instead of the backbone network, so the hydrogel can prolong the survival of islets without the sacrifice of revascularization.

Section snippetsINTRODUCTION

Due to glucose homeostasis and the prevention of complications, islet transplantation is regarded as the most promising therapy for type 1 diabetes [1], [2], [3]. However, both hypoxia and immune rejection damage the grafted islets, eventually resulting in 85% failure of grafts after 2 years [4]. Inflammation and immune attack, especially by T cells impair the grafts; lack of blood supply in the first 7 days after transplantation results in more than 60% loss of islets [3], [4], [5], [6], [7].

Materials

Chitosan and acrylic acid were purchased from Sinopharm Chemical Reagent Co., Ltd. Sodium alginate, spA, 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC), sulfo-N-Hyfroxyl succinimide (sulfo-NHS), sodium periodate, spA, and ethylene glycol were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. 0.05M 2-(N-morpholine) sulphonic acid (MES) buffer and β-mercaptoethanol were purchased from Shanghai Macklin Biochemical Co., Ltd. Fatal bovine serum (FBS) was purchased from Gibco.

Fabrication of mAB-spA Gel

The procedure of preparing mAB-spA Gel was demonstrated in Figure 1A. Firstly, we prepared spA-CEC. The fabrication of spA-CEC was performed in two steps. To enhance the solubility under physiological conditions, chitosan was grafted with carboxyethyl by reacting with acrylic acid through Michael's addition. Next, through the condensation reaction of primary amines on CEC and carboxyls on spA, the CEC was further modified with spA. The absorption bond of 1650 cm−1 in the spectrum of chitosan

DISCUSSION

Islet transplantation is the most promising strategy for type 1 diabetes nowadays [1], [2], [3]. However, this strategy is challenged by both hypoxia and immune attack from the host [4]. To prevent islets grafts from contact with immune cells, many micro- or macro-biodevices forming physical barriers have been built up [10], [11], [12], [13], [14]. However, immune attack and hypoxia both contribute to islet graft failure, those devices reducing immune attack by sacrificing revascularization

CONCLUSIONS

We designed a spA-modified hydrogel facilitated in situ immune modulations for islet grafts by slowly releasing anti-HMGB1 antibodies. Different from those biomaterials protecting islet grafts through nanoscale barriers, the mAB-spA Gel prolonged the survival of islet grafts by precisely targeting the secreted HMGB1; this strategy protected islets without the cost of sacrificing revascularization. The mAB-spA Gel could also capture other mAB without any modification to immunosuppressive mAB. In

Supporting Information

The supporting information contains schematic illustrating the components of the mAB-spA Gel, additional details of rheological property of mAB-spA Gel, bright field image of HUVECs seeded on the surface of mAB-spA Gel, H&E stain of β-TC-6 cells and rat islets encapsulated in mAB-spA Gel or not, and immunofluorescence of α-SMA and insulin of the transplants encapsulated in mAB-spA Gel or not.

Data Statement

Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices) as well as the study protocol, statistical analysis plan, and analytic code is made available to researchers who provide a methodologically sound proposal to achieve aims in the approved proposal on request to the corresponding author.

Declaration of Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding

The work was supported by the Program of Natural Science Foundation of China [Nos. 81701950; 82172135]; the Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-MSX0058); the Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJQN202200436); the Basic Research and Frontier Exploration Project of Yuzhong District, Chongqing [No. 20210120]; the CQMU Program for Youth Innovation in Future Medicine [No. W0100] and the Kuanren Talents Program of the second

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