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An injectable and biodegradable zwitterionic gel for extending the longevity and performance of insulin infusion catheters

Nature Biomedical Engineering (2023)Cite this article

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Abstract

Continuous subcutaneous insulin infusion (CSII) is an essential insulin replacement therapy in the management of diabetes. However, the longevity of clinical CSII is limited by skin complications, by impaired insulin absorption and by occlusions associated with the subcutaneous insertion of CSII catheters, which require replacement and rotation of the insertion site every few days. Here we show that a biodegradable zwitterionic gel covering the tip end of commercial off-the-shelf CSII catheters fully resolves early skin irritations, extends the longevity of catheters and improves the rate of insulin absorption (also with respect to conventional syringe-based subcutaneous injection) for longer than 6 months in diabetic mice, and by 11 days in diabetic minipigs (from 2 to 13 days, under standard CSII-wearing conditions of insulin pump therapy and in a continuous basal-plus-bolus-infusion setting). The implanted gel displayed anti-inflammatory and anti-foreign-body-reaction properties and promoted the local formation of new blood vessels. The gel is subcutaneously injected before the tip of catheter is inserted into it, and should be generally applicable to CSII catheters and other implantable devices.

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Fig. 1: Schematic representation of injectable zwitterionic gel enabling the long-term use of infusion catheter and faster insulin absorption.
Fig. 2: Zwitterionic gel fully resolved early inflammatory responses and skin irritation.
Fig. 3: Zwitterionic gel enabled the long-term use of infusion catheters and faster insulin absorption in non-diabetic C57BL/6 mice.
Fig. 4: Zwitterionic gel enabled long-term use of an insulin infusion catheter and faster insulin absorption in fresh-induced diabetic C57BL/6 mice.
Fig. 5: Zwitterionic gel enabled the long-term use of insulin infusion catheters and faster insulin absorption in mice with a 3 month diabetic history.
Fig. 6: Zwitterionic gel retained both presence and function in diabetic mice under practical pump therapy conditions.
Fig. 7: Zwitterionic gel enabled the long-term use of subcutaneous infusion catheters and faster insulin absorption in diabetic pigs.
Fig. 8: Degradable gel enables the long-term use of SC infusion catheters and faster insulin absorption in diabetic pigs.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated or analysed during the study are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grant no. DP2DK111910). This work was partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grant no. R01DK123293), National Science Foundation (grant nos. 410853 and 1809229), Juvenile Diabetes Research Foundation (grant nos. 1-SRA-2015-41-A-N, 1-SRA-2016-270-A-N, 2-PNF-2016-324-S-B and 2-SRA-2017-429-S-B) and the faculty start-up fund at Wayne State University.

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  1. Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA

    Ershuai Zhang, Yuanjie Shi, Xiangfei Han, Hui Zhu, Boyi Song, Chengbiao Yang & Zhiqiang Cao

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Contributions

E.Z. and Z.C. conceived the project and designed the experiments. E.Z. conducted all experiments. Y.S. helped with pig experiments. X.H. helped with the inflammatory cytokines assay. H.Z. helped with mouse experiments. B.S. helped with synthesis of CBAA. C.Y. helped with statistical analysis. E.Z. and Z.C. analysed experimental data and wrote the paper. Z.C. supervised the entire study.

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Correspondence to Zhiqiang Cao.

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Extended data

Extended Data Fig. 1 Blood glucose and time to the lowest blood glucose at day 60 and 180 post-implantation in non-diabetic C57BL/6 mice.

Mice received insulin administration (2 IU/kg) through the lumen of the completely implanted catheter in treated and untreated groups and mice receiving syringe-based SC insulin injection at the same dosage were used as control (n = 6 biologically independent animals in each group, mean ± s.d.). A one-way ANOVA with Tukey multi-comparison was used for statistical analysis. For the untreated group at day 180 post-implantation, insulin administration through the lumen of the implanted catheter only can be performed in 2 of 6 mice due to the occlusion of the untreated catheter, and the valid blood glucose data are presented as mean (n = 2 biologically independent animals).

Extended Data Fig. 2 Representative blood vessel staining images in non-diabetic C57BL/6 mice.

Blood vessel staining (brown) using MECA-32 antibody on tissues surrounding SC implanted catheter from different groups at day 14, 30, 60, and 90 post-implantation in healthy C57BL/6 mice. Skin tissue samples collected from mice without implantation surgery were used as a control. Arrow indicates newly formed blood vessels around the zwitterionic gel treated catheter. C: catheter. Scale bar, 100 μm.

Extended Data Fig. 3 Blood glucose and time to the lowest blood glucose at day 60 and 180 post-implantation in fresh-diabetic mice.

Mice received insulin administration (4 IU/kg) through the lumen of the completely implanted catheter in treated and untreated groups and mice receiving syringe-based SC insulin injection at the same dosage were used as control (n = 6 biologically independent animals in each group, mean ± s.d.). A one-way ANOVA with Tukey multi-comparison was used for statistical analysis at day 60. A two-tailed t-test analysis was used for statistical analysis at day 180. For the untreated group at day 180 post-implantation, insulin administration through the lumen of the implanted catheter only can be performed in 1 mouse due to the occlusion of the untreated catheter.

Extended Data Fig. 4 Representative blood vessel staining images in fresh-diabetic C57BL/6 mice.

Blood vessel staining (brown) using MECA-32 antibody on tissues surrounding SC implanted catheter from different groups at day 14, 30, 60, and 90 post-implantation in fresh-diabetic C57BL/6 mice. Skin tissue samples collected from mice without implantation surgery were used as a control. Arrow indicates newly formed blood vessels around the zwitterionic gel treated catheter. C: catheter. Scale bar, 100 μm.

Extended Data Fig. 5 Blood glucose and time to the lowest blood glucose at day 60 and 180 post-implantation in three-month diabetic mice.

Mice received insulin administration (4 IU/kg) through the lumen of the completely implanted catheter in treated and untreated groups and mice receiving syringe-based SC insulin injection at the same dosage were used as control (n = 6 biologically independent animals in each group, mean ± s.d.). A one-way ANOVA with Tukey multi-comparison was used for statistical analysis at day 60. A two-tailed t-test analysis was used for statistical analysis at day 180. For the untreated group at day 180 post-implantation, no insulin administration through the lumen of the implanted catheter only can be performed due to the occlusion of the untreated catheter.

Extended Data Fig. 6 Representative blood vessel staining images in three-month diabetic C57BL/6 mice.

Blood vessel staining (brown) using MECA-32 antibody on tissues surrounding SC implanted catheter from different groups at day 14, 30, 60, and 90 post-implantation in three-month diabetic C57BL/6 mice. Skin tissue samples collected from mice without implantation surgery were used as a control. Arrow indicates newly formed blood vessels around the zwitterionic gel treated catheter. C: catheter. Scale bar, 100 μm.

Extended Data Fig. 7 Representative immunofluorescence staining images in three-month diabetic C57BL/6 mice.

Blood vessel staining using MECA-32 antibody and alpha-smooth muscle actin (α-SMA) antibody on tissues surrounding SC implanted catheter from mice with three-month diabetic history at day 14, 30, and 90 post-implantation. Skin tissue samples collected from mice with three-month diabetic history without receiving implantation surgery were used as a control. SC: subcutaneous; C: catheter. Arrow indicates newly formed blood vessels around the zwitterionic gel treated catheter. Scale bar, 100 μm.

Extended Data Fig. 8 The macrophage recruitment and accumulation in tissues surrounding SC implanted catheter from mice with three-month diabetic history at day 14 and 30 post-implantation.

a, Representative immunofluorescence staining using F4/80 antibody on tissues surrounding SC implanted catheter. Skin tissue samples collected from mice with three-month diabetic history without receiving implantation surgery were used as a control. C: catheter. Arrow indicates the zwitterionic gel around the treated catheter. Scale bar, 100 μm. b, c, Mean fluorescence intensity of F4/80 surrounding SC implanted catheter at day 14 (b) and 30 (c) post-implantation (n = 3 biologically independent samples, mean ± s.d.). Quantitative analysis was performed by ImageJ. A one-way ANOVA with Tukey multi-comparison was used for statistical analysis. Both treated and untreated catheters showed a remarkable macrophage accumulation at both time points relative to the control.

Extended Data Fig. 9 The pro-inflammatory M1 polarization and anti-inflammatory M2 polarization in tissues surrounding SC implanted catheter from mice with three-month diabetic history at day 14 and 30 post-implantation.

a, Representative immunofluorescence staining using CD86 antibody for M1 and CD206 antibody for M2 on tissues surrounding SC implanted catheter from mice with three-month diabetic history at day 14 and 30 post-implantation. Skin tissue samples collected from mice with three-month diabetic history without receiving implantation surgery were used as a control. C: catheter. Arrow indicates the zwitterionic gel around the treated catheter. Scale bar, 100 μm. b, c, The ratio of M2/M1 surrounding SC implanted catheter at day 14 (b) and 30 (c) post-implantation (n = 3 biologically independent samples, mean ± s.d.) was calculated by measuring the mean fluorescence intensity of CD206 over CD86. A one-way ANOVA with Tukey multi-comparison was used for statistical analysis.

Extended Data Fig. 10 The rheological properties, in vitro and in vivo degradability, and vascularizing function of degradable zwitterionic gel after SC injection in healthy C57BL/6 mice.

a, Photograph of the prepared degradable zwitterionic gel (100 uL). b, Representative micrograph of degradable zwitterionic gel after dispersed in DI water. c, d, Frequency-dependent (c, under 1% strain, 25 °C) and strain-dependent (d, 10 rad/s frequency, 25 °C) oscillatory sweeps of degradable zwitterionic gel. e, In vitro degradation of degradable zwitterionic gel in PBS containing 20 µM GSH (n = 3 independent samples, mean ± s.d.) f, The degradable zwitterionic gel (100 uL) was SC implanted into the mice (n = 5 for each group at each time point). g, h, Representative Masson trichrome staining images (g) and blood vessel staining (brown) using MECA-32 antibody (h) on tissues surrounding SC injected degradable zwitterionic gel at day 30, 60, and 90. Scale bar, 1000 μm in g and 200 μm in h. i, Blood vessel density at different time points post-injection (n = 5 biologically independent samples at each time point, mean ± s.d.). A one-way ANOVA with Tukey multi-comparison was used for statistical analysis.

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Zhang, E., Shi, Y., Han, X. et al. An injectable and biodegradable zwitterionic gel for extending the longevity and performance of insulin infusion catheters. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01108-z

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