Advancements in Injectable Hydrogels for Controlled Insulin Delivery: A Comprehensive Review of the Design, Properties and Therapeutic Applications for Diabetes and Its Complications

Abstract

Glycemic management in diabetes patients remains heavily reliant on multiple daily insulin injections, which often leads to poor patient compliance and an elevated risk of hypoglycemia. To overcome these limitations, injectable hydrogels capable of encapsulating insulin within polymeric networks have emerged as a promising alternative. Ideally, a single injection can form an in situ depot that allows prolonged glycemic control and lower injection frequency. This review summarizes recent advances in injectable hydrogels for controlled insulin delivery, focusing on the polymer sources, crosslinking strategies, and stimuli-responsive release mechanisms. Synthetic polymers such as PEG, PNIPAM, and Pluronics dominate the current research due to their highly tunable properties, whereas naturally derived polysaccharides and proteins generally require further modifications for enhanced functionality. The crosslinking types, ranging from relatively weak physical interactions (hydrogen bonds, hydrophobic interactions, etc.) to dynamic covalent bonds with higher binding strength (e.g., Schiff base, phenylboronate ester), significantly influence the shear-thinning behavior and stimuli-responsiveness of hydrogel systems. Hydrogels' responsiveness to temperature, glucose, pH, and reactive oxygen species has enabled more precise insulin release, offering new options for improved diabetic management. Beyond glycemic regulation, this review also explores insulin-loaded hydrogels for treating complications. Despite the progress, challenges such as burst release, long-term biocompatibility, and scalability remain. Future research should focus on optimizing hydrogel design, supported by robust and comprehensive data.

Keywords: controlled insulin delivery; diabetes; diabetic complications; injectable hydrogels.

Figure 2

The structures of injectable hydrogels prepared with natural polymers, including polysaccharides and proteins. (a) A scanning electron microscopy (SEM) image of the guar-gum-based hydrogel. The hydrogel showed a large number of pores with thin pore walls, demonstrating the tightly crosslinked polymer network. (b) A field emission scanning electron microscopy (FESEM) image of the silk-fibroin-based hydrogel. A layer of silk fibroin nanofibers was formed and tightly covered the pores. Reproduced with permission from [65] Copyright 2021, Wiley-VCH GmbH (a) and [76] Copyright 2020, American Chemical Society (b).

Figure 1

Injectable hydrogels for controlled insulin delivery to treat diabetes and its complications. Injectable hydrogels fabricated from natural or synthetic polymers and crosslinked via physical interactions or chemical covalent bonds can achieve stimuli-responsive insulin release for not only glycemic control but also treatment of complications such as nephropathy, skin ulcers, and retinopathy.

Figure 3

The synthesis schemes for injectable hydrogels prepared from synthetic polymers. (a) The synthesis routes of the PNIPAM-based hydrogel. N-isopropylacrylamide (NIPAM) and 3-acrylamidophenylboronic acid (AAPBA) were copolymerized and then grafted with alginate. (b) The synthesis route of amphiphilic polymers from PEG, enabling self-assembly into the hydrogel. (c) The synthesis routes of PF127-Ad ((i) and (ii)) and CDP (iii). Reproduced with permission from [97] Copyright 2021, American Chemical Society (a), [98] Copyright 2022, Wiley-VCH GmbH (b), and [99] Copyright 2021, Elsevier (c).

Figure 4

A schematic picture of physical and chemical crosslinking in injectable hydrogels prepared for insulin delivery.

Figure 5

The mechanism of glucose-responsive units. (a) The mechanism of the PBA–diol structure for developing glucose-responsiveness. When pH ≥ pKa, PBA shifts to the negatively charged tetrahedral form with a higher affinity for glucose [145]. (b) The mechanism of GOx for developing glucose-responsiveness.

Figure 6

Glucose-responsive PF127-PBA hydrogel with PBA–diol crosslinking. (a) A schematic representation of PF127-PBA hydrogel. PBA-presenting Pluronic micelles were crosslinked with 4-arm PEG diol via dynamic phenylboronate ester bonds. (b) Glycemic control of PF127-PBA hydrogel in diabetic mice. GTT#1 and GTT#2 represent the intraperitoneal injection of glucose. Reproduced with permission from [135] Copyright 2022, American Chemical Society (a,b).

Figure 7

The ZIF@Ins&GOx-PF127 hydrogel. (a) A schematic picture of ZIF@Ins&GOx nanoparticles encapsulated in the PF127 hydrogel matrix. (b) In vivo glycemic control of injectable ZIF@Ins&GOx-PF127 hydrogel. The green arrow indicates intraperitoneal glucose injection. ∗∗ indicates p < 0.01. Reproduced with permission from [170] Copyright 2020, Elsevier (a,b).

Figure 8

Glucose-responsive injectable hydrogel with both phenylboronate ester bonds and GOx as glucose sensors. (a) A schematic diagram of glucose-responsive chitosan-based hydrogel with dual sensors. (b) The profile of the insulin release rate of chitosan-based hydrogel at alternating glucose levels (100 mg/dL and 300 mg/dL). (c) The effect of chitosan-based hydrogel loaded with 0.6 wt% (H) insulin on the glycemic levels in diabetic mice. (d) A schematic diagram of glucose-responsive silk fibroin hydrogel with dual sensors. (e) The effect of silk fibroin hydrogel on the glycemic levels in diabetic mice (green line). Reproduced with permission from [58] Copyright 2023, Elsevier (a–c) and [83] Copyright 2023, American Chemical Society (d,e).

Figure 9

pH-responsive injectable hydrogel systems for insulin delivery. (a) A schematic diagram of NP-encapsulated alginate microgel and glucose-mediated pH-responsive insulin release. (b) The effect of microgel–NPs on the glycemic levels in diabetic mice. Blue arrows indicate subcutaneous injections of the 60 IU/kg microgel-NPs system at days 0 and 6. (c) A schematic diagram of CIN-encapsulated OS-b-PLA-b-PEG-b-PLA-b-OS hydrogel with OS being pH-sensitive modules. (d) The effect of PeCo2-CINs on the glycemic levels in diabetic mice. The PeCo2–CINs systems loaded with 3.75 wt% CINs demonstrated a sustained glycemic control effect. Reproduced with permission from [139] Copyright 2021, Elsevier (a,b) and [118] Copyright 2020, Royal Society of Chemistry (c,d).

Figure 10

Glucose-responsive KGM/PBA–PGA hydrogel for the treatment of diabetic nephropathy. (* p < 0.05; ** p < 0.01, n = 3, compared with control group; # p < 0.05; ## p < 0.01, n = 3, compared with Ins/Lir-hydrogel group, ns, not significant) (a) A schematic of KGM/PBA–PGA hydrogel for the codelivery of insulin and liraglutide. (b) The kidney volume of diabetic rats. The renal hypertrophy of diabetic rats was relieved with Ins/Lir-H treatment. (c) The renal blood resistive index (RI) of diabetic mice. After 6 weeks of Ins/Lir-H treatment, the relatively low RI indicated the recovery of renal blood flow. (d) The immunohistochemical staining of renal TNF-α and MCP-1. (bar upper: 50 μm, bar below: 100 μm) (e) The quantitative statistics of TNF-α and MCP-1. The expressions of TNF-α and MCP-1 with Ins/Lir-H were reversed the most obvious. Reproduced with permission from [10] Copyright 2021, Elsevier (a–e).