Factors That Influence Base-Catalyzed Thiol-Ene Hydrogel Synthesis

Abstract

Injectable, localized drug delivery using hydrogels made from ethoxylated trimethylolpropane tri-3-mercaptopropionate (ETTMP) and poly(ethylene glycol) diacrylate (PEGDA) has shown great potential due to these hydrogels' ability to exhibit non-swelling behavior and tunable drug release properties. However, current synthesis methods in the literature suffer from poor ETTMP solubility in water, slow gelation times exceeding 20 min, and a lack of reproducibility. To address these limitations, we have developed a reliable synthesis procedure and conducted a sensitivity analysis of key variables. This has enabled us to synthesize ETTMP-PEGDA hydrogels in a polymer concentration range of 15 to 90 wt% with gelation times of less than 2 min and moduli ranging from 3.5 to 190 kPa. We overcame two synthesis limitations by identifying the impact of residual mercaptopropionic acid and alumina purification column height on gelation time and by premixing ETTMP and PEGDA to overcome low ETTMP solubility in water. Our ETTMP-PEGDA mixture can be stored at -20 °C for up to 2 months without crosslinking, allowing easy storage and shipment. These and previous results demonstrate the potential of ETTMP-PEGDA hydrogels as promising candidates for injectable, localized drug delivery with tunable drug release properties.

Keywords: ETTMP; PEGDA; erodible; hydrogels; injectable; thiol-ene.

Figure 1

Conjugate Michael reaction to form the thiol–acrylate crosslinking network. A 2:3 ratio of ETTMP to PEGDA is used to achieve stoichiometric equivalence.

Figure 2

Increasing the purification column height reduces the gelation time and MPA concentration. All samples were made using a buffer pH of 7.4 and a 15 s vortex to mix. Error bars represent standard deviation, where n = 3.

Figure 3

Time required to purify ETTMP and PEGDA at various purification column heights (PCHs).

Figure 4

Higher pH and a 35 wt% gel formulation resulted in faster gelation times. Error bars represent standard deviation, where n = 3.

Figure 5

Storing stoichiometric mixtures of ETTMP and PEGDA at −20 °C prevents unwanted storage crosslinking for at least 60 d compared to storing in a refrigerator and at 25 °C.

Figure 6

A stoichiometric mixture of ETTMP and PEGDA froze after being stored at −20 °C (left) and thawed at room temperature (right).

Figure 7

Purification schematic using basic alumina as the adsorbent. Note that the red arrow represents the flow of ETTMP through the column of basic alumina to remove degraded MPA.