Yield‐Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration

Abstract

Hydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic cargo. In particular, physically cross‐linked hydrogels exhibit shear‐thinning and self‐healing behaviors enabling facile injectability and depot formation upon administration. While prior efforts to characterize these systems have focused on injectability and cargo release behaviors, prediction of cargo release in the body often assumes these materials form a depot rather than spreading out upon administration. Here, it is evaluated how hydrogel rheology correlates with depot formation and persistence following subcutaneous administration in mice with two physiochemically distinct, physically cross‐linked hydrogel systems. Calcium‐alginate and polymer‐nanoparticle hydrogel systems exhibit variable mechanical behaviors across several rheological properties (stiffness, viscoelasticity, yield stress, and creep). By relating measured rheological properties to depot formation and persistence time following subcutaneous administration, it is identified that yield stress is predictive of initial depot formation while creep is predictive of depot persistence for these two gel systems. Indeed, only materials with yield stresses >25 Pa form robust depots, and reduced creep correlates with longer depot persistence. These findings provide predictive insights into design considerations for hydrogel technologies capable of extended controlled release of therapeutic cargo.

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS-CoV-2 Subunit Vaccine

“…We observed a dramatically decreasing viscosity with an increasing shear rate, thereby confirming the hydrogels’ ability to shear-thin, which is necessary for facile injectability. A stress-controlled flow sweep was also performed to measure the hydrogels’ yield stresses, a critical characteristic for maintaining a robust depot upon administration, [13,19] by determining the stress where the viscosity decreases by 3 orders of magnitude (Figure 2c). We observed decreasing yield stresses as network density decreased, suggesting shorter depot lifetimes.…”

“…In vivo erosion of the hydrogels, which can also be measured as the persistence time of the hydrogels in the subcutaneous space, has been previously reported. [19] Half-lives of hydrogel retention were found to be 8.5 days for PNP-1-5 and 10.9 days for PNP-1-10. While the half-life of hydrogel retention was not measured for PNP-2-10, prior work has also demonstrated that yield stress and pre-shear viscosity are respectively predictive of depot formation and depot persistence time.…”

Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot

“…50 Both of these formulations exhibit sufficiently high yield stress to form a persistent depot in the mouse subcutaneous space upon injection. 48 In addition, the hydrogel is rheologically stable for more than 5 weeks at room temperature (Fig. S2 †).…”

“…50 Finally, the yield stress of each formulation was determined to assess the ability of the depot to retain its shape under the forces present at the site of injection; it has previously been demonstrated that yield stress is an important rheological property for subcutaneous depot formation and retention. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Yield stresses of 70 and 350 Pa were measured for the 1:5 and 2:10 formulations, respectively (Fig. 2g).…”

“…shown that increasing stiffness (modulus) leads to an increase in hydrogel depot persistence time in the subcutaneous space of mice; a 1:5 formulation persists for up to 25 days while a 2:10 formulation should persist for several weeks. 48 One way to assess injectability, a critical attribute for a subcutaneous delivery vehicle, is to measure the shear rate dependence of the viscosity. Both formulations show a decrease in viscosity of nearly three orders of magnitude with increasing shear rate and are shear-thinning (Fig.…”