High-strength and fibrous capsule-resistant zwitterionic elastomers

Abstract

The high mechanical strength and long-term resistance to the fibrous capsule formation are two major challenges for implantable materials. Unfortunately, these two distinct properties do not come together and instead compromise each other. Here, we report a unique class of materials by integrating two weak zwitterionic hydrogels into an elastomer-like high-strength pure zwitterionic hydrogel via a "swelling" and "locking" mechanism. These zwitterionic-elastomeric-networked (ZEN) hydrogels are further shown to efficaciously resist the fibrous capsule formation upon implantation in mice for up to 1 year. Such materials with both high mechanical properties and long-term fibrous capsule resistance have never been achieved before. This work not only demonstrates a class of durable and fibrous capsule-resistant materials but also provides design principles for zwitterionic elastomeric hydrogels.

Fig. 1. pCB/pSB ZEN hydrogels with high mechanical properties.

(A) Schematic illustration of the design principles of the high-strength poly(carboxybetaine) (pCB)/poly(sulfobetaine) (pSB) ZEN hydrogel. Left: Masson’s trichrome staining results for skin tissues of mice with hydrogel subcutaneous implantation for 1 year. Skin tissue of mice that were implanted with poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel was set as positive control with fibrous capsule formation. Scale bars, 100 μm. (B to E) Representative uniaxial compressive curves (B); compressive modulus, fracture stress, and fracture strain (C); representative tensile curves (D); and tensile modulus, fracture stress, and fracture strain (E) of the pCB/pSB ZEN, pCB [1-4-0.1], and pSB [4-0.1-0.01] hydrogels. (F) The pCB/pSB ZEN hydrogel sheet can be stretched, twisted, and folded repeatedly without any visible damage observed. (G and H) The pCB/pSB ZEN hydrogel rope with a cross-sectional diameter of 6 mm can hold a weight of 500 g (G) and can tie knots without breaking (H). Note that x, y, and z for [x-y-z] represent the molar monomer concentration, cross-linker concentration [mole percent (mol %) with respect to the monomer], and initiator concentration (mol % with respect to the monomer), respectively. Photo credit: D. Dong (University of Washington, Tianjin University).

Fig. 2. Mechanical and swelling properties of a series of pCB/pSB hydrogels.

(A to D) Compressive fracture stress (A), compressive fracture strain (B), compressive modulus (C), and component mass percentage (D) of a series of pCB/pSB hydrogels with combinations of three pCB network (1-2-0.1, 1-4-0.1, and 2-4-0.1) and seven pSB network (4-0-0.01, 4-0.01-0.01, 4-0.1-0.01, 4-0.2-0.01, 4-0.5-0.01, 2-0.1-0.01, and 6-0.1-0.01) component ratios. (E) Volume change of the pCB/pSB ZEN hydrogel before and after reaching equilibrium in water. The volume of the equilibrated pCB/pSB ZEN hydrogel was normalized to the corresponding as-prepared ZEN hydrogel. Photo credit: D. Dong (University of Washington, Tianjin University). (F) Equilibrium swelling ratios and equilibrium water contents of a series of pCB/pSB hydrogels with combinations of three pCB network and seven pSB network component ratios. Note that x, y, and z for x-y-z represent the molar monomer concentration, cross-linker concentration (mol % with respect to the monomer), and initiator concentration (mol % with respect to the monomer) of the corresponding network, respectively.

Fig. 3. Essential design principles of the ZEN hydrogels.

A minor component network with high swellability and a major component network with the locking effect are the essential design principles of the ZEN hydrogels. (A to C) Compressive fracture stress of pCB/pCB (A), pSB/pCB (B), and pSB/pSB hydrogels (C). The minor component network of these hydrogels was made according to the composition of 1-4-0.1. The major component network was made according to seven different compositions as indicated on the x axis. x, y, and z for x-y-z represent the molar monomer concentration, cross-linker concentration (mol % with respect to the monomer), and initiator concentration (mol % with respect to the monomer) of the corresponding network, respectively. (D to F) Representative compressive curves (D); compressive modulus, fracture stress, and fracture strain (E); and equilibrium swelling ratios and equilibrium water contents (F) of the pCB/pSB ZEN, pCB/pCB, pSB/pCB, and pSB/pSB hydrogels. The pCB/pSB ZEN and pSB/pSB hydrogels were made according to the composition of 1-4-0.1/4-0.1-0.01, while pCB/pCB and pSB/pCB hydrogels were made according to the composition of 1-4-0.1/4-0.2-0.01. Note that x, y, and z for x₁-y₁-z₁/x₂-y₂-z₂ represent the molar monomer concentration, cross-linker concentration (mol % with respect to the monomer), and initiator concentration (mol % with respect to the monomer) for the two component networks, respectively.

Fig. 4. pCB/pSB ZEN hydrogels present long-term fibrous capsule resistance and durability after subcutaneous implantation in mice up to 1 year.

(A and B) H&E staining for skin tissues in contact with the ZEN and pHEMA hydrogels after 1 week of implantation (A). The basophilic discoloration and increased cell counts (stained dark purple) at the interface in contact with pHEMA hydrogels indicate the accumulation of cells into the interface. Masson’s trichrome staining for skin tissues with different hydrogel samples after implantation for 1, 4, and 12 weeks, and 1 year (B). Black arrows indicate the fibrous capsule. Positive controls were skin tissues collected from mice that were implanted with pHEMA hydrogels, while negative controls were collected from mice that did not undergo any surgeries or other experiments. Scale bars, 100 μm. n = 3 for all the implantation experiments (three mice per experiment group/condition and two hydrogel samples per mouse for ZEN or pHEMA hydrogels implantation). (C) Collagen density in the skin tissues adjacent to the hydrogel samples after implantation for 1, 4, and 12 weeks, and 1 year. Data were collected in the skin tissues within 50 μm from the interface (at 10-μm increments). **P < 0.01 versus control; ns, no statistical difference versus control. (D) Normalized dry weight and compressive strength (compressive modulus, stress, and strain) remaining of the ZEN hydrogels during the implantation for 1 year. All data were normalized to that of the original ZEN hydrogels before implantation (0 weeks). (E) Representative images of the implanted mice and retrieved ZEN hydrogels after 1-year implantation. Photo credit: C. Tsao (University of Washington).