Fast-forming hydrogel with ultralow polymeric content as an artificial vitreous body



Kaori Hayashi, Fumiki Okamoto, Sujin Hoshi, Takuya Katashima, Denise C. Zujur, Xiang Li, Mitsuhiro Shibayama, Elliot P. Gilbert, Ung-il Chung, Shinsuke Ohba, Tetsuro Oshika & Takamasa Sakai



Degradation-induced swelling in implanted hydrogels can cause severe adverse reactions in surrounding tissues. Here, we report a new class of hydrogel with extremely low swelling pressure, and demonstrate its use as an artificial vitreous body. The hydrogel has ultralow polymer content (4.0 g l−1), low cytotoxicity, and forms in situ in 10 minutes via the crosslinking of clusters of highly branched polymers of tetra-armed poly(ethylene glycol) prepolymers. After injection and gelation in the eyes of rabbits, the hydrogel functioned as an artificial vitreous body for over a year without adverse effects, and proved effective for the treatment of retinal detachment. The properties of the hydrogel make it a promising candidate as an infill biomaterial for a range of biomedical applications.

An optimal biomaterial for implantation would be that which can be introduced into the body without the need for a surgical procedure, effectively provides treatment for its target disease, and causes no harm to surrounding tissues throughout its life. Although some hydrogels can be introduced into the body via injection of a polymer solution followed by in situ polymer crosslinking, conventional hydrogels often swell, which compromises their morphological and mechanical compatibility in vivo. Typically, hydrogels that form in situ have a higher osmotic pressure (Πos) than that of the physiological aqueous environment. Because of this difference in osmotic pressure, the hydrogel absorbs water from the surrounding environment, resulting in swelling. This induces elastic pressure within the hydrogel (Πel). Still, because in good solvent Πos tends to be much larger than Πel, most hydrogels swell in aqueous conditions, with a swelling pressure, Πsw = ΠosΠel. After a certain magnitude of swelling has occurred, a hydrogel reaches a swollen equilibrium state (Πsw = 0; ref. ). Owing to hydrogel degradation, this equilibrium is typically transient; the degradation-induced reduction of Πel shifts the equilibrium to a more swollen condition. Because conventional hydrogels degrade in vivo on a long-term basis, additional swelling may be delayed but cannot be prevented, even in the case of ‘non-swellable’ hydrogels. Such additional swelling has caused serious adverse reactions in ophthalmological applications. For example, the MIRAgel hydrogel was commercialized in the 1980s as an eye buckle for the treatment of detached retinas; yet more than 7 years after installation, swelling caused by the degradation of MIRAgel in the eye socket eventually compressed the eyeball, which led to blindness in some patients.



The maximum Πsw that can be exerted by a hydrogel is Πos. Hence, to eliminate problems caused by swelling, Πos should be reduced. The simplest procedure for reducing Πos is to decrease polymer concentration. However, the slower gel formation that results from lower polymer content often precludes the use of such a gel in biomedical applications. For example, for tetra-armed poly(ethylene glycol) (Tetra-PEG) gels at the lowest polymer concentration for gel formation, 6.0 g l−1, gelation takes about 7 hours, which far exceeds possible surgical timescales. Here we describe a hydrogel with extremely low polymer content (~4.0 g l−1) that forms in situ within 10 minutes, and demonstrate the application of the hydrogel as an artificial vitreous body for treating retinal detachment.


Nature Biomedical Engineering: