Stimulus-responsive materials that discriminate between pathological and physiological concentrations of a metabolite or disease marker hold high promises as smart biomedical devices. They might be able to detect a disease state and autonomously trigger a therapeutic response.
The synthesis of materials to specifically detect desired metabolites has been, however, limited by a lack of specific sensors that translate the concentration of an analyte into the desired response of the material. This challenge could be overcome by the development of a generic strategy to functionally incorporate the large variety of biological metabolite sensors into biohybrid materials. The predominant mechanism of such metabolite sensing is based on transcriptional regulator proteins that bind to a cognate DNA sequence in response to the concentration of a specific metabolite.
Wilfried Weber and co-workers (University of Freiburg, Germany) now show how such transcriptional regulator proteins can be used to confer metabolite-responsive properties to a hydrogel. For this aim, the transcriptional regulator protein HucR was used. It binds its cognate hucO DNA sequence and dose-dependently dissociates at increasing concentrations of urate, a salt that at elevated concentrations can lead to gouty arthritis.
The hydrogel was synthesized by coupling HucR to polyacrylamide and crosslinking this polymer by multimeric hucO DNA motifs. The addition of increasing urate concentrations triggered the dissociation of the protein-DNA interactions, the weakening of the hydrogel network and finally its dissolution. It was shown that this hydrogel rapidly dissolves at pathological urate concentrations commonly found in patients suffering from gouty arthritis while the dissolution was strongly reduced at physiological concentrations of this metabolite.
While this material might be further developed as smart implant against gouty arthritis, the general strategy described here can be expanded to other metabolites by simply exchanging HucR/hucO with a protein/DNA pair responsive to the desired metabolite.
Link to the original paper on Wiley Online Library
About Kirsten Severing
Dear Dr. Severing :
It is with much interest that I read the paper on “Metabolite responsive hydrogels”, by Prof. Wilfried Weber and his collaborators. The principle of sensing a metabolie is well demonstrated.
Yet, from this paper I could not fully understand how a device based on this principle can be used as an implanted sensors that further causes the release of a drug.
The dissociation of the system components at high uric acid levels seems to be a “one shot proces”, that is : when the uric acid concentration is restored to normal level as the result of drug action, the system components cannot reassemble themselves back to the original state since, after dissociation, the thus libersted components move away from one another. Or did I miss something ? Thank you for considering my comment.
Sincerely yours,
Noah Lotan
Dear Prof. Lotan,
Thank you for your comment. Indeed, in the present form the hydrogel dissolves at pathological urate concentrations and is unlikely to reassemble upon lowered urate levels. As you mentioned, it represents a possible “one shot” mechanism for releasing an anti-gouty arthritis drug in response to one surge of urate levels. This hydrogel might therefore be further developed as safeguard against sudden uric acid surges as associated with tumor lysis syndrome.
While this study represents the first demonstration of a hydrogel that discriminates between physiological and pathological urate levels, further work might be directed at incorporating this urate-sensing mechanism in semi-interpenetrating networks that are known to reversibly swell and shrink in response to external stimuli that alter the polymer crosslink density. Such hydrogels might be used for repeated releases of drugs in response to repeated increases in urate.
Sincerely,
Wilfried Weber