Supramolecular polymers for drug-induced tissue regeneration

Amphibians and primitive organisms have the ability of complete restoration of tissue architecture and function (i.e. epimorphic regeneration), whereas most mammals including humans generally heal large wounds by scar. An exception is found in Murphy Roths Large (MRL) mouse, an inbred strain that is capable of regenerating multiple tissues, enabled by robust expression of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). HIF- 1α is constitutively expressed, but its levels are normally kept in check due to degradation induced by prolyhydroxylase (PHD) modification. This suggests that transient stabilization of HIF-1α, achieved by therapeutic inhibition of PHD, can be exploited for tissue regeneration. We refer to this concept as drug-induced regeneration, an approach that differs from conventional tissue engineering strategies in two important ways: 1) tissue regeneration is enabled pharmacologically rather than through the use of polymer scaffolds, cells and/or growth factors; 2) in most cases regeneration can be orchestrated without the implantation of a biomaterial or biologic within the wound itself.

We designed polymer-drug conjugates that self-assemble into supramolecular nanostructures, driven by the hydrophobic nature of a conjugated PHD inhibitor that is released by hydrolysis in-vivo. I will describe the design and properties of the supramolecular polymer prodrug and its use in both hard and soft tissue regeneration. One example is periodontal regeneration, where our approach is being investigated as a novel nonsurgical adjunctive treatment for aveolar bone regeneration in periodontal disease. A second clinical target is inflammatory bowel disease, which is characterized by breakdown of the epithelial barrier of the intestines, leading ultimately to scar formation. We show that supramolecular polymer prodrug leads to restoration of tissue architecture in a mouse model of colitis.