Supramolecular Injectable Hyaluronate Hydrogels for Tissue Regeneration

Abstract

Hydrogels have been widely investigated as a delivery carrier of cells, biochemicals, and small molecule drugs for tissue regeneration and engineering. In particular, supramolecular hydrogels (sHGs) have been widely investigated as an emerging cell delivery carrier due to the high biocompatibility and injectability. However, there are still some limitations including the difficulty in the control of cell proliferation and differentiation in hydrogels for specific tissue regeneration and the low delivery efficiency of biochemical drugs. Hyaluronate (HA) is a natural biopolymer in body fluids and skin tissue, which has shown outstanding performance for biomedical applications with high cytocompatibility, versatile chemical modifications, good mechanical properties, and enhancing drug stability and delivery efficiency to target cells. In this context, HA based sHGs can be an efficient cell delivery scaffold with biochemical drug delivery strategies for advanced tissue regeneration. In Part II, sHGs composed of HA modified with cyclodextrin and adamantane (HA- CD/Ad-HA) were developed for mesenchymal stem cell (MSC) delivery for cartilage tissue regeneration. CD and Ad are FDA approved molecules, which have a high binding affinity through supramolecular interaction between the inside cavity of CD and Ad molecules. CD/Ad interaction is reversible, enabling the injection of HA-CD/Ad-HA with cells encapsulated in the resulting hydrogels. The HA-CD/Ad-HA hydrogels with MSCs were transplanted into the damaged cartilage tissue. The MSCs delivered by HA-CD/Ad-HA hydrogels were successfully settled in the damaged target site and showed the high differentiation rate to cartilage cells, leading to the accelerated cartilage tissue regeneration. In Part III, biomimetic drug delivery sHGs were described for accelerated skin tissue regeneration. HA-CD/Ad-HA hydrogels demonstrated their feasibility for cell delivery in Part II. However, there are some unmet needs including low cell-hydrogel scaffold interaction and the lack of bioactive molecules, which lead to delayed cell proliferation and tissue formation. To overcome these limitations, gelatin (GE) modified CD and human growth hormone modified Ad-HA (Ad-HA-hGH) were mixed together to prepare GE-CD/Ad-HA-hGH sHGs. GE provided RGD peptide as an adhesion moiety to enhance the cell-hydrogel interaction. Furthermore, Ad-HA-hGH exhibited enhanced hGH delivery efficiency with sustained release and high stability. The additional function of GE-CD/Ad-HA-hGH enabled the accelerated skin tissue regeneration, which was confirmed from the transplanted fibroblast cells in the hydrogels. In Part IV, sHGs with precisely controlled antimicrobial peptide (AMP) delivery were developed for diabetic infected wound healing. Although multi-responsive controlled drug delivery hydrogels were proposed to block the uncontrolled drug release of mono-responsive or sustained drug releasing hydrogel, the previous reports showed the gradually increased dosage of drugs responding to multiple external stimulations. In this work, AMP modified Ad- HA (Ad-HA-AMP) and HA-CD/Ad-AMP hydrogels were synthesized using the cyclic linker composed of matrix metalloproteinase (MMPs) and reactive oxygen species (ROS) cleavable peptide sequence. After that, the controlled release of AMP from the hydrogels was demonstrated in response to the simultaneous stimulation of MMP and ROS in the bacteria infected wound tissue. As a result, HA-CD/Ad-AMP hydrogels induced the precisely controlled AMP dosage with a high delivery efficiency, leading to the minimization of negative side effect of AMP and the enhanced wound healing. In summary, during my Ph.D. course, HA based sHGs have been developed with advanced cell and drug delivery strategies for accelerated tissue regeneration. The materials designed for the sHGs such as GE for cell adhesion, HA-drug modification for high delivery efficacy, and the cyclic peptide linker for controlled delivery of drugs have improved the feasibility of sHGs for tissue regeneration. These efforts would greatly contribute to open a new big avenue for the development of sHGs for various biomedical applications.