Anti-Pathogenic Hydrogel Nanospike Patch for Controlling Stem Cell Behavior

Stem cell-based therapy is anticipated to contribute to the future of healthcare by enabling the regeneration of damaged or diseased tissues with minimal immune response elicitation. Special characteristics of the stem cell have their abilities to (i) differentiate into other mature cells, (ii) produce crucial soluble factors, (iii) modulate immune responses, (iv) migrate to damaged tissues. Unfortunately, unsolved critical issues in stem cell research remain of the precise and efficient regulation of stem cell proliferation and their differentiation into specific cell phenotypes. To solve the problems, soluble biochemical cues, such as growth factors, cytokines, and organic molecules have been used of conventional approaches. Otherwise, nanotopography has been used to modulate the behaviors of stem cells and improve their abilities by providing them with specific biophysical cues and appropriate microenvironments. Still, those methods have limiting factors of poor engraftments, difficulty in controlling the differentiation into specific mature cells, the potential of tumorigenesis, and ability to stimulate or penetrate cell membranes.<br/>Recently, vertically aligned one-dimensional (1D) nanomaterials, such as nanowire and nanoneedles, have been proposed as efficient platforms. The nanoscale diameters and sharp tips of these nanomaterials enable them to pierce the plasma cell membrane without inducing damage to the membrane integrity, while their long structural height facilitates cellular interfacing with the external environment. Furthermore, the high aspect ratio structures with the sharp nanoscale tips are effective for preventing biofilm formation on the nanomaterial surface based on mechanical lysis. Therefore, the nanostructure holds strong potential as efficient platforms onto which living cells or tissues can be interfaced for use in advanced biomedical applications. However, their rigid mechanical properties and complex fabrication processes limit their practical applications by hindering their integration onto flexible, tissue-adaptable, and large-area patch-type scaffolds.<br/>Here, we present a highly flexible patch that possesses a spiky hydrogel nanostructure array, based on the biocompatible poly(ethylene glycol) dimethacrylate (PEGDMA) polymer with sharp protrusions of 50 nm in tip diameter, as a transplantable platform for enhancing the growth and differentiation of stem cells and efficiently suppressing biofilm formation. In vitro studies show that the hydrogel nanospike patch enhances Dental pulp stem cells (DPSCs) of osteogenic, chondrogenic, and adipogenic differentiation and the secretion of crucial soluble factors without altering cell viability, imposing a strong physical stimulus to the membranes of stem cells. Simultaneously, the array exhibits effective bactericidal properties against Gram-positive and Gram-negative bacteria. In vivo studies further demonstrate that the flexible hydrogel patch with its spiky vertical nanostructures significantly promotes the regeneration of damaged cranial bone tissues while suppressing pathogenic bacterial infections in mouse models. Based on several distinct advantages of the hydrogel nanospike patch, including enhanced stem cell differentiation, enhanced secretion of growth factors, enhanced tissue adhesion, intrinsic antibacterial properties, and high mechanical flexibility, the hydrogel nanospike patch has strong potential for being used as a bioactive stem cell scaffold or implant for use in the field of regenerative medicine.<br/><br/>This work was supported by the National Research Foundation of Korea (NRF-2019M3C1B7025092, 2021R1A2C3006297).