Adhesive Hydrogels for Maxillofacial Tissue Regeneration Using Minimally Invasive Procedures

Abstract

Minimally invasive surgical procedures aiming to repair damaged maxillofacial tissues are hampered by its small, complex structures and difficult surgical access. Indeed, while arthroscopic procedures that deliver regenerative materials and/or cells are common in articulating joints such as the knee, there are currently no treatments that surgically place cells, regenerative factors or materials into maxillofacial tissues to foster bone, cartilage or muscle repair. Here, hyaluronic acid (HA)‐based hydrogels are developed, which are suitable for use in minimally invasive procedures, that can adhere to the surrounding tissue, and deliver cells and potentially drugs. By modifying HA with both methacrylate (MA) and 3,4‐dihydroxyphenylalanine (Dopa) groups using a completely aqueous synthesis route, it is shown that MA‐HA‐Dopa hydrogels can be applied under aqueous conditions, gel quickly using a standard surgical light, and adhere to tissue. Moreover, upon oxidation of the Dopa, human marrow stromal cells attach to hydrogels and survive when encapsulated within them. These observations show that when incorporated into HA‐based hydrogels, Dopa moieties can foster cell and tissue interactions, ensuring surgical placement and potentially enabling delivery/recruitment of regenerative cells. The findings suggest that MA‐HA‐Dopa hydrogels may find use in minimally invasive procedures to foster maxillofacial tissue repair.

Complementary techniques to analyse pericellular matrix formation by human MSC within hyaluronic acid hydrogels

“…Double modified HA monomers (methacrylate, MA; 3,4dihydroxyphenylalanine, Dopa) were synthesised as previously described. 22 Firstly, HA (100-150 kDa, LifeCore Biomedical) was reacted with methacrylic anhydride (20-fold excess relative to primary HA hydroxyl groups, Santa Cruz Biotechnology) in an aqueous environment (pH 8). The reaction mixture was incubated at room temperature (RT) for 4 h and its pH adjusted by addition of NaOH (pH 8).…”

“…Dithiol-PEG (65 mM, 1 kDa, from JenKem Technology) and eosin-Y (154 mM, Fisher Scientific) in cell culture media, were sterilised using 0.22 mm syringe filters and mixed with the monomer (3% w/v, final concentration) on an Eppendorf Thermomixer at 37 1C. These hydrogels form in o2 min and have a G 0 of B1000 Pa. 22 hMSC (1 Â 10 6 cells mL À1 ) were added to the dissolved monomer and homogenised on an Eppendorf Thermomixer for 15 min at 37 1C. Hydrogels were formed using a step-growth reaction, triggered by blue light exposure (400-500 nm, 500-600 mW cm À2 , 4 min, S1500 OmniCure Light System, Lumen Dynamics).…”

“…1). 22 These hydrogels also contain Dopa groups, the active component of the mussel foot protein, which is well known for its adhesive properties. 23 When HA is modified with both MA and Dopa, the Dopa moieties do not participate in cross-linking, but rather function as a scavenging group, reducing kinetic chain formation.…”

“…These hydrogels have previously been shown to support hMSC viability and allow for pericellular matrix formation. 22 In this system, the Dopa in its reduced form can later oxidise, allowing for biological interactions. Hydrogels containing the Dopa modification (MA-HA-Dopa) adhere to cartilage tissue and support the viability of encapsulated hMSC, likely by binding serum proteins to provide sites for integrin-mediated interactions.…”

“…Hydrogels containing the Dopa modification (MA-HA-Dopa) adhere to cartilage tissue and support the viability of encapsulated hMSC, likely by binding serum proteins to provide sites for integrin-mediated interactions. 22 Hypoxia is known to drive chondrogenesis in vitro and in vivo 24,25 and plays important roles in both the secretion and maintenance of the cartilage ECM. 26,27 Therefore, means to harness hypoxia for cartilage tissue engineering are widely pursued.…”