Multi-functional Biomaterials with Clinical Utility

Abstract

This manuscript reports the development of a new multi-functional biomaterial to treat periodontal disease that possesses antimicrobial—as well as adhesive—properties and supports bone regeneration. The impact of this work is larger than just the specific application of antimicrobial dental materials; results impact tissue engineered biomaterials, antimicrobial peptides, and osteoimmunology.

Many biomaterials—especially dental materials—serve a space-filling role, but not a biologically-instructive role, and have limited ability to regenerate native tissue. Many biomaterials have been developed as “interesting” materials first, with only secondary considerations given to targeting a specific clinical application. Modern biomaterials strive to serve more than a space-filling role and should be designed with a specific clinical need and well-defined end goals in mind. An ideal biomaterial should satisfy design requirements of: (i) biocompatibility and ability to negate inflammatory responses; (ii) ability to guide attachment and proliferation of cells (conductivity); (iii) ability to incorporate inductive factors to direct and enhance new tissue growth (inductivity); (iv) support of vascular ingrowth for oxygen and biomolecule transport; (v) mechanical integrity to support loads at the graft site and adhesion to tissue; (vi) controlled, predictable, and reproducible rate of degradation; and (vii) easy and cost-effective processing into irregular 3D shapes of sufficient size to fill clinically relevant defects.

In the manuscript, “An Antimicrobial Dental Light Curable Bioadhesive Hydrogel for Treatment of Peri-Implant Diseases,” Sani et al.¹ report the development of a multi-functional hydrogel with antimicrobial and adhesive properties. The authors present information on a new biomaterial that integrates elements of anti-microbial materials with elements of adhesive biomaterials and with elements of tissue engineering. These three elements are integrated into a design that can be used in conjunction with a standard dental implant. Moreover, processing approaches were developed that consider practical considerations of how the material will ultimately be used by clinicians. Thus, design criteria (i), (ii), (v), (vi), and (vii) above have potential to be met, with the potential for (iii) to be met if growth factors are encapsulated in the gel.

The biomaterial described in this paper was designed for the treatment of peri-implant diseases (PIDs). PIDs take one of two forms: peri-implant mucositis (PIM), the formation of a biofilm around an implant, or peri-implantitis (PI), inflammation that is frequently associated with bone loss, leading to failure of the implant. Combating problems of infection, inflammation, and bone loss necessitates a multi-functional solution. The authors have done just this, developing a biomaterials approach (in lieu of surgical and/or local delivery of antibiotics) to not only combat inflammation but also to catalyze bone formation (either directly via tissue engineering strategies or indirectly via the reduced inflammation). The hydrogel (GelAMP) is composed of a naturally derived gelatin-based polymer (gelatin methacryloyl, a form of hydrolyzed collagen containing cell binding motifs and sites that degrade when exposed to proteinases) and an anti-microbial peptide (AMP tet213).

The first critical element of the design, antimicrobial activity, was achieved by using an anti-microbial peptide comprised of cationic amino acids and possessing broad spectrum antimicrobial activity. AMPs bind to the negatively charged exterior cell membrane of bacteria, increasing membrane permeability, resulting in cell death. The second critical element of the design was the development of an adhesive hydrogel. Periodontal repair and regeneration are facilitated by “closing” the system—developing adhesion between the space-filling antimicrobial hydrogel and implant on one side and native tissue on the other side of the gel. Through a combination of in vitro and in situ tests, the authors demonstrated that the GelAMP adhered well to gingiva, skin, bone, and titanium. The adhesive serving as a reservoir for the AMPs could protect the AMPs from proteolytic degradation and allow for controlled release of the AMPs. In this regard, the hydrogel exhibited antimicrobial activity against Porphyromonas gingivalis.

Hydrogels are used extensively in tissue engineering because of their tunable properties, and antimicrobial hydrogel adhesives have been developed for the treatment of chronic wounds, as well as cell carriers. The authors’ approach further advances hydrogel-based adhesive biomaterials into periodontal applications, with practical clinical issues considered as part of the design. The GelAMP system is synthesized using a combination of photo-initiators (triethanolamine (TEA)/N-vinyl caprolactam (VC)/ Eosin Y). To provide a photopolymerizable system that has clinical utility, the authors needed to move away from the commonly used cleavage photo-initiators, which are activated at UV wavelengths of 360–400 nm, and develop a system that is activated at wavelengths of FDA-approved dental curing systems (420–480 nm). For this reason, Eosin Y, a visible light activated non-cleavage photoinitiator, was introduced into the system, allowing hydrogel precursors to be rapidly crosslinked in situ under clinical conditions.

A third critical element of the multi-functional design was the ability of the adhesive to support infiltration, attachment, and proliferation of cells throughout the 3D hydrogel network. The hydrogels also promoted cell proliferation and migration and support bone regeneration in vivo, albeit in a different model.

The hydrogels engineered in this study could serve the multiple functions of providing adhesion and antimicrobial resistance and supporting the growth of bone cells, thus solving the concomitant problems of preventing infection, reducing inflammation, and promoting regeneration. The impact of this work is larger than just the specific application of antimicrobial dental materials; results impact tissue engineered biomaterials, antimicrobial peptides, and osteoimmunology.