MULTIFUNCTIONAL BIOMATERIAL TECHNOLOGIES WITH SUSTAINED DRUG DELIVERY FOR DIVERSE PERIODONTAL AND CRANIOFACIAL REGENERATION APPLICATIONS

Abstract

Biomaterial constructs serve as space-filling templates for guided tissue regeneration in critical-sized defects where the tissue would otherwise be unable to regenerate on its own. Such constructs are frequently used in dental and craniofacial bone regeneration applications where trauma, infections, and common diseases (e.g., periodontal disease) usually degrade these skeletal tissues beyond natural repair. However, current biomaterial technologies have limited long-term efficacies and produce bone of varying quality across patients, ultimately making them unpredictable. Current biomaterial constructs are severely limited by their lack of chemical signals (i.e., therapeutic drug delivery) to aid the physical microenvironment signals of the construct design that control stem cell differential fate for predictable regeneration. Additionally, current constructs display an inability to be precisely shaped to defects without destroying specific design features of the physical microenvironment (e.g., scaffold macropores) necessary to guide quality bone formation with.

This thesis rectifies these problems with a series of biomaterial construct technologies optimized from a semi-interpenetrating network of poly-ε-caprolactone-diacrylate (PCL-DA) in poly-L-lactide (PLLA) that possess thermal shape memory (TSM) and nanofiber formation through thermally-induced phase separation. The TSM biomaterials exhibited thermosensitive properties at temperatures above 50C, enabling them to attain a rubbery state with enhanced shaping properties or recover their memorized shape via shape memory. The first technology utilizes the partial phase separation of PCL-DA and PLLA within a two-dimensional TSM biomaterial thin film construct and its consequential biphasic morphology to develop a novel tissue engineering membrane for periodontal regeneration capable of defect protection and regeneration. This tissue engineering membrane presents high sutureability and shapeability at clinically-feasible transition temperatures but resists suture pull-out at physiological temperatures. Furthermore, a novel drug delivery system was installed into the nanofibrous bottom layer of these membranes by embedding PLGA nanoparticles encapsulating protein and small molecule therapeutics into the nanofibers. The nanoparticles were unidirectionally released due to the biphasic hydrolytic degradation of the membranes at an approximately linear rate measured for up to 81 days, allowing for sustained unidirectional therapeutic delivery. The drug delivery system was used to deliver platelet-derived growth factor (PDGF) in-vivo directly into a periodontal defect, resulting in significantly enhanced periodontal regeneration and bone mineralization in a critical-sized periodontal defect rat model that outperformed a clinical-standard commercial brand of FDA-approved periodontal membranes. Overall, this membrane technology presents a versatile strategy for facilitating tissue regeneration and sustained therapeutic delivery, while also offering protection from the oral cavity and possessing convenient clinical-handling properties. It represents an important advance over current periodontal membranes.

The second technology utilizes the invented TSM biomaterial in a three-dimensional application for the development of a novel thermosensitive, memorized-microstructure (TS-MMS) scaffold. The TS-MMS scaffold showed a homogenous, nanofibrous morphology with thermosensitive shaping and macropore shape memory. The scaffold was characterized for its physical and thermal properties to be optimized for its ability to be shaped to irregular defects and to recover its spherical macropores via thermal shape memory. Additionally, a nanofiber-embedded nanoparticle drug delivery system was incorporated into the TS-MMS scaffold using a newly designed sugar-particle adhesion method. The release from the drug delivery system was measured for up to 40 days but was projected to extend as far out as 90 days. In-vivo experiments using TS-MMS scaffolds and TS- MMS scaffolds with simvastatin showed that the scaffolds promoted cell migration, adhesion, microvascular formation, and osteogenesis. The TS-MMS scaffolds with simvastatin release showed the most significant advances in these areas, resulting in highly mature tissue and extracellular matrix formation within those scaffolds.