Temporal and Spatial Nanobiomaterials for Tissue Engineering and Drug Delivery

Abstract

The intersection of materials science, biology, and nanotechnology has allowed for the development of advanced nanobiomaterials for tissue engineering and drug delivery. With more knowledge of how physical and chemical properties of a biomaterial influence cell function and response, it is important to impart different characteristics to materials with which cells will interact. Characteristics to consider for tissue engineering and/or drug delivery applications include: biocompatibility, mechanical properties, surface area, and ligand presentation. As foreign materials that are placed into the body and are not necessary permanently, these materials should also be biodegradable. Previous biomaterials have fallen short in many ways (i.e. lack of degradability, poor modulus matching, lack of porosity), as it is difficult to design a material with all necessary attributes. The more biomimetic and tailorable a material is, the better suited it is for these applications. New chemistries and approaches must be considered to incorporate all necessary characteristics. This work introduces two new materials that are characterized and evaluated for biomaterials applications and successfully overcome the temporal and spatial shortcomings of previous research. 2-methylene-1,3,6-trioxocane (MTC) is a hydrophobic monomer that is crosslinked with poly(ethylene glycol) diacrylate, a hydrophilic crosslinker, at varying crosslinker concentrations and molecular weights. In this work, with respect to tissue engineering, the materials’ morphological changes, swelling, degradation, and elastic modulus properties are all assessed. Tunability is found in these properties as the crosslinker is adjusted and a hydrophobic-hydrophilic balance dictates many behavioral properties, including an atypical increase in swelling as crosslinker concentration is increased. The biocompatibility is assessed with MTC formulations with 575 Da and 2 kDa crosslinker at 1.0% crosslinker concentrations exhibiting moderate swelling (< 100%) and modulus of ~100 kPa showing good biocompatibility and utility for soft tissue engineering applications. As a drug delivery system (DDS), crosslinked MTC samples were evaluated in terms of tunability and kinetics of drug release behavior. Drug release was tested for three different types of drugs: small molecule hydrophobic, small molecule hydrophilic, and a protein. From the 10-week studies, MTC hydrogels importantly demonstrated suitability for controlled release of the small molecule hydrophobic drug, with constant zero order kinetics displayed across crosslinker variations at physiological pH; the model protein, exhibited first order behavior and increasing drug release as crosslinker concentration increases. Rapid, 1 minute subcutaneous in situ gelling was also demonstrated in a mouse, making MTC advantageous as an injectable DDS. Finally, polymeric nanoparticle functionalization is explored to improve drug targeting/internalization to treat HER2+ breast cancer. This strategy is tested by (1) comparing nanoparticles fabricated from a linear PEGMA-PLGA copolymer versus a novel palm-tree PEGPET-PLGA copolymer chemistry and (2) testing a new targeting peptide sequence and its modified targeting-internalization sequences through the addition of the TAT cell-penetrating peptide sequence. Through early experiments, more than 2 times the binding affinity was measured in vitro for multi-functionalized nanoparticles compared to linear nanoparticles, showing that the increased peptide presentation on the nanoparticles’ surface fabricated with the PEGPET-PLGA copolymer helps enhance cell targeting. Select combination peptide sequences with TAT also show evidence of increased HER2+ affinity. From this thesis, contributions are made to the field of biomaterials by not only providing new materials and chemistries available for varied biomaterials use, but most critically, provides commentary on their necessity, methods to modulate these nanobiomaterials temporally and spatially and appropriate characterization, and their ongoing use.