Citrate-based Biomaterials for Bioimaging

Restricted (Penn State Only)
- Author:
- Shan, Dingying
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 10, 2018
- Committee Members:
- Jian Yang, Dissertation Advisor/Co-Advisor
Jian Yang, Committee Chair/Co-Chair
Nanyin Zhang, Committee Member
Yong Wang, Committee Member
Harry R Allcock, Outside Member - Keywords:
- citrate
degradation
bioimaging
fluorescence
photoacoustic
MRI
optical fiber - Abstract:
- Increasing occurrences of degenerative diseases, defective tissues and severe cancers heightens the importance of advanced theranostic healthcare, enhancing the need for more powerful bioimaging techniques to produce diagnoses with greater accuracy. To provide safe and effective bioimaging, polymeric biomaterials have been greatly involved in developing imaging probes and devices. However, traditional polymeric biomaterials, which have limited designability and processability, are still inadequate to meet the increasingly sophisticated demands of bioimaging applications. To address this challenge, a new family of biocompatible and biodegradable citrate-based polymers has been developed, whose design flexibility provides the polymers with programmable degradation rates, adjustable mechanical strengths, and versatile functionalities. This dissertation encompasses projects that seek to utilize citrate chemistry to develop biocompatible and biodegradable polymers with strong bioimaging capbilities. The development of three imaging systems are described in this dissertation, including citrate-based fluorescence/photoacoustic dual-imaging enabled electroactive polymers, citrate-based fluorescence/MR dual-imaging enabled biodegradable polymers, and flexible citrate-based biodegradable polymeric step-index optical fiber. Specifically, citrate-based aniline tetramer doped biodegradable photoluminescent polymers (BPLPATs) was first developed, which not only possess programmable degradation profiles (<1 to >6 months) and tunable mechanical strengths (~20 MPa to > 400 MPa), but also present a combination of intrinsic fluorescence, photoacoustic (PA) and electrical conductivity properties. BPLPAT nanoparticles are able to label cells for fluorescence imaging and perform deep-tissue detection with PA imaging. Coupled with significant photothermal performance, BPLPAT nanoparticles present great potential for thermal treatment and in vivo real-time detection of cancers. BPLPAT scaffolds demonstrate three-dimensional (3D) high-spatial-resolution deep tissue PA imaging (~23 mm), as well as promote growth and differentiation of nerve cells. The biodegradable dual-imaging-enabled electroactive citrate-based biomaterial platform has potential to expand the currently available theranostic material systems and open new avenues for diversified biomedical and biological applications via the demonstrated multi-functionalities. Later, in order to achieve bioimaging with deeper penetration and more comprehensive information, citrate-based Gadolinium doped biodegradable photoluminescent polymers (BPLPMGds) were developed. The obtained biocompatible and biodegradable BPLPMGds were fabricated into porous scaffolds possessing fluorescence (from visible light to NIR light) and magnetic resonance (MR) dual imaging capabilities. After implanting BPLPMGd scaffolds subcutaneously and under deep muscle tissues in animals, the combination of NIR and MR imaging successfully enabled quantitative evaluation of fluorescence intensities, distributions, volumes and 3D images of scaffolds at each degradation time point. As such, the fluorescence and MR dual-imaging enabled citrate-based materials successfully realized non-invasive real-time tracking of in vivo scaffold degradation and tissue infiltration/regeneration. In addition to multiple-modality imaging methods, implanting optical fibers into deep-tissues is among the most specific and effective bioimaging approaches to collect biological information. By leveraging the rich designability and processability of citrate-based polymers, a new type of biodegradable, biocompatible, and low-loss (0.4 db/cm) step-index optical fiber was developed for organ-scale light delivery and collection. Practically, two exemplary biodegradable elastomers with a fine refractive index difference and yet matched mechanical properties and biodegradation profiles were employed as the core and cladding materials for the optical fiber. The resulting step-index optical fiber demonstrated favorable biocompatibility, flexible mechanical properties, and high light transmission efficiency. Image transmission and in vivo deep tissue fluorescence sensing through the optical fiber were demonstrated, laying the groundwork for realizing future implantable devices for long-term implantation where deep-tissue light delivery, sensing and imaging are desired, such as cell, tissue, and scaffold imaging in regenerative medicine and in vivo optogenetic stimulation.