Recently, a variety of naturally occurring nanoparticles from English ivy, sundew, fungus, tea, and Chinese yam have drawn researchers’ attention due to their uniqueness properties, promising biocompatibility, less environmental toxicity associated with their production, and their features desired in medicine. These naturally occurring nanoparticles have been demonstrated as good candidates for tissue engineering, drug delivery, immunostimulation, and cosmetic applications. However, they all have some limitations such as low yields for real demand, not fully understand chemical components or structures, and hard to tune the unique functions of naturally occurring nanoparticles. To this end, bio-inspired tunable nanoparticles can solve these issues and offering important advantages.
In this dissertation, we first reviewed the naturally occurring nanoparticles and their limitations (Chapter 1). We then discussed the need and the parameters to design and fabricate bio-inspired tunable nanoparticles for wound healing, Alzheimer’s disease (AD) diagnosis and progression monitoring. Tunable nanoparticles enhanced adhesive was inspired from the self-assembly processes, nanocomposite and chemical structures. Fluorescent peptide nanoparticles were inspired from the biological peptide self-assembly and naturally occurring fluorescent proteins.
Then we reported the development of an in situ synthesis approach for fabricating tunable nanoparticle enhanced adhesives inspired from the strong adhesive produced by English ivy in Chapter 2. Special attention was given to tunable features of the adhesive produced by the biological process. Parameters that may be used to tune properties of the adhesive were proposed. To illustrate and validate the proposed approach, an experimental platform was presented for fabricating tunable chitosan adhesive enhanced by Au nanoparticles synthesized in situ. This study contributes to a bio-inspired approach for in situ synthesis of tunable nanocomposite adhesives by mimicking the natural biological processes of ivy adhesive synthesis.
Using a bio-inspired approach, we synthesized adhesive hydrogels comprised of sodium alginate, gum arabic, and calcium ions to mimic the properties of the natural sundew-derived adhesive hydrogels in Chapter 3. We then characterized and showed that these sundew-inspired hydrogels promote wound healing through their superior adhesive strength, nanostructure, and resistance to shearing; when compared to other hydrogels in vitro. In vivo, sundew-inspired hydrogels promoted a “suturing” effect to wound sites; which was demonstrated by enhanced wound closure following topical application of the hydrogels. In combination with mouse adipose derived stem cells (ADSCs), and compared to other therapeutic biomaterials, the sundew-inspired hydrogels demonstrated superior wound healing capabilities. Collectively, our studies show that sundew-inspired hydrogels contain ideal properties that promote wound healing and suggest that sundew-inspired-ADSCs combination therapy is an efficacious approach for treating wounds without eliciting noticeable toxicity or inflammation.
While tremendous efforts have been spent in investigating scalable approaches for fabricating nanoparticles, less progress has been made in scalable synthesizing cyclic peptide nanoparticles and nanotubes, despite their great potential for broader biomedical applications. In Chapter 4, tunable synthesis of self-assembled cyclic peptide nanotubes and nanoparticles using three different methods, phase equilibrium, pH-driven, and pH-sensitive methods were proposed and investigated. The goal is for scalable nano-manufacturing of cyclic peptide nanoparticles and nanotubes with different sizes in large quality by controlling multiple process parameters. The dimensions of the self-assembled nanostructures were found to be strongly influenced by the cyclic peptides concentration, side chains modification, pH value, reaction time, stirring intensity, and sonication time. This study proposed an overall strategy to integrate all the parameters to achieve optimal synthesis outputs.
AD is associated with the accumulation of insoluble forms of amyloid-beta (Aß) in plaques in extracellular spaces, as well as in the walls of blood vessels, and aggregation of microtubule protein tau in neurofibrillary tangles in neurons. In Chapter 5, we designed and synthesized a series of fluorescent cyclic peptide nanoparticles that can be used to detect Aß aggregates in both the cerebrospinal fluid (CSF) and serum, which were obtained from healthy people and AD patients in different disease stages. Our experimental studies indicate that the fluorescence intensities and wavelengths generated from the interactions between the negatively charged fluorescent cyclic peptide nanoparticles and Aß aggregates in both the CSF and serum changed with disease status, as compared to healthy individuals. The morphological and cytotoxicity studies demonstrated a potential inhibitory effect of the negatively charged nanoparticles on amyloid fibril growth. The underlying mechanisms leading to these changes are interpreted based on the aromatic, hydrophobic, and electrostatic interactions between c-PNPs and Aß peptides.
There is a critical need to diagnose and monitor the progression of AD using blood-based biomarkers. At present, it is believed that no single biomarker can be utilized to reliably detect AD. Combined biomarkers using multimodal techniques are highly sought after for AD diagnosis and progression monitoring. For this purpose, we developed a fluorescent peptide nanoparticles arrayed microfluidic chip that is capable of detecting multiple blood-based AD biomarkers simultaneously in Chapter 6. The concentration, aggregation stages, and Young’s modulus of biomarkers could be analyzed by monitoring the changes of multimodal fluorescence intensity, nano-morphological, and nano-mechanical properties of the f-PNPs array. In this study, Aß polypeptides and tau proteins were used to verify the proposed idea. Experimental results indicated that, compared to healthy human, the concentration, Young’s modulus, and aggregation levels of Aß polypeptides and tau proteins in blood samples of clinically diagnosed AD patients increased continuously with the increase of disease severity.
To conclude, we demonstrate that how to design and fabrication of tunable nanoparticles for biomedical applications. Inspired from English ivy and sundew nanoadhesive, tunable nanoparticles enhanced adhesive hydrogels were prepared and validated for wound healing applications. Moreover, fluorescent peptide nanoparticles were designed, synthesized, characterized, and validated for AD diagnosis and progression monitoring.