Browsing by Author "Lai, Cheuk Sun Edwin"

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    Multidomain peptide hydrogel adjuvants elicit strong bias towards humoral immunity
    (Royal Society of Chemistry, 2022) Pogostin, Brett H.; Yu, Marina H.; Azares, Alon R.; Euliano, Erin M.; Lai, Cheuk Sun Edwin; Saenz, Gabriel; Wu, Samuel X.; Farsheed, Adam C.; Melhorn, Sarah M.; Graf, Tyler P.; Woodside, Darren G.; Hartgerink, Jeffrey D.; McHugh, Kevin J.
    Adjuvants play a critical role in enhancing vaccine efficacy; however, there is a need to develop new immunomodulatory compounds to address emerging pathogens and to expand the use of immunotherapies. Multidomain peptides (MDPs) are materials composed of canonical amino acids that form injectable supramolecular hydrogels under physiological salt and pH conditions. MDP hydrogels are rapidly infiltrated by immune cells in vivo and have previously been shown to influence cytokine production. Therefore, we hypothesized that these immunostimulatory characteristics would allow MDPs to function as vaccine adjuvants. Herein, we demonstrate that loading antigen into MDP hydrogels does not interfere with their rheological properties and that positively charged MDPs can act as antigen depots, as demonstrated by their ability to release ovalbumin (OVA) over a period of 7–9 days in vivo. Mice vaccinated with MDP-adjuvanted antigen generated significantly higher IgG titers than mice treated with the unadjuvanted control, suggesting that these hydrogels potentiate humoral immunity. Interestingly, MDP hydrogels did not elicit a robust cellular immune response, as indicated by the lower production of IgG2c and smaller populations of tetramer-positive CD8+ T splenocytes compared to mice vaccinated alum-adjuvanted OVA. Together, the data suggest that MDP hydrogel adjuvants strongly bias the immune response towards humoral immunity while evoking a very limited cellular immune response. As a result, MDPs may have the potential to serve as adjuvants for applications that benefit exclusively from humoral immunity.
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    Multidomain Peptide Hydrogels for Transected Nerve Regeneration
    (2022-10-20) Lai, Cheuk Sun Edwin; Hartgerink, Jeffrey D; Grande-Allen, K. Jane
    Transected peripheral nerve injury (PNI) is caused by traumatic accidents or medical interventions, leading to the loss of motor and sensory functions in patients. While autografts and FDA-approved nerve guidance conduits (NGCs) are partially effective in treating transected PNI, they suffer from multiple constraints that confine their use to human nerve defects < 3 cm. Hence, further research is conducted to create bioengineered NGCs that strive for accelerated axonal growth, which correlates to better surgical outcome. Recent tissue engineering strategies consist of neurotrophic factors delivery, stem cell encapsulation, and inner structural support. Multidomain peptide (MDP) hydrogels are of interest due to their extracellular matrix-like architecture and bioactive nature that recapitulate native nerve tissues. In this thesis, the neuroregenerative capability of MDP hydrogels and NGCs was vigorously investigated by bridging 10 mm in vivo rat nerve defects and performing functional characterizations at sacrificial timepoints. In chapter 1, the background information of self-assembling peptide hydrogels was reviewed, followed by the previous and current developments of NGCs. In chapter 2, an electrospun poly(ϵ-caprolactone) (PCL) nerve conduit was successfully developed to hold MDP hydrogels and nerve segments in place. In chapter 3, preliminary in vitro and in vivo studies were conducted to optimize the experimental design and to perform initial evaluation on MDPs. Chapter 4 focuses on assessing the efficacy of cationic and anionic MDP hydrogels in restoring motor and electrical functions after rat sciatic nerve transections. Anionic MDP outperforms its cationic counterpart 16 weeks post operation. In chapter 5, the acrylamidation and nucleobase-conjugation on MDPs were examined with potential application in promoting peripheral nerve regeneration. Despite its poor biocompatibility, photo-responsive peptide material can be created by incorporating acrylamides in cationic MDPs. The research on nucleobase modification remains in progress. Fundamentally, the objective of this research is to determine whether MDP hydrogels, when placed within PCL nerve conduits, can accelerate nerve regeneration after sciatic nerve injury and to explore the additional functionalities of MDPs with two modifications.