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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2023)

The immune system serves as a vital defense mechanism, protecting the body against exogenous pathogens and endogenous aberrations through a complex network of cells and signaling pathways. Many diseases arise as a consequence of imbalanced or ineffective immune responses. However, altering the immune system systematically can lead to a range of complications and negative outcomes. Thus, targeted and controlled modulation of the local immune cells and their responses is highly desirable, which minimizes side effects throughout the body and provide precision medicine with the lowest effective dose at local tissues. My thesis harnesses principles of immunoengineering, drug delivery and regenerative medicine to achieve local immune modulation via engineered microneedle patches (MNP) that enables minimally invasive tissue penetration and local retention. To address the critical role of destructive immune cells in tissue loss and achieve periodontal tissue regeneration, I engineered a modular MNP that allows a multistage and controlled release of antibiotics and cytokines. My work demonstrated that the dual delivery of antibiotics and cytokines modulated immune cells, promoted pro-regenerative signals locally, and reversed the degeneration of soft tissue and bone. I further simplified the formulation by identifying a bifunctional antibiotic that not only suppresses bacterial growth but also modulates the macrophages to suppress inflammation, and utilized a fast-degrading MNP loaded with biodegradable PLGA microparticles. Significant therapeutic effects, including suppression of pro-inflammatory cytokine secretion, induction of pro-regenerative cytokines and promotion of tissue/bone regeneration markers were observed in rat periodontitis model. In another application, to suppress the immunogenicity of viral vectors during in vivo gene delivery and boost gene transduction efficiency, I optimized a dissolvable MNP that maintains the virus integrity and releases immunomodulatory agents slowly via microparticles that can be integrated into MNP, and showed that local and slow release of immunosuppressants (i.e. dexamethasone) enhances gene transfer efficiency. Our results in mouse ischemia-reperfusion model demonstrated a significant increase of gene transduction efficiency in the heart. Overall, this work uses MNP as a drug delivery strategy for its minimal invasiveness, local penetration, sustained release and controlled delivery. It reveals the feasibility and efficacy to locally modulate immune responses for more efficient tissue regeneration and gene therapy.

    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2021)
    Infection by SARS-CoV-2 virus often induces the dysregulation of immune responses, tissue damage, and blood clotting. Engineered biomaterials from the nano- to the macroscale can provide targeted drug delivery, controlled drug release, local immunomodulation, enhanced immunity, and other desirable functions to coordinate appropriate immune responses and to repair tissues. Based on the understanding of COVID-19 disease progression and immune responses to SARS-CoV-2, we discuss possible immunotherapeutic strategies and highlight biomaterial approaches from the perspectives of preventive immunization, therapeutic immunomodulation, and tissue healing and regeneration. Successful development of biomaterial platforms for immunization and immunomodulation will not only benefit COVID-19 patients, but also have broad applications for a variety of infectious diseases.
      Cover page: Biomaterial-based immunoengineering to fight COVID-19 and infectious diseases
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2022)
      Periodontal disease begins as an inflammatory response to a bacterial biofilm deposited around the teeth, which over time leads to the destruction of tooth-supporting structures and consequently tooth loss. Conventional treatment strategies show limited efficacy in promoting regeneration of damaged periodontal tissues. Here, a delivery platform is developed for small extracellular vesicles (sEVs) derived from gingival mesenchymal stem cells (GMSCs) to treat periodontitis. EVs can achieve comparable therapeutic effects to their cells of origin. However, the short half-lives of EVs after their administration along with their rapid diffusion away from the delivery site necessitate frequent administration to achieve therapeutic benefits. To address these issues, "dual delivery" microparticles are engineered enabling microenvironment-sensitive release of EVs by metalloproteinases at the affected site along with antibiotics to suppress bacterial biofilm growth. GMSC sEVs are able to decrease the secretion of pro-inflammatory cytokines by monocytes/macrophages and T cells, suppress T-cell activation, and induce the formation of T regulatory cells (Tregs) in vitro and in a rat model of periodontal disease. One-time administration of immunomodulatory GMSC sEV-decorated microparticles leads to a significant improvement in regeneration of the damaged periodontal tissue. This approach will have potential clinical applications in the regeneration of a variety of tissues.
        Cover page: Engineered Delivery of Dental Stem‐Cell‐Derived Extracellular Vesicles for Periodontal Tissue Regeneration
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2021)
        Cell reprogramming is considered a stochastic process, and it is not clear which cells are prone to be reprogrammed and whether a deterministic step exists. Here, asymmetric cell division (ACD) at the early stage of induced neuronal (iN) reprogramming is shown to play a deterministic role in generating elite cells for reprogramming. Within one day, fibroblasts underwent ACD, with one daughter cell being converted into an iN precursor and the other one remaining as a fibroblast. Inhibition of ACD significantly inhibited iN conversion. Moreover, the daughter cells showed asymmetric DNA segregation and histone marks during cytokinesis, and the cells inheriting newly replicated DNA strands during ACD became iN precursors. These results unravel a deterministic step at the early phase of cell reprogramming and demonstrate a novel role of ACD in cell phenotype change. This work also supports a novel hypothesis that daughter cells with newly replicated DNA strands are elite cells for reprogramming, which remains to be tested in various reprogramming processes.
          Cover page: Asymmetric Cell Division of Fibroblasts is An Early Deterministic Step to Generate Elite Cells during Cell ReprogrammingCreative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2013)
          The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
            Cover page: Discovery of Potent, Selective Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1) Inhibitors Through Prescription Drug Profiling and Computational Modeling
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2020)
            Immune cells can sense and respond to biophysical cues - from dynamic forces to spatial features - during their development, activation, differentiation and expansion. These biophysical signals regulate a variety of immune cell functions such as leukocyte extravasation, macrophage polarization, T cell selection and T cell activation. Recent studies have advanced our understanding on immune responses to biophysical cues and the underlying mechanisms of mechanotransduction, which provides rational basis for the design and development of immune-modulatory therapeutics. This review discusses the recent progress in mechanosensing and mechanotransduction of immune cells, particularly monocytes/macrophages and T lymphocytes, and features new biomaterial designs and biomedical devices that translate these findings into biomedical applications.
              Cover page: Unraveling the mechanobiology of immune cells.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2022)
              Periodontal diseases are caused by microbial infection and the recruitment of destructive immune cells. Current therapies mainly deal with bacteria elimination, but the regeneration of periodontal tissues remains a challenge. Here we developed a modular microneedle (MN) patch that delivered both antibiotic and cytokines into the local gingival tissue to achieve immunomodulation and tissue regeneration. This MN patch included a quickly dissolvable gelatin membrane for an immediate release of tetracycline and biodegradable GelMA MNs that contained tetracycline-loaded poly(lactic-co-glycolic acid) nanoparticles and cytokine-loaded silica microparticles for a sustained release. Antibiotic release completely inhibited bacteria growth, and the release of IL-4 and TGF-β induced the repolarization of anti-inflammatory macrophages and the formation of regulatory T cells in vitro. In vivo delivery of MN patch into periodontal tissues suppressed proinflammatory factors and promoted pro-regenerative signals and tissue healing, which demonstrated the therapeutic potential of local immunomodulation for tissue regeneration.
                Cover page: Immunomodulatory microneedle patch for periodontal tissue regeneration
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2016)

                Introduction

                Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers.

                Methods

                Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1].

                Results

                Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005].

                Conclusions

                These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.
                  Cover page: The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin
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