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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2022)

Precision medicine has the potential to revolutionize cancer care by identifying promising treatment strategies specific to each patient’s disease. While advances in genome sequencing have facilitated the identification of mutations within tumors, only a small number of strict relationships between gene alterations and drug response have been established. Functional precision medicine is an emerging paradigm that exposes living patient-derived tissue to drugs to observe response. The work presented in this thesis will describe the development and implementation of high-throughput platforms for organoid screening. First, I will discuss the varied approaches that have been used to model tumors in vitro. Then, I will present our findings from screening organoids derived from 127 patients with sarcoma specimens collected at UCLA. Next, I describe the development of a pipeline for screening bioprinted organoids with high-speed live cell interferometry to enhance consistency and assess response to treatment with single-organoid resolution. Finally, I will detail the development of new methods for screening radiotherapy and liver-metabolized prodrugs on tumor organoids. This work contributes to the overall goal of creating robust, automated, and informative organoid screening pipelines for the implementation of functional precision medicine in clinical oncology.

    Cover page: High-Throughput Tumor Organoid Models for Functional Precision Medicine
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2020)
    Organ-on-a-chip technology tries to mimic the complexity of native tissues in vitro. Important progress has recently been made in using this technology to study the gut with and without microbiota. These in vitro models can serve as an alternative to animal models for studying physiology, pathology, and pharmacology. While these models have greater physiological relevance than two-dimensional (2D) cell systems in vitro, endocrine and immunological functions in gut-on-a-chip models are still poorly represented. Furthermore, the construction of complex models, in which different cell types and structures interact, remains a challenge. Generally, gut-on-a-chip models have the potential to advance our understanding of the basic interactions found within the gut and lay the foundation for future applications in understanding pathophysiology, developing drugs, and personalizing medical treatments.
      Cover page: Gut-on-a-chip: Current progress and future opportunities
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2024)
      Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.
        Cover page: A platform for rapid patient-derived cutaneous neurofibroma organoid establishment and screening.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2023)
        High throughput drug screening is an established approach to investigate tumor biology and identify therapeutic leads. Traditional platforms use two-dimensional cultures which do not accurately reflect the biology of human tumors. More clinically relevant model systems such as three-dimensional tumor organoids can be difficult to scale and screen. Manually seeded organoids coupled to destructive endpoint assays allow for the characterization of treatment response, but do not capture transitory changes and intra-sample heterogeneity underlying clinically observed resistance to therapy. We present a pipeline to generate bioprinted tumor organoids linked to label-free, time-resolved imaging via high-speed live cell interferometry (HSLCI) and machine learning-based quantitation of individual organoids. Bioprinting cells gives rise to 3D structures with unaltered tumor histology and gene expression profiles. HSLCI imaging in tandem with machine learning-based segmentation and classification tools enables accurate, label-free parallel mass measurements for thousands of organoids. We demonstrate that this strategy identifies organoids transiently or persistently sensitive or resistant to specific therapies, information that could be used to guide rapid therapy selection.
          Cover page: Drug screening at single-organoid resolution via bioprinting and interferometry
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2020)
          Animal models and traditional cell cultures are essential tools for drug development. However, these platforms can show striking discrepancies in efficacy and side effects when compared to human trials. These differences can lengthen the drug development process and even lead to drug withdrawal from the market. The establishment of preclinical drug screening platforms that have higher relevancy to physiological conditions is desirable to facilitate drug development. Here, a heart-on-a-chip platform, incorporating microgrooves and electrical pulse stimulations to recapitulate the well-aligned structure and synchronous beating of cardiomyocytes (CMs) for drug screening, is reported. Each chip is made with facile lithographic and laser-cutting processes that can be easily scaled up to high-throughput format. The maturation and phenotypic changes of CMs cultured on the heart-on-a-chip is validated and it can be treated with various drugs to evaluate cardiotoxicity and cardioprotective efficacy. The heart-on-a-chip can provide a high-throughput drug screening platform in preclinical drug development.
            Cover page: Combined Effects of Electric Stimulation and Microgrooves in Cardiac Tissue‐on‐a‐Chip for Drug Screening
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2020)
            Microneedles (MNs) have been used to deliver drugs for over two decades. These platforms have been proven to increase transdermal drug delivery efficiency dramatically by penetrating restrictive tissue barriers in a minimally invasive manner. While much of the early development of MNs focused on transdermal drug delivery, this technology can be applied to a variety of other non-transdermal biomedical applications. Several variations, such as multi-layer or hollow MNs, have been developed to cater to the needs of specific applications. The heterogeneity in the design of MNs has demanded similar variety in their fabrication methods; the most common methods include micromolding and drawing lithography. Numerous materials have been explored for MN fabrication which range from biocompatible ceramics and metals to natural and synthetic biodegradable polymers. Recent advances in MN engineering have diversified MNs to include unique shapes, materials, and mechanical properties that can be tailored for organ-specific applications. In this review, we discuss the design and creation of modern MNs that aim to surpass the biological barriers of non-transdermal drug delivery in ocular, vascular, oral, and mucosal tissue.
              Cover page: Non-transdermal microneedles for advanced drug delivery
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