{
  "abstract": "Malaria remains a major global health burden, with diagnosis often relying on ex vivo analysis of infected red blood cells (RBCs), which incompletely samples key stages of parasite development. In particular, early ring-stage parasites exhibit subtle structural perturbations, while a significant fraction of parasite burden─including immature gametocytes─is sequestered within the microvasculature and is not readily captured in peripheral blood smears. Here, we present a label-free imaging and analysis framework that integrates oblique back-illumination microscopy (OBM) with data-driven classification to detect malaria infection by sensing parasite-induced intracellular heterogeneity. Unlike stained brightfield microscopy and quantitative phase imaging (QPI) methods that depend on interferometric acquisition and phase reconstruction, OBM directly converts intracellular refractive-index gradients into measurable intensity variations through noninterferometric phase-gradient contrast. By exploiting multiply scattered illumination and asymmetric detection, OBM enhances sensitivity to parasite-induced refractive-index gradients associated with Plasmodium falciparum development, capturing morphological complexity across the intraerythrocytic lifecycle. This enables the discrimination of uninfected cells, early ring-stage infections, and mature gametocytes. Fourier-domain analysis further reveals infection-stage-dependent redistribution of spatial-frequency content, providing a physically interpretable description of progressive intracellular remodeling during parasite development. Using synchronized in vitro cultures with brightfield validation, we demonstrate automated classification of infected RBCs with accuracies of 95% for binary classification and 82% for multiclass classification, with consistent precision, recall, and F1-scores across repeated randomized data splits. Together, these results establish OBM as a scalable, label-free sensing strategy that leverages intracellular heterogeneity as a diagnostic signal while providing access to stage-resolved optical phenotypes that remain difficult to interrogate with existing approaches. By building on prior studies of in vivo phase-gradient imaging, this framework provides a pathway toward integrating OBM with real-time analysis for noninvasive and field-deployable malaria diagnostics, particularly where conventional ex vivo measurements are limited by parasite sequestration.",
  "abstract_shown": true,
  "affiliations": [
    "Johns Hopkins University , , , ,",
    "Georgia Institute of Technology and Emory University , , , ,",
    "Johns Hopkins University School of Medicine , , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Michael Ka Ho Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "Yilin Guan"
    },
    {
      "affs": [
        0
      ],
      "name": "Caoze Huang",
      "orcid": "0009-0004-2873-8055"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ayan Guha"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Ishan Barman",
      "orcid": "0000-0003-0800-0825"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6njsp7e3wx8j2.bib",
  "cited_by": 0,
  "doi": "10.1021/acsomega.6c11324",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736857/",
  "id": "6njsp7e3wx8j2",
  "issns": [
    "2470-1343"
  ],
  "landing_url": "https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c11324/5454864/Oblique-Back-Illumination-Microscopy-Enables-Phase",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "3107|Digital Holography and Microscopy"
    ]
  ],
  "openalex": "W7223144571",
  "pdf_url": "https://pubs.acs.org/doi/pdf/10.1021/acsomega.6c11324",
  "pmcid": "PMC13736857",
  "pmid": "42991882",
  "published": "2026-10-21",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/6njsp7e3wx8j2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:39Z",
      "native_id": "10.1021/acsomega.6c11324",
      "source": "crossref",
      "url": "https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c11324/5454864/Oblique-Back-Illumination-Microscopy-Enables-Phase"
    },
    {
      "first_seen": "2026-11-09T12:22:13Z",
      "native_id": "PMC13736857",
      "source": "pmc",
      "url": "https://doi.org/10.1021/acsomega.6c11324"
    }
  ],
  "subjects": [
    {
      "field": "physics",
      "origin": "openalex:3107|Digital Holography and Microscopy",
      "subfield": "amo"
    }
  ],
  "title": "Oblique Back-Illumination Microscopy Enables Phase-Gradient Optical Sensing of Malaria-Induced Intracellular Heterogeneity",
  "title_text": "Oblique Back-Illumination Microscopy Enables Phase-Gradient Optical Sensing of Malaria-Induced Intracellular Heterogeneity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:13Z",
  "url": "https://research.draconitic.com/paper/6njsp7e3wx8j2",
  "venue": "ACS Omega",
  "versions": []
}