Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans

The 2021 follow-up to Benias et al. 2018 from substantially the same author group — Rebecca Wells at Penn, Neil Theise at NYU, with Cenaj as first-author senior pathology resident at NYU at the time of the work — extending the original claim into the territory it always implied but had not yet tested: that the interstitial spaces are not merely structured within organs but continuous across organ boundaries.

Published in Communications Biology (a Nature-family open-access journal) on 31 March 2021, the paper is a primary anatomical report using two methodological probes. The first tracked non- biological particles — tattoo pigment in skin sections and colloidal silver in colon sections — and followed their distribution through interstitial spaces into adjacent fascia. The second visualised hyaluronic acid, a macromolecular component of interstitial matrix, across tissue boundaries. Both techniques showed continuity of the interstitial spaces across the boundaries between organs, between organ and fascia, and along perineural and perivascular spaces traversing organs.

The piece sits as the substantive empirical extension of the 2018 framing from structured-within-organ to body-wide-continuous-network. The strong version of the claim — that signalling molecules, immune cells, and metastatic tumour cells may travel through this continuous network — is what the discussion section proposes; the empirical work shows continuity of the spaces themselves, not the functional traffic. The 2025 Ordner et al. follow-up in the Journal of Anatomy extends the empirical work into the lung.

The stake is professional-scientific and continues the Theise-and- Wells programme that the 2018 paper initiated. The framing avoids the new organ language that drew critique from Mestres- Ventura in 2019, and the empirical methodology is more careful than the 2018 paper's. Read it as the 2018 findings made more defensible, with the continuity claim adding the architectural specificity the original framing had implied without showing.