TY  - JOUR
AB  - The efficacy of drug therapy in multiple myeloma is conventionally assessed by whole-cell-population methods, serum analysis of light chains and monoclonal antibodies, immunofixation electrophoresis, or by flow cytometry of bone marrow aspirates and biopsies. These methods provide relevant information on the presence of specific immunoglobulins at high sensitivity and specificity but require a large number of cells, involve long and laborious sample preparation steps, and provide only tumour bulk information. Here we develop a single-cell imaging technique requiring a reduced number of primary cells for longitudinal evaluation of patient-specific treatment and assessment of treatment heterogeneity. By exploiting the mechanistic action of proteasome inhibition and in synergy with the label-free protein-structure specificity of mid-infrared optoacoustic microscopy, we present a technology that facilitates longitudinal evaluation of myeloma treatment and a patient's heterogeneous response. Detecting optical-generated ultrasound waves that intensify with optical absorption, this technology allows observation of proteins in living cells with high sensitivity. Specifically, we use intermolecular β-sheet formation as a biomarker for cell viability during therapy and apply it to assess drug-treatment performance in multiple myeloma patients.
AU  - Gasparin, F.
AU  - Tietje, M.R.*
AU  - Katab, E.*
AU  - Nurdinova, A.
AU  - Yuan, T.
AU  - Chmyrov, A.
AU  - Uluc, N.
AU  - Jüstel, D.
AU  - Bassermann, F.*
AU  - Ntziachristos, V.
AU  - Pleitez, M.A.
C1  - 75144
C2  - 57837
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Label-free protein-structure-sensitive live-cell microscopy for patient-specific assessment of myeloma therapy.
JO  - Nat. Bio. Eng.
PB  - Nature Portfolio
PY  - 2025
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance and mortality rates. However, such morphological and phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the phenotypic landscape seen in murine and human PDAC, that the pronounced molecular and morphological intratumoural and intertumoural heterogeneity of organoids is governed by defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), and that different organoid phenotypes represent distinct tumour-cell states with unique biological features in vivo. We also show that phenotype-specific therapeutic vulnerabilities and modes of treatment-induced phenotype reprogramming can be captured in phenotypic heterogeneity maps. Our methodology and analyses of tumour-cell heterogeneity in PDAC may guide the development of phenotype-targeted treatment strategies.
AU  - Papargyriou, A.
AU  - Najajreh, M.*
AU  - Cook, D.P.*
AU  - Maurer, C.H.*
AU  - Bärthel, S.*
AU  - Messal, H.A.*
AU  - Ravichandran, S.K.*
AU  - Richter, T.
AU  - Knolle, M.*
AU  - Metzler, T.*
AU  - Shastri, A.R.*
AU  - Öllinger, R.*
AU  - Jasper, J.*
AU  - Schmidleitner, L.*
AU  - Wang, S.
AU  - Schneeweis, C.*
AU  - Ishikawa-Ankerhold, H.*
AU  - Engleitner, T.*
AU  - Mataite, L.*
AU  - Semina, M.*
AU  - Trabulssi, H.*
AU  - Lange, S.*
AU  - Ravichandra, A.*
AU  - Schuster, M.*
AU  - Mueller, S.*
AU  - Peschke, K.*
AU  - Schäfer, A.*
AU  - Dobiasch, S.
AU  - Combs, S.E.
AU  - Schmid, R.M.*
AU  - Bausch, A.R.*
AU  - Braren, R.*
AU  - Heid, I.*
AU  - Scheel, C.
AU  - Schneider, G.*
AU  - Zeigerer, A.
AU  - Luecken, M.
AU  - Steiger, K.*
AU  - Kaissis, G.
AU  - van Rheenen, J.*
AU  - Theis, F.J.
AU  - Saur, D.*
AU  - Rad, R.*
AU  - Reichert, M.*
C1  - 72732
C2  - 56719
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma.
JO  - Nat. Bio. Eng.
PB  - Nature Portfolio
PY  - 2024
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Skin microangiopathy has been associated with diabetes. Here we show that skin-microangiopathy phenotypes in humans can be correlated with diabetes stage via morphophysiological cutaneous features extracted from raster-scan optoacoustic mesoscopy (RSOM) images of skin on the leg. We obtained 199 RSOM images from 115 participants (40 healthy and 75 with diabetes), and used machine learning to segment skin layers and microvasculature to identify clinically explainable features pertaining to different depths and scales of detail that provided the highest predictive power. Features in the dermal layer at the scale of detail of 0.1-1 mm (such as the number of junction-to-junction branches) were highly sensitive to diabetes stage. A 'microangiopathy score' compiling the 32 most-relevant features predicted the presence of diabetes with an area under the receiver operating characteristic curve of 0.84. The analysis of morphophysiological cutaneous features via RSOM may allow for the discovery of diabetes biomarkers in the skin and for the monitoring of diabetes status.
AU  - Karlas, A.
AU  - Katsouli, N.
AU  - Fasoula, N.-A.
AU  - Bariotakis, M.
AU  - Chlis, N.-K.
AU  - Omar, M.
AU  - He, H.
AU  - Iakovakis, D.*
AU  - Schäffer, C.*
AU  - Kallmayer, M.*
AU  - Füchtenbusch, M.*
AU  - Ziegler, A.-G.
AU  - Eckstein, H.H.*
AU  - Hadjileontiadis, L.J.*
AU  - Ntziachristos, V.
C1  - 68872
C2  - 53731
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1667-1682
TI  - Dermal features derived from optoacoustic tomograms via machine learning correlate microangiopathy phenotypes with diabetes stage.
JO  - Nat. Bio. Eng.
VL  - 7
IS  - 12
PB  - Nature Portfolio
PY  - 2023
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.
AU  - Lesch, S.*
AU  - Blumenberg, V.*
AU  - Stoiber, S.*
AU  - Gottschlich, A.*
AU  - Ogonek, J.*
AU  - Cadilha, B.L.*
AU  - Dantes, Z.*
AU  - Rataj, F.*
AU  - Dorman, K.*
AU  - Lutz, J.*
AU  - Karches, C.H.*
AU  - Heise, C.*
AU  - Kurzay, M.*
AU  - Larimer, B.M.*
AU  - Grassmann, S.*
AU  - Rapp, M.*
AU  - Nottebrock, A.*
AU  - Krüger, S.*
AU  - Tokarew, N.*
AU  - Metzger, P.*
AU  - Hoerth, C.*
AU  - Benmebarek, M.R.*
AU  - Dhoqina, D.*
AU  - Grünmeier, R.*
AU  - Seifert, M.*
AU  - Oener, A.*
AU  - Umut, Ö.*
AU  - Joaquina, S.*
AU  - Vimeux, L.*
AU  - Tran, T.*
AU  - Hank, T.*
AU  - Baba, T.*
AU  - Huynh, D.*
AU  - Megens, R.T.A.*
AU  - Janssen, K.P.*
AU  - Jastroch, M.
AU  - Lamp, D.
AU  - Ruehland, S.*
AU  - Di Pilato, M.*
AU  - Pruessmann, J.N.*
AU  - Thomas, M.
AU  - Marr, C.
AU  - Ormanns, S.*
AU  - Reischer, A.*
AU  - Hristov, M.*
AU  - Tartour, E.*
AU  - Donnadieu, E.*
AU  - Rothenfußer, S.
AU  - Duewell, P.*
AU  - König, L.M.*
AU  - Schnurr, M.*
AU  - Subklewe, M.*
AU  - Liss, A.S.*
AU  - Halama, N.*
AU  - Reichert, M.*
AU  - Mempel, T.R.*
AU  - Endres, S.
AU  - Kobold, S.
C1  - 62196
C2  - 50751
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1246-1260
TI  - T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours.
JO  - Nat. Bio. Eng.
VL  - 5
IS  - 11
PB  - Nature Research
PY  - 2021
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - The pathological assessment of surgical specimens during surgery can reduce the incidence of positive resection margins, which otherwise can result in additional surgeries or aggressive therapeutic regimens. To improve patient outcomes, intraoperative spectroscopic, fluorescence-based, structural, optoacoustic and radiological imaging techniques are being tested on freshly excised tissue. The specific clinical setting and tumour type largely determine whether endogenous or exogenous contrast is to be detected and whether the tumour specificity of the detected biomarker, image resolution, image-acquisition times or penetration depth are to be prioritized. In this Perspective, we describe current clinical standards for intraoperative tissue analysis and discuss how intraoperative imaging is being implemented. We also discuss potential implementations of intraoperative pathology-assisted surgery for clinical decision-making.
AU  - Voskuil, F.J.*
AU  - Vonk, J.*
AU  - van der Vegt, B.*
AU  - Kruijff, S.*
AU  - Ntziachristos, V.
AU  - van der Zaag, P.J.*
AU  - Witjes, M.J.H.*
AU  - van Dam, G.M.*
C1  - 63503
C2  - 51342
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 503-514
TI  - Intraoperative imaging in pathology-assisted surgery.
JO  - Nat. Bio. Eng.
VL  - 6
IS  - 5
PB  - Nature Portfolio
PY  - 2021
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Creating in vitro models of diseases of the pancreatic ductal compartment requires a comprehensive understanding of the developmental trajectories of pancreas-specific cell types. Here we report the single-cell characterization of the differentiation of pancreatic duct-like organoids (PDLOs) from human induced pluripotent stem cells (hiPSCs) on a microwell chip that facilitates the uniform aggregation and chemical induction of hiPSC-derived pancreatic progenitors. Using time-resolved single-cell transcriptional profiling and immunofluorescence imaging of the forming PDLOs, we identified differentiation routes from pancreatic progenitors through ductal intermediates to two types of mature duct-like cells and a few non-ductal cell types. PDLO subpopulations expressed either mucins or the cystic fibrosis transmembrane conductance regulator, and resembled human adult duct cells. We also used the chip to uncover ductal markers relevant to pancreatic carcinogenesis, and to establish PDLO co-cultures with stellate cells, which allowed for the study of epithelial-mesenchymal signalling. The PDLO microsystem could be used to establish patient-specific pancreatic duct models.
AU  - Wiedenmann, S.
AU  - Breunig, M.*
AU  - Merkle, J.*
AU  - von Toerne, C.
AU  - Georgiev, T.
AU  - Moussus, M.
AU  - Schulte, L.N.*
AU  - Seufferlein, T.*
AU  - Sterr, M.
AU  - Lickert, H.
AU  - Weissinger, S.E.*
AU  - Möller, P.*
AU  - Hauck, S.M.
AU  - Hohwieler, M.*
AU  - Kleger, A.*
AU  - Meier, M.
C1  - 62518
C2  - 50901
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 897-913
TI  - Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip.
JO  - Nat. Bio. Eng.
VL  - 5
PB  - Nature Research
PY  - 2021
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - The Author(s), under exclusive licence to Springer Nature Limited. In the HTML version of the Article originally published, Shy Shoham was mistakenly not denoted as a corresponding author; this has now been corrected. The PDF version was unaffected.
AU  - Gottschalk, S.
AU  - Degtyaruk, O.
AU  - Mc Larney, B.
AU  - Rebling, J.
AU  - Hutter, M.A.
AU  - Shoham, S.
AU  - Razansky, D.
C1  - 60485
C2  - 49880
TI  - Publisher Correction: Rapid volumetric optoacoustic imaging of neural dynamics across the mouse brain (Nature Biomedical Engineering, (2019), 3, 5, (392-401), 10.1038/s41551-019-0372-9).
JO  - Nat. Bio. Eng.
VL  - 4
IS  - 11
PY  - 2020
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - The monitoring of vascular-targeted therapies using magnetic resonance imaging, computed tomography or ultrasound is limited by their insufficient spatial resolution. Here, by taking advantage of the intrinsic optical properties of haemoglobin, we show that raster-scanning optoacoustic mesoscopy (RSOM) provides high-resolution images of the tumour vasculature and of the surrounding tissue, and that the detection of a wide range of ultrasound bandwidths enables the distinction of vessels of differing size, providing detailed insights into the vascular responses to vascular-targeted therapy. Using RSOM to examine the responses to vascular-targeted photodynamic therapy in mice with subcutaneous xenografts, we observed a substantial and immediate occlusion of the tumour vessels followed by haemorrhage within the tissue and the eventual collapse of the entire vasculature. Using dual-wavelength RSOM, which distinguishes oxyhaemoglobin from deoxyhaemoglobin, we observed an increase in oxygenation of the entire tumour volume immediately after the application of the therapy, and a second wave of oxygen reperfusion approximately 24 h thereafter. We also show that RSOM enables the quantification of differences in neoangiogenesis that predict treatment efficacy.
AU  - Haedicke, K.*
AU  - Agemy, L.*
AU  - Omar, M.
AU  - Berezhnoi, A.
AU  - Roberts, S.*
AU  - Longo-Machado, C.*
AU  - Skubal, M.*
AU  - Nagar, K.*
AU  - Hsu, H.T.*
AU  - Kim, K.*
AU  - Reiner, T.*
AU  - Coleman, J.*
AU  - Ntziachristos, V.
AU  - Scherz, A.*
AU  - Grimm, J.*
C1  - 58577
C2  - 48527
SP  - 286-297
TI  - High-resolution optoacoustic imaging of tissue responses to vascular-targeted therapies.
JO  - Nat. Bio. Eng.
VL  - 4
IS  - 3
PY  - 2020
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - A Correction to this paper has been published: https://doi.org/10.1038/s41551-020-0569-y.
AU  - Saif, M.*
AU  - Kwanten, W.J.*
AU  - Carr, J.A.*
AU  - Chen, I.X.*
AU  - Posada, J.M.*
AU  - Srivastava, A.*
AU  - Zhang, J.*
AU  - Zheng, Y.*
AU  - Pinter, M.*
AU  - Chatterjee, S.*
AU  - Softic, S.*
AU  - Kahn, C.R.*
AU  - van Leyen, K.*
AU  - Bruns, O.T.
AU  - Jain, R.K.*
AU  - Bawendi, M.G.*
C1  - 60605
C2  - 49886
TI  - Author Correction: Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin (Nature Biomedical Engineering, (2020), 4, 8, (801-813), 10.1038/s41551-020-0569-y).
JO  - Nat. Bio. Eng.
VL  - 4
IS  - 12
PY  - 2020
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.Label-free imaging of the endogenous pigment lipofuscin at near-infrared and shortwave-infrared wavelengths enables the longitudinal monitoring of liver injury in mice and in biopsied human livers.
AU  - Saif, M.*
AU  - Kwanten, W.J.*
AU  - Carr, J.A.*
AU  - Chen, I.X.*
AU  - Posada, J.M.*
AU  - Srivastava, A.*
AU  - Zhang, J.*
AU  - Zheng, Y.*
AU  - Pinter, M.*
AU  - Chatterjee, S.*
AU  - Softic, S.*
AU  - Kahn, C.R.*
AU  - van Leyen, K.*
AU  - Bruns, O.T.
AU  - Jain, R.K.*
AU  - Bawendi, M.G.*
C1  - 59469
C2  - 48875
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 801–813
TI  - Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin.
JO  - Nat. Bio. Eng.
VL  - 4
PB  - Nature Publishing Group
PY  - 2020
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Efforts to scale neuroimaging towards the direct visualization of mammalian brain-wide neuronal activity have faced major challenges. Although high-resolution optical imaging of the whole brain in small animals has been achieved ex vivo, the real-time and direct monitoring of large-scale neuronal activity remains difficult, owing to the performance gap between localized, largely invasive, optical microscopy of rapid, cellular-resolved neuronal activity and whole-brain macroscopy of slow haemodynamics and metabolism. Here, we demonstrate both ex vivo and non-invasive in vivo functional optoacoustic (OA) neuroimaging of mice expressing the genetically encoded calcium indicator GCaMP6f. The approach offers rapid, high-resolution three-dimensional snapshots of whole-brain neuronal activity maps using single OA excitations, and of stimulus-evoked slow haemodynamics and fast calcium activity in the presence of strong haemoglobin background absorption. By providing direct neuroimaging at depths and spatiotemporal resolutions superior to optical fluorescence imaging, functional OA neuroimaging bridges the gap between functional microscopy and whole-brain macroscopy.
AU  - Gottschalk, S.
AU  - Degtyaruk, O.
AU  - Mc Larney, B.
AU  - Rebling, J.
AU  - Hutter, M.A.
AU  - Dean-Ben, X.L.
AU  - Shoham, S.*
AU  - Razansky, D.
C1  - 55798
C2  - 46575
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 392–401
TI  - Rapid volumetric optoacoustic imaging of neural dynamics across the mouse brain.
JO  - Nat. Bio. Eng.
VL  - 3
IS  - 5
PB  - Nature Publishing Group
PY  - 2019
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Fuelled by innovation, optical microscopy plays a critical role in the life sciences and medicine, from basic discovery to clinical diagnostics. However, optical microscopy is limited by typical penetration depths of a few hundred micrometres for in vivo interrogations in the visible spectrum. Optoacoustic microscopy complements optical microscopy by imaging the absorption of light, but it is similarly limited by penetration depth. In this Review, we summarize progress in the development and applicability of optoacoustic mesoscopy (OPAM); that is, optoacoustic imaging with acoustic resolution and wide-bandwidth ultrasound detection. OPAM extends the capabilities of optical imaging beyond the depths accessible to optical and optoacoustic microscopy, and thus enables new applications. We explain the operational principles of OPAM, its placement as a bridge between optoacoustic microscopy and optoacoustic macroscopy, and its performance in the label-free visualization of tissue pathophysiology, such as inflammation, oxygenation, vascularization and angiogenesis. We also review emerging applications of OPAM in clinical and biological imaging.
AU  - Omar, M.
AU  - Aguirre Bueno, J.
AU  - Ntziachristos, V.
C1  - 55861
C2  - 46620
CY  - Macmillan Building, 4 Crinan St, London N1 9xw, England
SP  - 354-370
TI  - Optoacoustic mesoscopy for biomedicine.
JO  - Nat. Bio. Eng.
VL  - 3
IS  - 5
PB  - Nature Publishing Group
PY  - 2019
SN  - 2157-846X
ER  - 

TY  - JOUR
AB  - Imaging plays a critical role in the diagnosis and assessment of dermatological conditions. However, optical or optoacoustic microscopy techniques are limited to visualizing superficial skin features owing to strong photon scattering, whereas ultrasound methods, which can probe deeper-seated tissue, lack the contrast to image pathophysiological mechanisms in detail. Here, we demonstrate that raster-scan optoacoustic mesoscopy (RSOM) implemented in ultra-broadband (10–180 MHz) detection mode bridges the depth capabilities of ultrasound and the resolution range and high contrast of optical methods in clinical dermatology. Using tomographic reconstruction and frequency equalization to represent low and high spatial-frequency components, we visualize skin morphology and vascular patterns in the dermis and sub-dermis of psoriasis patients, enabling quantification of inflammation and other biomarkers of psoriasis without the need for contrast agents. Implemented in a handheld device, we showcase how label-free biomarkers detected by RSOM correlate with clinical score. The method can also be extended to assess a larger spectrum of dermatological conditions.
AU  - Aguirre Bueno, J.
AU  - Schwarz, M.
AU  - Garzorz-Stark, N.
AU  - Omar, M.
AU  - Bühler, A.
AU  - Eyerich, K.
AU  - Ntziachristos, V.
C1  - 51579
C2  - 43233
CY  - London
TI  - Precision assessment of label-free psoriasis biomarkers with ultra-broadband optoacoustic mesoscopy.
JO  - Nat. Bio. Eng.
VL  - 1
IS  - 5
PB  - Nature Publishing Group
PY  - 2017
SN  - 2157-846X
ER  -