Advances in multimodal biomedical imaging of small animals_Journal of Biomedical Engineering

Authors：

DENG Zhengyan ¹ , XI Peng ¹ , TANG Juan ² , REN Qiushi ^1,3 ,  YU Yuanjun ²

1. Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, P. R. China;
2. Chongqing Technical Center for Durg Evaluation & Inspection, Chongqing 401120, P. R. China;
3. National Biomedical Imaging Center, Peking University, Beijing 100871, P. R. China;

Corresponding author：

Keywords：

Biomedical imaging; Multimodality; Small animals

DOI：

10.7507/1001-5515.202406024

Video：

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Small animal multimodal biomedical imaging refers to the integration of multiple imaging techniques within the same system or device to acquire comprehensive physiological and pathological information of small animals, such as mice and rats. With the continuous advancement of biomedical research, this cutting-edge technology has attracted extensive attention. Multimodal imaging techniques, based on diverse imaging principles, overcome the limitations of single-modal imaging through information fusion, significantly enhancing the overall system's sensitivity, temporal/spatial resolution, and quantitative accuracy. In the future, the integration of new materials and artificial intelligence will further boost its sensitivity and resolution. Through interdisciplinary innovation, this technology is expected to become the core technology of personalized medicine and expand its applications to drug development, environmental monitoring, and other fields, thus reshaping the landscape of biomedical research and clinical practice. This review summarized the progress on the application and investigation of multimodal biomedical imaging techniques, and discussed its development in the future.

1.	赵勇, 王浩, 师长宏. 近红外荧光(NIRF)染料在肿瘤诊断中的应用. 中国比较医学杂志, 2018, 28(3): 98-102.
2.	Adel F W, Chen H H. The role of multimodality imaging in diabetic cardiomyopathy: a brief review. Front Endocrinol (Lausanne), 2024, 15: 1405031.
3.	Lu Y, Yang K, Zhou K, et al. An integrated quad-modality molecular imaging system for small animals. Journal of Nuclear Medicine, 2014, 55(8): 1375-1379.
4.	王荣福, 王飞. 多模态生物医学成像技术-PET/CT的临床应用价值. 肿瘤学杂志, 2017, 23(6): 461-463.
5.	De Luca A, Schilling K G, Ianus A. Editorial: Is two better than one? Exploring tissue microstructure with multi-modal imaging: quantitative MRI and beyond. Front Neurosci, 2023, 17: 1139400.
6.	Shi B, Zhang B, Zhang Y, et al. Multifunctional gap-enhanced Raman tags for preoperative and intraoperative cancer imaging. Acta Biomaterialia, 2020, 104: 210-220.
7.	Zanzonico P. Principles of nuclear medicine imaging: planar, SPECT, PET, multi-modality, and autoradiography systems. Radiat Res, 2012, 177(4): 349-364.
8.	Abdelmoula W M, Regan M S, Lopez B G C, et al. Automatic 3D nonlinear registration of mass spectrometry imaging and magnetic resonance imaging data. Analytical Chemistry, 2019, 91(9): 6206-6216.
9.	Townsend D W, Carney J P J, Yap J T, et al. PET/CT today and tomorrow. Journal of Nuclear Medicine, 2004, 45(Suppl 1): 4S-14S.
10.	Kinahan P E, Townsend D W, Beyer T, et al. Attenuation correction for a combined 3D PET/CT scanner. Med Phys, 1998, 25(10): 2046-2053.
11.	Judenhofer M S, Wehrl H F, Newport D F, et al. Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nature Medicine, 2008, 14(4): 459-465.
12.	Mao J, Gao M, Cui B, et al. Super early scan of PSMA PET/CT in evaluating primary and metastatic lesions of prostate cancer. Molecules, 2022, 27(14): 4661.
13.	Liu X, Li J, Huang Q, et al. Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer. Mol Med, 2024, 30(1): 56.
14.	Li K, Liu W, Yu H, et al. 68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer. J Clin Invest, 2024, 134(4): e170490.
15.	Lin K, Shi D, Wang A, et al. Noninvasive monitoring of early cardiac fibrosis in diabetic mice by [⁶⁸Ga]Ga-DOTA-FAPI-04 PET/CT imaging. ACS Omega, 2024, 9(15): 17195-17203.
16.	Wargocka-Matuszewska W, Fiedorowicz K, Rugowska A, et al. Molecular imaging of myogenic stem/progenitor cells with [¹⁸F]-FHBG PET/CT system in SCID mice model of post-infarction heart. Sci Rep, 2021, 11(1): 19825.
17.	Filip T, Mairinger S, Neddens J, et al. Characterization of an APP/tau rat model of Alzheimer's disease by positron emission tomography and immunofluorescent labeling. Alzheimers Res Ther, 2021, 13(1): 175.
18.	Schröder S, Lai T H, Toussaint M, et al. PET imaging of the adenosine A2A receptor in the rotenone-based mouse model of Parkinson’s disease with [¹⁸F]FESCH synthesized by a simplified two-step one-pot radiolabeling strategy. Molecules, 2020, 25(7): 1633.
19.	Wu N, Zhang L, Zhang X, et al. Synthesis and bioevaluation of 2-styrylquinoxaline derivatives as Tau-PET tracers. Molecular Pharmaceutics, 2023, 20(11): 5865-5876.
20.	Fonseca Cabrera G O, Ma X, Lin W, et al. Synthesis of ⁶⁴Cu-, ⁵⁵Co-, and ⁶⁸Ga-labeled radiopharmaceuticals targeting neurotensin receptor-1 for theranostics: adjusting in vivo distribution using multiamine macrocycles. Journal of Nuclear Medicine, 2024, 65(8): 1250-1256.
21.	Liu Q, Li C, Liu J, et al. Technical note: performance evaluation of a small-animal PET/CT system based on NEMA NU 4-2008 standards. Med Phys, 2021, 48(9): 5272-5282.
22.	Cheng X, Yang D, Saha D, et al. Integrated small animal PET/CT/RT with onboard PET/CT image guidance for preclinical radiation oncology research. Tomography, 2023, 9(2): 567-578.
23.	Kim K Y, Son J W, Kim K, et al. Performance evaluation of SimPET-X, a PET insert for simultaneous mouse total-body PET/MR imaging. Mol Imaging Biol, 2021, 23(5): 703-713.
24.	Wang G, Kaira M, Murugan V, et al. Vision 20/20: simultaneous CT-MRI--Next chapter of multimodality imaging. Med Phys, 2015, 42(10): 5879-5889.
25.	Yu X, Liu X, Wu W, et al. CT/MRI-guided synergistic radiotherapy and X-ray inducible photodynamic therapy using Tb-doped Gd-W-nanoscintillators. Angew Chem Int Ed Engl, 2019, 58(7): 2017-2022.
26.	Chen L, Zhong H, Qi X, et al. Modified core-shell magnetic mesoporous zirconia nanoparticles formed through a facile “outside-to-inside” way for CT/MRI dual-modal imaging and magnetic targeting cancer chemotherapy. RSC Adv, 2019, 9(23): 13220-13233.
27.	Zhang X, Zhao M, Wen L, et al. Sequential SPECT and NIR-II imaging of tumor and sentinel lymph node metastasis for diagnosis and image-guided surgery. Biomater Sci, 2021, 9(8): 3069-3075.
28.	Kang Y, Zhai X, Lu S, et al. A Hybrid imaging platform(CT/PET/FMI) for evaluating tumor necrosis and apoptosis in real-time. Frontiers in Oncology, 2022, 12: 772392.
29.	Beekman F J, Kamphuis C, Koustoulidou S, et al. Positron range-free and multi-isotope tomography of positron emitters. Phys Med Biol, 2021, 66(6): 065011.
30.	Wang H, Zhang R, Jia X, et al. Highly sensitive magnetic particle imaging of abdominal aortic aneurysm NETosis with anti-Ly6G iron oxide nanoparticles. Cell Death Discovery, 2024, 10(1): 395.
31.	Zhang W, Liang X, Zhu L, et al. Optical magnetic multimodality imaging of plectin-1-targeted imaging agent for the precise detection of orthotopic pancreatic ductal adenocarcinoma in mice. eBioMedicine, 2022, 80: 104040.
32.	Hou W, Xia F, Alfranca G, et al. Nanoparticles for multi-modality cancer diagnosis: simple protocol for self-assembly of gold nanoclusters mediated by gadolinium ions. Biomaterials, 2017, 120: 103-114.
33.	Ren L, Wang Y, Tang Y, et al. US/PA/MR multimodal imaging-guided multifunctional genetically engineered bio-targeted synergistic agent for tumor therapy. Journal of Nanobiotechnology, 2024, 22(1): 615.
34.	Xu Y, Li X, Jie Y, et al. Simultaneous tri-modal medical image fusion and super-resolution using conditional diffusion model. arXiv preprint, 2024, arXiv: 2404.17357.
35.	Wang H, Li X, Xu L, et al. PET/SPECT/spectral-CT/CBCT imaging in a small-animal radiation therapy platform: a Monte Carlo study-Part I: quad-modal imaging. Med Phys, 2024, 51(4): 2941-2954.
36.	Li X, Wang H, Kuang Y. PET/SPECT/Spectral-CT/CBCT imaging in a small-animal radiation therapy platform: a Monte Carlo study-Part II: biologically guided radiotherapy. Med Phys, 2024, 51(5): 3619-3634.
37.	Chan H H L, Haerle S K, Daly M J, et al. An integrated augmented reality surgical navigation platform using multi-modality imaging for guidance. PLoS One, 2021, 16(4): e0250558.
38.	Liu M, Guo H, Liu H, et al. In vivo pentamodal tomographic imaging for small animals. Biomed Opt Express, 2017. 8(3): 1356-1371.
39.	郑睿, 陈警斌, 刘雨龙, 等. 全数字PET关键材料硅酸钇镥闪烁晶体研究进展. CT理论与应用研究, 2024, 33(4): 405-420.
40.	任文智, 李娟, 姚俊列, 等. 肿瘤边界成像驱动的分子探针研究进展. 分析化学, 2025, 53(1): 14-26.
41.	Rajagopal J R, Farhadi F, Solomon J, et al. Comparison of low dose performance of photon-counting and energy integrating CT. Academic Radiology, 2021, 28(12): 1754-1760.
42.	骆清铭, 周欣, 叶朝辉. 生物医学影像学科发展现状和展望. 中国科学: 生命科学, 2020, 50(11): 1158-1175.
43.	Suwanraksa C, Bridhikitti J, Liamsuwan T, et al. CBCT-to-CT translation ssing registration-based generative adversarial networks in patients with head and neck cancer. Cancers, 2023, 15(7): 2017.
44.	Patel A N, Srinivasan K. Deep learning paradigms in lung cancer diagnosis: a methodological review, open challenges, and future directions. Phys Med, 2025, 131: 104914.
45.	Vermeulen I, Isin E M, Barton P, et al. Multimodal molecular imaging in drug discovery and development. Drug Discovery Today, 2022, 27(8): 2086-2099.

1. 赵勇, 王浩, 师长宏. 近红外荧光(NIRF)染料在肿瘤诊断中的应用. 中国比较医学杂志, 2018, 28(3): 98-102.
2. Adel F W, Chen H H. The role of multimodality imaging in diabetic cardiomyopathy: a brief review. Front Endocrinol (Lausanne), 2024, 15: 1405031.
3. Lu Y, Yang K, Zhou K, et al. An integrated quad-modality molecular imaging system for small animals. Journal of Nuclear Medicine, 2014, 55(8): 1375-1379.
4. 王荣福, 王飞. 多模态生物医学成像技术-PET/CT的临床应用价值. 肿瘤学杂志, 2017, 23(6): 461-463.
5. De Luca A, Schilling K G, Ianus A. Editorial: Is two better than one? Exploring tissue microstructure with multi-modal imaging: quantitative MRI and beyond. Front Neurosci, 2023, 17: 1139400.
6. Shi B, Zhang B, Zhang Y, et al. Multifunctional gap-enhanced Raman tags for preoperative and intraoperative cancer imaging. Acta Biomaterialia, 2020, 104: 210-220.
7. Zanzonico P. Principles of nuclear medicine imaging: planar, SPECT, PET, multi-modality, and autoradiography systems. Radiat Res, 2012, 177(4): 349-364.
8. Abdelmoula W M, Regan M S, Lopez B G C, et al. Automatic 3D nonlinear registration of mass spectrometry imaging and magnetic resonance imaging data. Analytical Chemistry, 2019, 91(9): 6206-6216.
9. Townsend D W, Carney J P J, Yap J T, et al. PET/CT today and tomorrow. Journal of Nuclear Medicine, 2004, 45(Suppl 1): 4S-14S.
10. Kinahan P E, Townsend D W, Beyer T, et al. Attenuation correction for a combined 3D PET/CT scanner. Med Phys, 1998, 25(10): 2046-2053.
11. Judenhofer M S, Wehrl H F, Newport D F, et al. Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nature Medicine, 2008, 14(4): 459-465.
12. Mao J, Gao M, Cui B, et al. Super early scan of PSMA PET/CT in evaluating primary and metastatic lesions of prostate cancer. Molecules, 2022, 27(14): 4661.
13. Liu X, Li J, Huang Q, et al. Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer. Mol Med, 2024, 30(1): 56.
14. Li K, Liu W, Yu H, et al. 68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer. J Clin Invest, 2024, 134(4): e170490.
15. Lin K, Shi D, Wang A, et al. Noninvasive monitoring of early cardiac fibrosis in diabetic mice by [⁶⁸Ga]Ga-DOTA-FAPI-04 PET/CT imaging. ACS Omega, 2024, 9(15): 17195-17203.
16. Wargocka-Matuszewska W, Fiedorowicz K, Rugowska A, et al. Molecular imaging of myogenic stem/progenitor cells with [¹⁸F]-FHBG PET/CT system in SCID mice model of post-infarction heart. Sci Rep, 2021, 11(1): 19825.
17. Filip T, Mairinger S, Neddens J, et al. Characterization of an APP/tau rat model of Alzheimer's disease by positron emission tomography and immunofluorescent labeling. Alzheimers Res Ther, 2021, 13(1): 175.
18. Schröder S, Lai T H, Toussaint M, et al. PET imaging of the adenosine A2A receptor in the rotenone-based mouse model of Parkinson’s disease with [¹⁸F]FESCH synthesized by a simplified two-step one-pot radiolabeling strategy. Molecules, 2020, 25(7): 1633.
19. Wu N, Zhang L, Zhang X, et al. Synthesis and bioevaluation of 2-styrylquinoxaline derivatives as Tau-PET tracers. Molecular Pharmaceutics, 2023, 20(11): 5865-5876.
20. Fonseca Cabrera G O, Ma X, Lin W, et al. Synthesis of ⁶⁴Cu-, ⁵⁵Co-, and ⁶⁸Ga-labeled radiopharmaceuticals targeting neurotensin receptor-1 for theranostics: adjusting in vivo distribution using multiamine macrocycles. Journal of Nuclear Medicine, 2024, 65(8): 1250-1256.
21. Liu Q, Li C, Liu J, et al. Technical note: performance evaluation of a small-animal PET/CT system based on NEMA NU 4-2008 standards. Med Phys, 2021, 48(9): 5272-5282.
22. Cheng X, Yang D, Saha D, et al. Integrated small animal PET/CT/RT with onboard PET/CT image guidance for preclinical radiation oncology research. Tomography, 2023, 9(2): 567-578.
23. Kim K Y, Son J W, Kim K, et al. Performance evaluation of SimPET-X, a PET insert for simultaneous mouse total-body PET/MR imaging. Mol Imaging Biol, 2021, 23(5): 703-713.
24. Wang G, Kaira M, Murugan V, et al. Vision 20/20: simultaneous CT-MRI--Next chapter of multimodality imaging. Med Phys, 2015, 42(10): 5879-5889.
25. Yu X, Liu X, Wu W, et al. CT/MRI-guided synergistic radiotherapy and X-ray inducible photodynamic therapy using Tb-doped Gd-W-nanoscintillators. Angew Chem Int Ed Engl, 2019, 58(7): 2017-2022.
26. Chen L, Zhong H, Qi X, et al. Modified core-shell magnetic mesoporous zirconia nanoparticles formed through a facile “outside-to-inside” way for CT/MRI dual-modal imaging and magnetic targeting cancer chemotherapy. RSC Adv, 2019, 9(23): 13220-13233.
27. Zhang X, Zhao M, Wen L, et al. Sequential SPECT and NIR-II imaging of tumor and sentinel lymph node metastasis for diagnosis and image-guided surgery. Biomater Sci, 2021, 9(8): 3069-3075.
28. Kang Y, Zhai X, Lu S, et al. A Hybrid imaging platform(CT/PET/FMI) for evaluating tumor necrosis and apoptosis in real-time. Frontiers in Oncology, 2022, 12: 772392.
29. Beekman F J, Kamphuis C, Koustoulidou S, et al. Positron range-free and multi-isotope tomography of positron emitters. Phys Med Biol, 2021, 66(6): 065011.
30. Wang H, Zhang R, Jia X, et al. Highly sensitive magnetic particle imaging of abdominal aortic aneurysm NETosis with anti-Ly6G iron oxide nanoparticles. Cell Death Discovery, 2024, 10(1): 395.
31. Zhang W, Liang X, Zhu L, et al. Optical magnetic multimodality imaging of plectin-1-targeted imaging agent for the precise detection of orthotopic pancreatic ductal adenocarcinoma in mice. eBioMedicine, 2022, 80: 104040.
32. Hou W, Xia F, Alfranca G, et al. Nanoparticles for multi-modality cancer diagnosis: simple protocol for self-assembly of gold nanoclusters mediated by gadolinium ions. Biomaterials, 2017, 120: 103-114.
33. Ren L, Wang Y, Tang Y, et al. US/PA/MR multimodal imaging-guided multifunctional genetically engineered bio-targeted synergistic agent for tumor therapy. Journal of Nanobiotechnology, 2024, 22(1): 615.
34. Xu Y, Li X, Jie Y, et al. Simultaneous tri-modal medical image fusion and super-resolution using conditional diffusion model. arXiv preprint, 2024, arXiv: 2404.17357.
35. Wang H, Li X, Xu L, et al. PET/SPECT/spectral-CT/CBCT imaging in a small-animal radiation therapy platform: a Monte Carlo study-Part I: quad-modal imaging. Med Phys, 2024, 51(4): 2941-2954.
36. Li X, Wang H, Kuang Y. PET/SPECT/Spectral-CT/CBCT imaging in a small-animal radiation therapy platform: a Monte Carlo study-Part II: biologically guided radiotherapy. Med Phys, 2024, 51(5): 3619-3634.
37. Chan H H L, Haerle S K, Daly M J, et al. An integrated augmented reality surgical navigation platform using multi-modality imaging for guidance. PLoS One, 2021, 16(4): e0250558.
38. Liu M, Guo H, Liu H, et al. In vivo pentamodal tomographic imaging for small animals. Biomed Opt Express, 2017. 8(3): 1356-1371.
39. 郑睿, 陈警斌, 刘雨龙, 等. 全数字PET关键材料硅酸钇镥闪烁晶体研究进展. CT理论与应用研究, 2024, 33(4): 405-420.
40. 任文智, 李娟, 姚俊列, 等. 肿瘤边界成像驱动的分子探针研究进展. 分析化学, 2025, 53(1): 14-26.
41. Rajagopal J R, Farhadi F, Solomon J, et al. Comparison of low dose performance of photon-counting and energy integrating CT. Academic Radiology, 2021, 28(12): 1754-1760.
42. 骆清铭, 周欣, 叶朝辉. 生物医学影像学科发展现状和展望. 中国科学: 生命科学, 2020, 50(11): 1158-1175.
43. Suwanraksa C, Bridhikitti J, Liamsuwan T, et al. CBCT-to-CT translation ssing registration-based generative adversarial networks in patients with head and neck cancer. Cancers, 2023, 15(7): 2017.
44. Patel A N, Srinivasan K. Deep learning paradigms in lung cancer diagnosis: a methodological review, open challenges, and future directions. Phys Med, 2025, 131: 104914.
45. Vermeulen I, Isin E M, Barton P, et al. Multimodal molecular imaging in drug discovery and development. Drug Discovery Today, 2022, 27(8): 2086-2099.

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