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Miniaturized implantable temperature sensors for the long-term monitoring of chronic intestinal inflammation

Nature Biomedical Engineering volume 8, pages 1040–1052 (2024)Cite this article

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Abstract

Diagnosing and monitoring inflammatory bowel diseases, such as Crohn’s disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn’s disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn’s-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups.

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Fig. 1: Implantable temperature sensors for monitoring Crohn’s-disease-like ileitis and their use in studies in mouse models.
Fig. 2: Ultradian rhythms in intestinal temperature for mice with spontaneous ileitis.
Fig. 3: Circadian disruptions in temperature for mice with spontaneous ileitis.
Fig. 4: Long-term trends in temperature and tissue inflammation.
Fig. 5: Circadian disruptions and influence of aging on PPARγ concentrations in ileal tissue.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for Figs. 2d, 3b and 4f, as well as representative individual histology images used to produce Figs. 4g and 5d, are available with this paper. A larger number of additional individual histology images used to produce Figs. 4g and 5d are available from the corresponding authors on reasonable request. Source data are provided with this paper.

Code availability

Data analysis (spline fits, FFT, wavelet transform, peak/valley analysis, moving standard deviation) made use of inbuilt functions in MATLAB. All parameters used for analysis are available in Methods.

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Acknowledgements

We thank F. Turek, M. Hotz-Vitaterna and K. Summa for useful discussions; M. Seniw (Simpson Querrey Institute, Northwestern University) for the illustrations in Fig. 1c; and H. M. Arafa, D. Ostojich and J.T. Williams for preliminary efforts in microfabrication and near-field communication device prototypes. This work made use of the MatCI Facility supported by the Materials Research Science and Engineering Center (MRSEC) program of the National Science Foundation (NSF) (DMR-1720139) at the Materials Research Center of Northwestern University, and of the micro/nano-fabrication (NUFAB) facility of Northwestern University’s Atomic and Nanoscale Characterization Experimental Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the International Institute for Nanotechnology and Northwestern’s MRSEC program. S.R.M and J.L.C. disclose support for the research described in this study from the NSF Graduate Research Fellowship Program (NSF DGE-2234667). The work was supported by the Querrey–Simpson Institute for Bioelectronics.

Author information

Author notes

  1. These authors contributed equally: Surabhi R. Madhvapathy, Matthew I. Bury.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA

    Surabhi R. Madhvapathy, Joanna L. Ciatti & John A. Rogers

  2. Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA

    Surabhi R. Madhvapathy, Joanna L. Ciatti & John A. Rogers

  3. Division of Pediatric Urology, Department of Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Matthew I. Bury & Arun K. Sharma

  4. Stanley Manne Children’s Research Institute, Louis A. Simpson and Kimberly K. Querrey Biomedical Research Center, Chicago, IL, USA

    Matthew I. Bury & Arun K. Sharma

  5. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Larry W. Wang & Arun K. Sharma

  6. Department of Mechanical Engineering, Rice University, Houston, TX, USA

    Raudel Avila

  7. Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA

    Yonggang Huang

  8. Department of Civil Engineering, Northwestern University, Evanston, IL, USA

    Yonggang Huang

  9. Simpson Querrey Institute, Northwestern University, Chicago, IL, USA

    Arun K. Sharma

  10. Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA

    Arun K. Sharma & John A. Rogers

  11. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    John A. Rogers

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Contributions

S.R.M., M.I.B., A.K.S. and J.A.R. conceived the project. S.R.M. designed the device hardware, software and encapsulation; fabricated devices; calibrated devices; conducted video analysis; and performed benchtop testing/characterization (with assistance from J.L.C.) and temperature data analysis. M.I.B. designed the surgical procedure and conducted surgeries, post-operative animal monitoring/care (with assistance from L.W.W.), motility measurements, histology sample preparation (with assistance from L.W.W.), analysis of quantitative histology (with assistance from L.W.W.), radiograph collection, video collection and blood collection/analysis. R.A. and Y.H. helped with thermal, electromagnetic and mechanical-modelling efforts associated with device operation. S.R.M. and M.I.B. performed data visualization. S.R.M., M.I.B., A.K.S. and J.A.R. analysed the data. S.R.M., M.I.B., A.K.S. and J.A.R. wrote the paper. All authors read and provided comments on the paper. J.A.R. and A.K.S. jointly supervised the work.

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Correspondence to Arun K. Sharma or John A. Rogers.

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Competing interests

J.A.R., A.K.S., S.R.M., and M.I.B. are co-inventors on a patent related to the technology (US Patent App. 63/604,400) described in this work. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 FEA modeling of the temperature sensitivity of the device to temperature fluctuations in the intestines.

(a) Temperature profile in the sensor over a 5-hour period to reach steady state temperature when the temperature of the intestines increases by 1 °C (black), remains the same 0 °C (red), and decreases by 1 °C (blue) with respect to the body temperature. The core body temperature was fixed at 37 °C. (b) Steady state temperature change (ΔT = Tintestines – Tcore) profile between the surface of the intestines and the outer skin layer in a mouse for the three cases in (a); the distance between the intestines and skin is assumed to be 5 mm and the thickness of the skin layer is 1 mm. (c) FEA model for (a,b). (d) Sinusoidal temperature profile at the surface of the intestines over a 24-hr period and the corresponding temperature profile in the temperature sensors showing excellent agreement by capturing the thermal fluctuations. (e) A 4th order polynomial temperature profile at the surface of the ‘lesion’ intestines over a 24-hr period and the corresponding temperature profile in the temperature sensors showing excellent agreement by capturing the thermal fluctuations. In both (d,e), the distance between the sensor and intestines is 0.75 mm. (f) (Top) Temperature profile in the sensor as the vertical separation distance between the surface of the intestines and sensor increases from 5 mm to 100 mm, modeling the scenario in a human. The temperature in the intestines is modeled as a sinusoidal wave. As the vertical separation distance increases to 50 mm and 100 mm the sensor is unable to pick up the thermal fluctuations in the intestines. (Bottom) Schematic of the FEA model. (g) Temperature profiles in the sensor as a function of time when the vertical distance between the sensor increases from 0.75 mm to 3.75 mm showing that for all cases the sensor can capture the 4th order polynomial profile of the intestines. (h) Temperature profiles in the sensor as a function of time when the horizontal distance, or lateral misalignment, between the sensor increases from 5 mm to 30 mm. For the cases when the sensor is 20 mm and 30 mm away from the edge of the intestines the sensor is unable to capture the thermal fluctuations at the surface of the intestines. (i) (Top) Thermal profiles for the sensor when placed on top of the lesion region (solid red), normal region (solid blue), and between lesion and normal region (solid black). The thermal profiles are a sinusoidal wave for the normal intestine (dashed blue) and 4th order polynomial for the lesion intestine (dashed red). (Bottom) Schematic of the arrangement for the lesion intestines, normal intestines, and the sensor placement. (j) (Top) Steady state temperature limits at the sensor when the intestine is empty (dashed blue) and with fecal matter (dashed red). The black curve shows the thermal profile when fecal matter enters (temperature increases) and leaves (temperature decreases) the intestine over a period of 8 hrs. (Bottom) Schematic of the model showing the difference between the internal part of the intestine for the empty/fecal cases. (k) Surface plot of the steady state temperature in the sensor based on a parametric sweep of the distance between the sensor and intestine (horizontal axis) and the thermal conductivity of the intestines (vertical axis). (l) Transient heat transfer process over a 12-hr process to reach thermal equilibrium in the intestine’s region.

Extended Data Fig. 2 A DSS-induced model of colitis.

Tintestines as a function of time for individual AKR/J mice subject to intermittent administration of (a, b) 1% and (c, d) 3% by volume DSS in the drinking water over 107–110 days. The red shaded regions indicate the time period for which DSS was administered. Animals were killed on day 107 in panels (b, c) and day 110 in panels (a, d). (e, f) Tintestines as a function of time for individual mice subject to 5% by volume of DSS in the drinking water. The red shaded region indicates the time window for which DSS was administered. Animals were euthanized on day 35. The black arrows in all panels indicate a significant drop in Tintestines after administration of DSS, if applicable.

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Madhvapathy, S.R., Bury, M.I., Wang, L.W. et al. Miniaturized implantable temperature sensors for the long-term monitoring of chronic intestinal inflammation. Nat. Biomed. Eng 8, 1040–1052 (2024). https://doi.org/10.1038/s41551-024-01183-w

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