3D-printed perfused models of the penis for the study of penile physiology and for restoring erectile function in rabbits and pigs | Nature Biomedical Engineering

Mar 05, 2025

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The intricate topology of vascular networks and the complex functions of vessel-rich tissues are challenging to reconstruct in vitro. Here we report the development of: in vitro pathological models of erectile dysfunction and Peyronie’s disease; a model of the penis that includes the glans and the corpus spongiosum with urethral structures; and an implantable model of the corpus cavernosum, whose complex vascular network is critical for erectile function, via the vein-occlusion effect. Specifically, we 3D printed a hydrogel-based corpus cavernosum incorporating a strain-limiting tunica albuginea that can be engorged with blood through vein occlusion. In corpus cavernosum defects in rabbits and pigs, implantation of the 3D-printed tissue seeded with endothelial cells restored normal erectile function on electrical stimulation of the cavernous nerves as well as spontaneous erectile function within a few weeks of implantation, which allowed the animals to mate and reproduce. Our findings support the further development of 3D-printed blood-vessel-rich functional organs for transplantation.

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We thank Q. Zhang for providing technical assistance and M. Chai for participating in helpful discussions. Y.W. discloses support for the research described in this study from the National Natural Science Foundation of China (grant number T2288101). X.S. discloses support for the publication of this study from the National Natural Science Foundation Joint Fund of China (grant number U22A20157). X.L. discloses support for the publication of this study from the National Natural Science Foundation of China (grant no. 32301136 to X.L.).

These authors contributed equally: Zhenxing Wang, Xuemin Liu, Tan Ye, Zhichen Zhai.

National Engineering Research Centre for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, P. R. China

Zhenxing Wang, Tan Ye, Zhichen Zhai, Dan Shao, Yingjun Wang & Xuetao Shi

School of Materials Science and Engineering, South China University of Technology, Guangzhou, P. R. China

Zhenxing Wang, Tan Ye, Zhichen Zhai, Yingjun Wang & Xuetao Shi

Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, P. R. China

Zhenxing Wang, Tan Ye, Zhichen Zhai, Yingjun Wang & Xuetao Shi

The Third Affiliated Hospital, Department of Gynecology and Obstetrics, Guangzhou Medical University, Guangzhou, P. R. China

Xuemin Liu

School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, P. R. China

Kai Wu, Yudi Kuang & Dan Shao

Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University, Chiyoda, Japan

Serge Ostrovidov

School of Medicine, South China University of Technology, Guangzhou, P. R. China

Dan Shao

Department of Biomedical Engineering, Columbia University, New York, NY, USA

Dan Shao & Kam W. Leong

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K.W.L., Y.W. and X.S. conceived the project. Z.W., X.L., T.Y. and Z.Z. designed and performed most of the experiments. D.S., K.W., Y.K. and S.O. conducted experimental investigations and analysed the data. Z.W. and X.L. wrote the original draft. K.W.L., Y.W. and X.S. supervised the work and revised the paper. All authors reviewed and approved the final version of the paper.

Correspondence to Yingjun Wang, Kam W. Leong or Xuetao Shi.

The authors declare no competing interests.

Nature Biomedical Engineering thanks Andres Garcia, Petra de Graaf, Ji Liu, Y. Shrike Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

a, The stress‒strain curve of the hydrogel. b-c, Ashby chart of the mechanical properties for various 3D-printed hydrogels, tensile strength versus Young’s modulus (b) and elongation at break versus Young’s modulus (c). Hydrogels include the hydrogel prepared in this work (red area), gelatin methacryloyl (GelMA)35, polyethylene glycol diacrylate (PEGDA)36, glycidyl methacrylated silk fibroin (Sil-GMA)37, glycidyl methacrylated poly (vinyl alcohol) (PVAGMA)38, polyacrylamide (PAAm)/Alginate39, methacrylate-modified alginate (AlgMA)/GelMA40, and polyacrylic acid (PAA)/PEGDA41. d, Various 3D printing models of the hydrogel, including a fox (i), axial vessel and helix (ii) and a Hilbert microchannel (iii).

a-b, Displacement maps (a) and von Mises stress maps (b) show that the V.1.0 BCC model can achieve venous occlusion during erection. The height and diameter of the flaccid model in the numerical simulation are 9.6 mm and 16 mm, respectively. c, Time‒volume expansion curve, showing that the V.2.0 BCC model exhibits faster erectile deformation than the V.1.0 BCC model.

a, Procedural derivation of the two versions of the BCC models from the structural units. b, Statistics for the numbers of cavernous sinuses in the different versions of the BCC models. c, Statistics for the hollow rates of the different versions of BCC models.

The fixation frame ensures that the model remains stable during perfusion.

a, During perfusion (average flow, 90 mL/min), the BCC model exhibited notable local deformation without the constraint imposed by the biomimetic tunica albuginea. As a result, the BCC model suffers from local damage (scale bar: 9 mm). b, The outflow rate changes over time during in vitro erection perfusion in the BCC model wrapped with biomimetic tunica albuginea. The decrease in outlet flow caused by vein occlusion can be clearly observed. The blue shaded area indicates the venous occlusion state during BCC perfusion erection. c, Inflow rate of the ED model under high and low perfusion flow rates.

a, Surgical procedure for implanting the model into the corpus cavernosum defect site (scale bar: 10 mm). b-c, Routine blood test results for the samples obtained from pigs implanted with the hydrogel model, including the cell count index (b) and the cell percentage index (c) (scale bar: 10 mm).

a, Enriched Gene Ontology (GO) terms in the upregulated proliferation-related genes of the porcine penis corpus cavernosum tissues from the implantation group versus the normal group (n = 3 pigs). The statistical analysis was performed using one-side hypergeometric test. b, Heatmap showing the differences in the expression of proliferation-related genes and inflammation-related genes among the three different groups (normal, defect and implantation groups). The color key from red to blue represents high to low gene expression levels, respectively (n = 3 pigs). Statistical analysis was performed using two-sided One-way ANOVA followed by Tukey’s multiple comparison test. Data are presented as mean ± SD (n = 3 pigs).

Supplementary methods, table, figures, references and video captions.

BCC model perfusion.

BCC model perfusion with bionic tunica albuginea.

ED model perfusion.

PD model perfusion.

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Wang, Z., Liu, X., Ye, T. et al. 3D-printed perfused models of the penis for the study of penile physiology and for restoring erectile function in rabbits and pigs. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-025-01367-y

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Received: 23 October 2023

Accepted: 06 February 2025

Published: 04 March 2025

DOI: https://doi.org/10.1038/s41551-025-01367-y

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