For biological processes, the physical environment where the process takes place, which creates the chemical context for reactions to happen is all important. This is one of the key challenges of transposing processes between the in vitro bench and the human/animal body and vice versa.

Sperm production

Take sperm for instance. Within mammalian testicles, sperm cells are produced within the seminiferous tubules. The epithelium of the tubule consists of Sertoli cells, which are tall, columnar type cells that line the tubule.

Sandwiched between the Sertoli cell layer are the spermatogenic cells, which differentiate through meiosis to sperm cells. The Sertoli cells within this environment function to nourish the developing sperm cells by secreting androgen-binding protein, a binding protein that increases the concentration of testosterone inside the seminiferous tubules.

There are two types of seminiferous tubule: convoluted and straight, convoluted toward the lateral side and straight as the tubule comes medially to form ducts that will exit the testis.

Breakthrough research

This is one of the many highly specialised physiological environments that is very challenging to create outside of the body. However, researchers at the University of British Columbia report that they have developed a technique to 3D-print sperm cells into a hollow tubular structure that mimics the seminiferous tubules.

In the most severe form of male infertility, known as non-obstructive azoospermia (NOA) no sperm is found in ejaculate due to diminished sperm production within the seminiferous tubules. The researchers, led by Columbia’s Professor Ryan Flannigan, hope the technique will one day offer a solution for people living with presently untreatable forms of male infertility.

Professor Flannigan said, “Infertility affects 15% of couples and male factors are a contributing cause in at least half those cases. We’re 3D printing these cells into a very specific structure that mimics human anatomy, which we think is our best shot at stimulating sperm production. If successful, this could open the door to new fertility treatments for couples who currently have no other options.”

To create a viable environment for sperm cells to develop the researchers performed a biopsy to collect stem cells from the testicles of a patient living with NOA.

The cells were then 3D-printed into a hollow tubular structure resembling human seminiferous tubules.

Micrograph showing the artificially created seminiferous tubule substrate and sperm cells

Success

Two weeks after printing the team found that not only had the cells survived, but they had matured into several of the specialized cells involved in sperm production and were showing a significant improvement in spermatogonial stem cell maintenance i.e., demonstrating early signs of sperm-producing capabilities.

Professor Flannigan commented, “It’s a huge milestone, seeing these cells survive and begin to differentiate. There’s a long road ahead, but this makes our team very hopeful.”

New hope for the future

The team’s work has also provided insight into the genetic and molecular mechanisms that contribute to NOA.  This is an advantage of using various single cell sequencing techniques to understand the gene expression and characteristics of each individual cell and then applying computational modelling of the data gained.

Professor Flannigan concluded, “Increasingly, we’re learning that there are likely many different causes of infertility and that each case is very patient specific. With that in mind, we’re taking a personalised, precision medicine approach. We take cells from a patient, try to understand what abnormalities are unique to them, and then 3D print and support the cells in ways that overcome those original deficiencies.”

References

1. M Robinson, E Bedford, L Witherspoon, SM Willerth, R Flannigan. 2022. Using Clinically Derived Human Tissue to 3D Bioprint Personalized Testicular Tubules for In-Vitro Culturing. First Report. Fertility and Sterility. Published: February 16, 2022. DOI https://doi.org/10.1016/j.xfss.2022.02.004.