New 3-D model could improve treatment of TB, other diseases

A team of researchers and engineers has created a 3-D model that they say can improve the study and treatment of tuberculosis and other infections.

The team at the University of Southampton and University College London, United Kingdom, has conducted studies on how the new model can be used to observe human cellular response to TB infection. Researchers say it can also compensate for shortcomings in traditional 2-D models.

“This system will help us speed up the process of finding treatments and vaccines for human tuberculosis, an infection that kills 1.8 million people per year,” Paul Elkington, PhD, said in a news release.

“We will use our 3-D model to integrate engineering and biological approaches with clinical specimens to create an entirely new system of studying infection,” said Elkington, a professor of respiratory medicine at Southampton who was involved in two studies on the model.

By way of electrostatic encapsulation, the team created microspheres containing human cells, which were then infected with TB bacteria. The 3-D approach creates conditions — including the presence of an extracellular matrix — that are more like those existing in the human lung compared with the 2-D cultures on plastic, researchers said.

The new model also allows up to 3 weeks of experimentation, which is more than four times the window provided by the old method, the release said.

One study, published in eLife, measured the effect of collagen, used to imitate the extracellular matrix that provides structural support to cells, along with several interventions on Mycobacterium tuberculosis (Mtb) infection.

The use of type I collagen as a matrix “significantly reduced cell death after Mtb infection, while adherence to elastin increased cell death,” the researchers noted. Furthermore, cells in microspheres containing collagen “had a significantly greater ability to control Mtb proliferation … ”

3-D spheres infected with TB.

Source: University of Southampton

Treatments included supplimention of cytokines, augmentation with a prostaglandin, immunoaugmentation with T cell lines and others. Each option yielded either favorable results, unfavorable results or both.

The researchers concluded that the 3-D model is a versatile tool that can be used to find new treatment options for TB and other diseases.

Another study, published in mBio, assessed the new model’s use in fighting antimicrobial resistance posed by TB and other diseases.

“Antimicrobial resistance is a major global threat, and an emerging concept is that infection should be studied in the context of host immune cells,” the researchers wrote. They added that TB “is becoming progressively more resistant to antibiotics.”

Researchers infected human cells in microspheres with genetically-modified Mtb and tested various treatment options. They found that standard antibiotics rifampin, ethambutol and isoniazid all inhibited Mtb growth in 2-D cell cultures and the 3-D model, although to varying degrees.

Another antibiotic, pyrazinamide, was effective in killing Mtb in the 3-D model but not in 2-D cultures or in 7H9 broth without cells at neutral Ph.

Results also varied for second-line antibiotics D-cycloserine, moxifloxacin and Zyvox (linezolid, Pfizer), although they were most effective in the 3-D model.

Using rifampin, the researchers also employed microfluidics to replicate the change in antibiotic concentrations that occurs in a real-life patient. They found that Mtb levels fluctuated as the rifampin levels rose and fell in individual irrigated wells. The disease quickly recovered with the removal of the rifampin.

Again, the results convinced the researchers of the 3-D model’s efficacy.

“The system can equally be applied to diverse inflammatory and malignant human diseases … Therefore, this platform has global applicability to address the threat of antimicrobial resistance and deliver new treatments,” they wrote. – by Joe Green

For more information:

Bielecka MK, et al. mBio. 2017; doi: 10.1128/mBio.02073-16

Tezera LB, et al. eLife. 2017; doi: 10.7554/eLife.21283

Disclosure: The researchers report no relevant financial disclosures.