Engineered Hydrogel Implants for Tuberculosis Treatment

How would you explain your paper’s key results to the non-scientific community?

We are surrounded by vast numbers of microorganisms. They have different ways of living and can be pathogenic when they cause disease to other organisms. The human body can naturally fight against these infections, but due to advanced evolutionary adaptation processes, many of them can escape from it and cause the severity of the disease. Therefore we use different medicines to cure these infections. Tuberculosis (TB) is one such disease that can affect the lungs. It is a bacteria living within the human lungs for thousands of years. Apart from the lungs, TB can also infect other parts of the body like lymph nodes, central nervous system, bones, joints, gastrointestinal organs, and genitourinary organs. Like COVID it can spread by air and cause severe harm to the patients.

Sources suggest that almost a quarter of the world’s population is latently (inactively) infected with TB, while almost 3,816 people die every day. According to the W.H.O. report (2020), an estimated incidence of ~ 2,640,000 TB cases in India accounts for about a quarter of the world’s tuberculosis (TB) cases. Doctors and scientists are using various combinations of anti-TB drugs to fight against them. Regular treatment of tuberculosis comprises a combination of four drugs, rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol (EMB) daily for months. However conventional methods are quite effective, but irregular medicine, ignorance of caregivers and patients, and inefficient drug delivery/management systems can give a rise to drug-resistant bacteria that are difficult to treat. India has the highest-burden (total 465,000 cases) of tuberculosis (TB) patients having multidrug-resistant (MDR) TB and there is an urgent need to manage this.

Figure 1. Novel TB-Gel can release four front line anti-TB drugs and outperforms the oral doses of this combination. Thus reducing the TB infection in mice efficiently. (Image Credit: Nanoscale and Authors)

In this study, we tried to address these issues with a new approach. Under the guidance of Dr. Avinash Bajaj (from Regional Centre for Biotechnology-Faridabad) and Dr. Vinay K Nandicoori (National Institute of Immunology-New Delhi), we have developed a hydrogel-based delivery system (derived from a low molecular weight bile acid peptide) where we have entrapped four first-line anti-TB drugs (namely Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol) in it, and we called it TB-Gel. The TB-Gel maintained its integrity, elasticity, and strength, and can easily pass through the syringe. It is non-immunogenic (harmless) and implantable under the skin and can release these four drugs (in the therapeutic range) for a prolonged period (up to 15 days in mice). In our “TB infection mice model”, TB-Gel treated mice showed significantly lower infection as compared to the group of mice that were administered with daily oral doses. As TB-Gel can maintain the optimum drug levels in the blood, without taking daily oral medications, therefore we found that it reduces the systematic toxicity and side effects of these drugs. Hence this system can lessen the requirement of regular dosing, it can be very helpful for TB treatment management and decreases the likelihood of drug resistance emergence.

What are the possible consequences of these findings for your research area?

Existing antitubercular therapies are quite effective in the management of the disease. However long-term treatment with patient non-compliance poses a significant clinical threat for the evolution of multidrug-resistant tuberculosis. Finding a simple way to deliver the desired amount of drugs over an extended period can increase patient compliance. Implantable materials and devices are generating a huge impact on clinical treatments and diagnostics. However, designing an injectable soft material with desired mechanical and safety behavior at the biological interface is a considerable challenge. Our research provided a needed direction towards the design and development of novel biomaterials for effective and safer drug delivery applications. As we can easily tune the porosity of this hydrogel (to control the desired drug release rate) therefore it is a favorable approach for the treatment of several other diseases using such biocompatible biomaterials.

What was the exciting moment (eureka moment) during your research?

Soft synthetic materials generally disintegrate under stress and significantly impart undesirable toxicity at the implantable site. Surprisingly, our hydrogel exhibited superior mechanical properties like injectability, gel-like behavior even upon excessive load of chemotherapeutics medicines, and a controlled drug diffusion. Our hydrogel remained three weeks under the skin of the mouse without causing any rashes and other allergic or immune reactions. These were our desired results from the study, and then we started exploring this system further for drug delivery applications.

What do you hope to do next?

Considering the safety profile and robustness of our hydrogel system, we aim to develop and explore novel safer therapies against hard to treat brain tumors, topical hydrogel for skin infections, immunomodulatory local therapies for organ transplants, and a safer alternative to daily medication regimens in terms of weekly or monthly implantable formulation.

Where do you seek scientific inspiration?

SP: Inspiration is all around us. It is the researcher’s interest and curiosity that gets his attention and becomes his inspiration. Working with live animal models and observing the real-time effect of treatment inspired me to work more and design new methods and ideas to do better again and again.

VS: My scientific inspiration comes from nature, observations, and questions. Every time I see any phenomenon or problem, my mind seeks the reason or solutions for it, and that drives me to read literature, discuss with mentors and colleagues and finally design experiments to test it. The quest for the unknown clicks in the brain fuels my imagination to connect the dots to make a better picture.

SK: Scientific inspiration (inexpressible substance) originates from different sources, but it comes with a twist in your existing scientific career. With my chemistry experience, designing and making the bioactive chemical system in the laboratory is always a fun part. However, finding the biological aspect of the chemical system, possibly the need to gain a deeper understanding of how to manipulate the existing natural chemical pool for their surefire beneficial potential in the area of biomedical research, keeps me inspiring.

How do you intend to help Indian science improve?

We believe that innovation and translation of research work into the market can help India to be a more developed nation. Indian science is full of extraordinary minds and offers several growth opportunities. We intend to provide a very enthusiastic and learning environment in our research group and never let down anyone’s scientific temperament. We also believe in collaborative learning; therefore, we try to connect with new budding research minds and provide the necessary training and education in our laboratories.

Reference

Sanjay Pal*, Vijay Soni*, Sandeep Kumar*, Somesh Kumar Jha, Nihal Medatwal, Kajal Rana, Poonam Yadav, Devashish Mehta, Dolly Jain, Raunak Kar, Aasheesh Srivastava, Veena S. Patil, Ujjaini Dasgupta, Vinay Nandicoori, and Avinash Bajaj. Hydrogel-mediated Temporal Delivery of Combination of Four Antituberculosis Drugs Outperforms Oral Delivery against Tuberculosis. Nanoscale (RSC Publication) 2021, 13, 13225–13230, DOI: 10.1039/d0nr08806d (* First Co-author)

About first authors

Sanjay Pal

Current affiliation: Laboratory of Cancer ImmunoMetabolism, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD, USA.

Biography: Sanjay Pal, Ph.D., is currently working as a visiting fellow in Laboratory of Cancer ImmunoMetabolism, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick. He is investigating the role of the extracellular matrix (ECM) scaffold in activating host immune responses and delivery of tumor antigens for effective cancer vaccine. He has obtained his Ph.D. from Regional Centre for Biotechnology, Faridabad.

Vijay Soni

Current affiliation: Department of Medicine, Weill Cornell Medicine, New York.

Biography: Vijay Soni, Ph.D., is currently working as an instructor of microbiology in medicine at Weill Cornell Medical College, New York. Using microbial metabolomics approach, he is studying the drug metabolism against drug-resistant Mycobacterium tuberculosis and the co-vulnerability of various anti-TB drugs. He has completed his Ph.D. from BITS-Pilani Hyderabad and the National Institute of Immunology (NII, Delhi).

Sandeep Kumar

Current affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, USA.

Biography: Sandeep Kumar Ph.D., is currently working as a postdoctoral fellow at Department of Biomedical Engineering at Johns Hopkins University School of Medicine, Baltimore. He is developing novel biomaterials as immunomodulatory therapies in the form of adjuvant vaccines against cancer, autoimmune diseases, and pathogenic microbial infections. He has obtained his Ph.D. from Regional Centre for Biotechnology, Faridabad, in the area of drug delivery and nanotechnology.

Edited by: Ritvi Shah

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