Use Case Subscriber Only - 4D Printing Biotechnology

Source: Jakkarin/stock.adobe.com; generated with AI

Based on an interview with Tuhin Bhowmick
Despite the improvements in organ transplant techniques and technologies over the past seventy years, two factors continue to inhibit the reach of these often lifesaving procedures: availability and cost.

One such shortage is found in India, where the nation’s eight million–plus people living with corneal blindness face dismal odds. Only one out of every eighty of these patients have access to donor corneas. In addition, the traditional process of corneal transplantation—removing the diseased cornea, fitting the healthy cornea into the surgical cavity, and then suturing it onto the eye—becomes arduous, expensive, and often cost-prohibitive for patients.

“Just by the numbers—due to availability, cost, or both—few patients in India and other populous countries will be able to receive a traditional corneal transplant,” says Tuhin Bhowmick, co-founder and chief executive officer of India-based Pandorum Technologies, a tissue engineering and regenerative medicine company. 

Bhowmick launched Pandorum Technologies during his doctoral studies, supported by a grant from the Department of Biotechnology. Over the past decade, he and his team have developed a technology that uses Food and Drug Administration (FDA)-approved, high-quality, clinical-grade human mesenchymal stem cells to promote efficient tissue regeneration in areas such as the cornea, liver, and lung.

Several years ago, Bhowmick and the Pandorum team decided to accept the challenge of making corneal implants widely available and affordable to patients suffering from corneal blindness worldwide. The company is currently working closely with a globally renowned contract development and manufacturing organization (CDMO) partner for clinical manufacturing and also has three clinical trial centers in Chicago, US; New Delhi, India; and Kyoto, Japan; and plans to begin human studies in 2026 to reverse corneal blindness.

 Dr. Tuhin Bhowmick is the Co-Founder and Chief Executive Officer at Pandorum Technologies Pvt. Ltd. (India), and Pandorum International Inc. (US). As an entrepreneur in the biotechnology sector, he co-founded Pandorum Technologies in Bengaluru, India, in 2011. Tuhin initially served as the Director from 2011 to 2016 before becoming the Chief Executive Officer, a role in which he has been critical to the start-up’s success. Specializing in tissue engineering and regenerative medicine, Pandorum utilizes a proprietary technology platform to develop advanced therapeutics for promoting functional tissue regeneration.

Moving From 3D Printing to 4D Printing

Pandorum’s breakthrough technology revolves around a mixture of materials called “bioink,” a novel combination that can include two cutting-edge technologies:

•    Specialized exosomes derived from clinical-grade, cultured human mesenchymal stem cells, using a proprietary method that allows modulation of the stem cell “expression” to fit the needs of targeting tissue and disease. 

•    Biodegradable biopolymers (e.g., gelatin and collagen), which provide a controlled, sustained delivery vehicle for the exosomes and will eventually exit the patient’s tissues.
This bioink can be used to construct 3D functional tissues that can harbor human cells. Initially, Bhowmick and his team began using this bioink to 3D print corneas layer by layer. 

“By 3D printing a cornea, we could effectively bypass the need for donor cornea and solve the availability problem,” he says. “However, the rest of the process would remain the same. Doctors would still need to suture the new cornea onto the surgical cavity, which was one of the most difficult and time-consuming parts of the process. Patients would still be stuck with long recovery times, and often regular use of immune-suppressant therapies that have negative consequences in long-term use.” 

Bhowmick and his team were considering how their bioink could do more to improve the process, when they had a flash of inspiration. He recalls asking, “Why don’t we design the bioink in a way that—once the clinicians have removed the scar tissue and created the surgical cavity—we can directly deposit it in the cavity?” 

Once the bioink was placed in the cavity, they would only need to apply a process called “photocrosslinking” for the bioink to begin building a new cornea, right in the surgical cavity. With photocrosslinking, the visible light emitted by the surgical microscope in the operating room is used to stimulate bonding between molecules, instead of using harmful ultraviolet light.

“The ink would automatically spread to fit the size and shape of the cavity,” says Bhowmick. “Once it was photocrosslinked, which would take only eight to ten minutes, the ink would solidify, adhere to, and integrate with the surrounding eye tissue. This eliminated the need for suturing. We could send the patient home with a bandage contact lens, and, in only three to six months, a new cornea would have fully regenerated.”

This technology moves beyond 3D printing to what Bhowmick calls 4D printing. “It does not rely on a traditional 3D printing approach to create the entire tissue prior to surgery,” he says. “It self-builds over time. Once the photocrosslinking creates a scaffolding in the biopolymer gel, epithelial cells start to climb on the top of this matrix and build the outer layer within the first two to three weeks. Within the first two months, the eye’s neuronal plexus nerve regenerates and enters the deposited tissue. Within three to four months from the surgery, keratocytes have entered the matrix to build the inner stromal layer. In about four months, the biopolymer matrix biodegrades, leaving only a new, healthy cornea for the patient.”

Discovering Potential Impact

So far, the results Bhowmick cites come from studies performed on nonhuman subjects by three clinical partners at the Northwestern University Feinberg School of Medicine, Japan’s Kyoto University, and Dr. Shroff’s Charity Eye Hospital in New Delhi, with human trials coming soon. Already, however, Bhowmick is optimistic about the potential his novel combination of technologies could have for relieving the human and economic impacts of corneal and other diseases. Ultimately, he plans to scale his solution not only to serve first-world patients but also to supply impoverished areas of India with affordable options.

Bhowmick explains, “In the United States, people who suffer from certain forms of ulcerative corneal blindness, associated with severe inflammation, tissue melting and blood vessel formation in cornea might spend twenty to forty years of their lives blind.” He adds, “These patients are at advanced risk of donor cornea transplant failure.” Besides their suffering, the direct and indirect costs of the disease—from the loss of opportunities for the person and that person’s caregiver to the health care costs of approximately 50,000 to 60,000 USD per year—total a lifetime cost of 1.2 million to 2 million USD. Multiply that by the approximately fifty thousand sufferers of this disease in the United States alone or the one million sufferers in India, and you start to understand the massive relief this technology will provide for individuals and economies.” 

Developing Future Applications

Of course, corneal implants are just the starting point for this technology’s many potential applications, says Bhowmick. “The cornea has been a good first test because it’s small, relatively simple, and the intervention is local, but what about something large, like a liver? We can use our bioink to create liver tissue, but determining how to build and transplant bioengineered livers by the thousands at scale is a much more complex task. This is at least eight to ten years away,” he notes.
Topical or surface applications for the subdermal or subcutaneous tissues, he says, could be a good fit in the near term. “Reconstructive surgery as well as more aesthetic use cases could be ideal applications for our bioink,” asserts Bhowmick. “Instead of being reliant on dermal fillers to puff up damaged skin cells, our bioink could be injected into the skin to create brand-new, healthy skin cells that naturally integrate over time with the patient’s body and don’t need to be replenished every few months.”

This technology, admits Bhowmick, is only in its earliest stages, but as the technology is tested and becomes more recognized by regulatory bodies and pharmaceutical partners, the possibilities for healthcare are endless.