A cryomicroneedle patch ready for deployment. [Chang et al. /DOI number: 10.1038/s41551-021-00720-1]

A research team led by City University of Hong Kong (CityU) scientists has developed a new generation of microneedle technology that allows the intradermal delivery of living cells, in a minimally invasive manner. Their studies demonstrated that using the new cryomicroneedle technology to delivery therapeutic cells into melanoma-bearing mice elicited robust anti-tumor immune responses. The team claims the technology could pave the way to development of an easy-to-use system for delivering cell, and other treatments against various diseases.

“The application of our device is not limited to the delivery of cells,” said study lead Chenjie Xu, PhD, associate professor at the Department of Biomedical Engineering (BME) at CityU. ”This device can also package, store, and deliver other types of bioactive therapeutic agents, such as proteins, peptides, mRNA, DNA, and vaccines. I hope this device offers an easy-to-use and effective alternative method for the delivery of therapeutics in clinics.”

Xu and colleagues report on their development in Nature Biomedical Engineering, in a paper titled “Cryomicroneedles for Transdermal Cell Delivery.” First author of the paper is Hao Chang, PhD, from CityU’s BME. Xu is the corresponding author. Co-researchers from CityU BME included Dongan Wang PhD, and Peng Shi, PhD. The team collaborated with researchers from Nanyang Technological University and National University of Singapore. The research was partially funded by the CityU, and a patent application has been filed through CityU.

“The skin carries out important regulatory and defensive functions, and skin disorders may put patients at risk of cutaneous and systemic infections, trauma and malignancies,” the authors wrote. And while traditional treatment approaches have, proved of limited use, the team continued, developments in cell therapies could feasibly help to address previously incurable and untreatable diseases.

Cell therapy—or cell transplantation—is a treatment approach through which living cells, such as immune cells or stem cells, are injected, grafted or implanted into the patient to achieve a therapeutic effect. Advances in cell therapeutic technologies have generated promising treatment approaches for previously intractable diseases, including some cancers, and figures cited by the CityU suggest that the global market for cell therapies reached $7.8 billion in 2020.

Therapeutic cells are currently delivered via surgical graft or bolus injection. However, these methods are invasive, painful, complicated, relatively inefficient, and they bring the risk of infection and require experienced professionals to implement. “… these methods have difficulty in achieving controlled and precise delivery of targeted cells without sacrificing the comfort of patients, which presents challenges for their translation to clinical applications,” the investigators continued. “Conventional cell delivery by hypodermic-needle injection is associated with poor patient compliance, requires trained personnel, generates waste, and has non-negligible risks of injury and infection.”

It is also hard to store and transport the current solution-like formulations of cell therapeutics. “ … many problems related to the application of cell therapy yet to be solved,” Xu noted, And as the investigators commented, “Cell therapies for the treatment of skin disorders could benefit from simple, safe and efficient technology for the transdermal delivery of therapeutic cells …”

Microneedle (MN) technology represents a “promising option” for achieving the controlled and precise delivery of targeted drugs into specific skin layers and other tissues, the team pointed out. Unfortunately, they stated, “… none of these existing MN technologies can carry and deliver living formulations, such as therapeutic cells, into skin, without the assistance of extra devices. To carry and deliver cells, MNs have to maintain the viability of loaded cells and have mechanical strength to penetrate the skin.”

To solve the delivery challenge, Xu and his team at CityU developed a cryomicroneedle technology that carries and delivers living cells into the skin. The cryomicroneedles are effectively icy microneedles, shorter than 1mm, which can deliver therapeutic cells into the skin layers. “It is a skin patch-like device that can load, store, and intradermally deliver the living mammalian cells,” said Xu. The authors further explained, “This MN patch, termed cryomicroneedles (cryoMNs), is fabricated by stepwise cryogenic micromoulding of the optimized cryogenic medium and pre-suspended cells of interest in the pre-designed MN mould. CryoMNs can easily pierce skin and deliver loaded living cells into skin.”

The cryomicroneedle technology is constructed as a patch-like device that is placed on the skin. The microneedles penetrate through the skin, detach from the patch base and then melt. The cell payload is released, and the delivered cells migrate and proliferate inside the skin.

For their reported work Xu and colleagues carried out a proof-of-concept study in mice to evaluate cell-based cancer immunotherapy through the intradermal delivery of ovalbumin-pulsed dendritic cells. The results showed that vaccination using the cryomicroneedle platform elicited robust antigen-specific immune responses in the treated mice, and provided strong protection against tumors. Therapeutic outcomes using the new technology were better than those achieved using conventional standard vaccination methods such as subcutaneous and intravenous injection. “In mice, cells delivered by the cryomicroneedles retained their viability and proliferative capability,” the scientists noted. “In mice with subcutaneous melanoma tumors, the delivery of ovalbumin-pulsed dendritic cells via the cryomicroneedles elicited higher antigen-specific immune responses and led to slower tumor growth than intravenous and subcutaneous injections of the cells.”

The microholes gradually became invisible within 10 min in the safety and biocompatibility evaluation test. [Chang et al. /DOI number: 10.1038/s41551-021-00720-1]

The team pointed out that while their reported study evaluated dendritic cell (DC) vaccination as proof of concept, cryoMNs could be used to package other types of therapeutic cell, for example, stem cell-loaded cryoMNs could be used to promote skin regeneration. The technology is also not limited to delivering live therapeutics. “Similar to other types of MN, cryoMNs can carry bioactive therapeutic agents, including proteins, peptides and vaccines,” they wrote. “Due to the organic-free and low-temperature fabrication procedure, cryoMNs can maximally retain the bioactivity of those therapeutics.”

The authors do acknowledge that some challenges, or “translational considerations for this infant technology,” will need to be addressed. One of these is that, as with COVID-19 mRNA vaccines, cryoMNs require ultracold shipping and storage. And because cryoMNs will be inserted into human skin, a sterile production process is critical. “CryoMNs can be manufactured under aseptic or sterile conditions,” the team noted. Another consideration is the limited numbers of cells that can currently be carried by a single cryoMN patch. This could pose an issue if large numbers of cells are required to generate a therapeutic result, the scientists noted. However, they suggested, while applying multiple patches could be an answer, “An alternative solution is to increase the maximum cell capacity of a patch by either redesigning the cryoMNs with larger dimensions or enlarging the overall size of the patch with more MN arrays.”

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