Cryomicroneedles: the new intradermal therapeutic cell delivery


A research team led by City University of Hong Kong (CityU) scientists recently developed a new generation of microneedles technology which allows the intradermal delivery of living cells in a minimally invasive manner.

Their experiment showed that vaccination using therapeutic cells through this ground-breaking technology elicited robust immune responses against tumors in mice, paving the way for developing an easy-to-use cell therapy and other therapeutics against cancers and other diseases.

The study was led by Dr. Xu Chenjie, Associate Professor at the Department of Biomedical Engineering (BME) at CityU. The latest findings have been published in the scientific journal Nature Biomedical Engineering, titled “Cryomicroneedles for Transdermal Cell Delivery”.

The new technology “cryomicroneedles” are the icy microneedles shorter than 1mm and 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,” explained Dr. Xu.

Cell therapy, also called cell transplantation, is a therapy in which living cells like immune cells or stem cells are injected, grafted or implanted into a patient to achieve a medicinal effect. Advances in cell therapies have brought promising treating approach for previously intractable diseases like cancers. The global market size of cell therapy was valued at USD 7.8 billion in 2020.

“But many problems related to the application of cell therapy yet to be solved,” said Dr. Xu. For example, the therapeutic cells are currently delivered by either surgical grafts or bolus injection. These methods are invasive, painful, complicated, low-efficient, and they bring the risk of infection and require experienced professionals to implement. It is also hard to store and transport the current solution-like formulations of cell therapeutics.

A cryomicroneedle patch placed on the hand to demonstrate the melting of the needles on the skin (without pressing them to penetrate into the skin). Credit: Chang et al. DOI: 10.1038/s41551-021-00720-1

To solve this challenge, Dr. Xu and his team at CityU have developed these cryomicroneedles that carry and deliver living cells into the skin. By putting the patch-like device on the skin, the microneedles would penetrate through the skin, detach from the patch base and then melt. The loaded cells were released, and subsequently migrated and proliferated inside the skin. This innovative device can be stored for months in refrigerators. It is also easy for transportation and deployment.

As a proof-of-concept, the researchers explored cell-based cancer immunotherapy through intradermal delivery of ovalbumin-pulsed dendritic cells. In the study, vaccination with this device elicited robust antigen-specific immune responses and provided strong protection against tumor in mice, which were superior to the therapeutic outcomes by conventional standard vaccination methods such as subcutaneous and intravenous injection.

CityU scientists invent cryomicroneedles for intradermal therapeutic cell delivery
The microholes gradually became invisible within 10 min in the safety and biocompatibility evaluation test. Credit: Chang et al. DOI: 10.1038/s41551-021-00720-1

“The application of our device is not limited to the delivery of cells. 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,” Dr. Xu said.

Dr. Chang Hao from CityU’s BME is the first author, and Dr. Xu is the corresponding author. Professor Wang Dongan and Dr. Shi Peng from BME are also part of the research team. Other researchers come 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 coronavirus disease 2019 (COVID‐19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has had an unprecedented impact worldwide. 1 , 2 , 3 Effective vaccines are urgently needed to prevent infection/reinfection in the long term and allow life to return to normal. The SARS‐CoV‐2 spike glycoprotein (S protein) plays important roles in viral adhesion, fusion, and entry into cells, and has been identified as a key target for vaccine development.

Currently, multiple vaccines based on the SARS‐CoV‐2 spike protein are under evaluation. One candidate is the receptor‐binding domain (RBD) in the S1 subunit of the S protein that specifically binds to angiotensin‐converting enzyme 2 (ACE2) receptor on target cells. 4 For example, Ravichandran et al recently immunized rabbits with different targets of the SARS‐CoV‐2 S protein and found that immunization with RBD induced high‐affinity antibodies. 5 There is also an emerging global phase 3 clinical trial testing the efficacy, safety and immunogenicity of Ad5‐nCoV (adenovirus type 5 vector expressing S‐RBD). 6

After a viable vaccine is developed and manufactured, the storage, transportion, and administration of the vaccine will be of prime importance for successfully controlling the pandemic. The efficacy of a vaccine can be influenced by dosage, regimen, site of vaccination, and method of delivery.

Most SARS‐CoV‐2 vaccine candidates currently in clinical trials are delivered through intramuscular (IM) injection, including the nonreplicating viral vector vaccine (ChAdOx1‐S) from the University of Oxford/AstraZeneca and the mRNA‐1273 vaccine from Moderna whereas the DNA vaccine from Inovio Pharmaceuticals is delivered through intradermal injection. 7

Both IM and intradermal injections rely on conventional techniques, but they can have serious limitations including the need for trained professionals to accurately inject the formulation safely and the potential for blood‐related infections. 8 , 9 , 10 , 11 Therefore, other nonconventional techniques should be considered to minimize repeat doses and the need for trained personnel.

Microneedle (MN)‐based intradermal delivery is an emerging delivery method for vaccines. The skin is an immunologically active tissue and contains antigen‐presenting dendritic cells, Langerhans cells and other cells that can transfer antigens via lymphatic drainage to initiate antigen‐specific adaptive immune responses. 12 Compared with other delivery strategies, MN delivery of vaccines offers advantages such as smaller doses, reduced biohazard waste, and pain‐free and fast vaccination. The MNs can be pre‐formulated and stably stored for extended periods of time at room temperature (RT), which facilitates vaccine usage in developing countries with limited cold chain.

This addresses the common problems of vaccine storage stability and distribution challenges. For example, Kim et al recently used dissolvable MNs with carboxymethyl cellulose to deliver SARS‐CoV‐2 S1 subunit vaccines in mice, which induced significantly increased antigen‐specific antibodies by 2 weeks. 13

Inspired by these pioneering works, this study investigated the potential use of dissolvable MN‐based intradermal delivery of S‐RBD proteins as a potential vaccine for COVID‐19. The MN device was made from a mixture of S‐RBD proteins and low‐molecular weight hyaluronic acid (HA) using the micro‐molding method. 14 , 15 , 16 , 17 , 18 HA is a naturally occurring substance in skin with no known side effect and the low molecular weight HA (<50 kDa) quickly dissolves in skin as well.

The MN device was effective in penetrating the mouse skin and the resulting immunization elicited significant B cell antibody responses and interferon‐gamma (IFN‐γ)‐based T‐cell responses compared to nonimmunized controls. In contrast to conventional subcutaneous injection, MN‐based intradermal delivery of S‐RBD vaccine is a minimum invasive method that could facilitate rapid control of the COVID‐19 pandemic. However, we discovered that this platform is unsuitable for the delivery of mRNA. For example, we showed that luciferase mRNA embedded in the dissolvable MNs did not induce protein expression comparable to that of bolus injection.

reference link :

More information: Cryomicroneedles for transdermal cell delivery, Nature Biomedical Engineering (2021). DOI: 10.1038/s41551-021-00720-1


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