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Mesenchymal stem cells (MSCs) naturally replenish cell types of bone, cartilage, and adipose tissue. In addition, MSCs have a broad regenerative potential based on the ability to migrate into damaged tissues and secrete factors that stimulate the growth of new blood vessels, suppress inflammation, stop cell death and promote healing. This makes it possible to use them as cell therapy for various conditions, including cardiovascular diseases, liver, bone and cartilage diseases, lung and spinal cord injuries, autoimmune diseases, skin lesions and even cancer.
MSCs do not cause at all or cause minor adverse reactions in patients if obtained from healthy donors; they can be easily isolated from human tissues, multiplied to a clinical scale, bioconserved and stored for delivery to the place of medical care. This effectiveness in the preparation of MSCs contrasts with the relative inefficiency that is associated with poor delivery to target tissues in patients. Clinicians often need to inject a huge amount of MSCs in order to achieve a sufficient concentration of cells that will successfully take root and remain functional over time.
To overcome the problem of targeted delivery, researchers have developed approaches based on the creation of biomaterial scaffolds in which MSCs are placed and which can then be implanted as "patches" on damaged tissues. But even this does not make MSCS therapy more effective, because cells are limited in their ability to migrate, overcome tissue barriers and successfully take root in areas where their action is most necessary. In principle, injecting MSCs into tissues through hypodermic needles makes treatment more targeted, but any direct injection into tissue is invasive and can cause unintended tissue damage, as well as side effects in the form of scar tissue formation.
In a new study, a team from the Terasaki Institute for Biomedical Innovation in Los Angeles and the University of California, Los Angeles (UCLA) developed a minimally invasive approach that uses microneedles to provide a depot of active MSCs. The gel-like material is able to prolong the viability and functionality of the MSCs placed in it. Its introduction with the help of microneedles helps MSCs accumulate in damaged tissues with high spatial accuracy; the researchers demonstrated a new approach to wound healing in a mouse model with removed skin segments.
Microneedles have previously been successfully used for painless drug delivery to target tissues – skin, blood vessels and eyes. For MSCs cell therapy, researchers have developed a completely new patch with microneedles that preserves the viability of stem cells and supports their ability to respond to stimuli and accelerate wound healing.
At the beginning of the study, Ali Khademhosseini and his colleagues hypothesized that embedding MSCs in a biocompatible and biodegradable matrix would help create a hydrated environment with mechanical properties that stem cells need to survive and function for a longer time.
The matrix is a collection of gelatin fibers sewn together into a network in which the MSC can be placed. It mimics the normal extracellular environment of tissues in which MSCs are usually located. This helped to reconstruct the specific matrix medium in such a way that MSCs could absorb nutrients and bind to damaged tissue through the soluble factors they normally receive and send.
Another part of the task was to create a microneedle device for delivering MSCs, which would allow them to gently penetrate into the tissues, reaching the target areas. To do this, the researchers enclosed a soft gelatin matrix containing MSCs in a shell made of a second harder biomaterial – lactic and glycolic acid copolymers (PLGA). When applied to the wound surface, the PLGA shell, which is also biocompatible and biodegradable, slowly dissolves, preserving the gelatin matrix with MSCs during this process, allowing the latter to release their therapeutic factors into the damaged tissue through the resulting ruptures in the shell.
In order to be able to place individual microneedles directly on the wound, it was decided to attach an array of microneedles to a strip of plaster so that their sharp ends were directed away from the tape. The authors showed that in a patch with microneedles, 90% of MSCs were viable for 24 hours and did not lose their potential as stem cells.
The group investigated their concept of microneedles on mice that had previously had a section of skin removed within the epidermis. The exact location of the tape with a microneedle surface applied to it allowed individual microneedles to penetrate into the wound itself. Then the tape was removed, and the microneedles were detached from it and remained implanted in the damaged tissue. Hademhoseini and his colleagues called the delivery device a Removable Hybrid Microneedle Depot (d-HMND).
In mice, the d-HMND device carrying MSCs stimulated a number of key parameters related to wound healing. Compared with an equal number of MSCs injected directly into the wound, delivery using d-HMND accelerated wound healing and promoted the growth of the epidermal layers of the skin. The researchers used a panel of histological and molecular markers for 14 days to confirm that d-HMND with MSCs suppressed inflammation and stimulated tissue remodeling, the formation of new blood vessels, and hair regrowth.
In the future, d-HMND can be quickly manufactured in clinical laboratories shortly before use and used to treat skin damage. The authors intend to investigate the device more widely as a delivery of MSCs for a variety of other disorders, including melanoma and other skin diseases. This concept will also be compatible with the use of patient-derived cells for a more personalized approach.
Article K.Lee et al. A Patch of Detachable Hybrid Microneedle Depot for Localized Delivery of Mesenchymal Stem Cells in Regeneration Therapy is published in the journal Advanced Functional Materials.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Terasaki Institute: Microneedling therapeutic stem cells into damaged tissues.