Laser printing technology: Creating the perfect bioprinter

Scientists from Russia, China, and the US have drawn the attention of the scientific community to one of the newest and most promising areas in bioprinting - laser-induced forward transfer (LIFT). The researchers have compared laser printing parameters, bioink composition, donor ribbons, and collector substrates for LIFT bioprinters, as well as post-printing treatments of fabricated materials - all of this may affect the properties of printed tissues and organs.

The study will help scientists select the most appropriate techniques and materials, avoid many pitfalls in the process of bioprinting, and set the priorities for the development of this technology in the coming years. The details of the analysis were published in Bioprinting.

Tissue-engineering materials are increasingly used in medicine, mainly because they are created through mimicking the natural environment for cell development. The use of cell carriers (scaffolds) is a step forward compared to traditional cell therapy, which employs stem cells on their own. Bioprinting technologies allow to recreate tissues or organ models ("organs-on-chips") through layer by layer deposition of cells and biomolecules such as drugs or growth factors (compounds regulating cell growth and development) on a three-dimensional support structure.

LIFT technology transfers cells and biomolecules using laser pulse energy. The laser beam of a LIFT bioprinter focuses on the donor ribbon - a glass slide coated with an energy absorbing material (e.g. metal) and a layer of bioink (hydrogel with cells and biomolecules). Where the laser beam hits the surface, it heats and evaporates the energy absorbing layer, generating a gas bubble that propels a jet from the hydrogel layer. The resulting jet lands on another glass slide, the collector substrate, depositing a droplet.

LIFT technology provides a high print speed and cell survival rate, precise transfer of cells or molecules, and allows to work with various objects including microorganisms and whole cell structures such as spheroids. However, each hydrogel-cell combination requires a calculation of specific laser transfer parameters.

The authors of the paper analyzed 33 studies of bioprinting using LIFT. They systematically analyzed the descriptions of laser sources, energy absorbing materials, donor ribbons, and collectors substrates, as well as comparing the objectives and outcomes of the studies.

The most commonly used laser wavelengths were 193 and 1064 nanometers (short ultraviolet and near infrared ranges, respectively), although much longer and shorter wavelengths were successfully experimented with as well. Gold, titanium, gelatin and gelatin-containing mixtures were used as an energy absorbing material, while researchers in five studies did not use this layer at all.

Most of the studies used murine fibroblasts (connective tissue cells that synthesize extracellular matrix proteins) or mesenchymal stromal cells (cells that can differentiate into various connective tissue cells). The choice depended on cell availability.

The bioink used by many research teams contained glycerol and methylcellulose to help the bioink retain moisture, or blood plasma to support cell growth. Another common component was hyaluronic acid because it improved bioink viscosity as well as promoting cell growth.

One of the best bioink materials was collagen, the main component of connective tissue. In some studies, the bioink also formed a "functional pair" with the collector substrate: for instance, if the donor ribbon was alginate-based, then the collector substrate contained calcium ions, while fibrinogen-containing donor ribbons were used with collector substrates containing thrombin. Such "functional pairs" allow to maintain the shape of the printed constructs effectively, because the substances in the collector substrate act as bioink fixatives.

The studies also used different types of printing: 2D, whereby the cells were arranged in a single layer (the researchers printed lines, shapes, letters, numbers, or the Olympic flag), or 3D, which allows to recreate complex cellular structures such as stem cell niches. Three-dimensional structures were created by depositing the bioink layer by layer.

The authors of the studies used various techniques to assess the impact of the bioprinting process on cells. Most researchers note that cell viability was fairly high, and there was no damage to the DNA despite the mechanical impact and the spike in temperature.

There were no changes in either the proliferation rate of cells or the ability of stem cells to differentiate (transform into more specialized cells). In some of the studies, printed tissues were implanted into laboratory animals. The authors of the review believe that with the improvement of this technology in the next few years, there will be more studies involving animals.

"LIFT technology is quite new, and is only beginning to 'conquer' the world of biomedicine. Naturally, it will be improved and further used in tissue engineering, possibly even in clinical practice. In my opinion, however, its most promising application is in combination with other technologies, which will allow to create tissues and organs for transplantation", says Peter Timashev, one of the paper's authors, Director of the Institute for Regenerative Medicine, Sechenov University.

Research paper

University of California - Los Angeles

New hydrogels show promise in treating bone defects
Los Angeles CA (SPX) Aug 21 - Bioengineers and dentists from the UCLA School of Dentistry have developed a new hydrogel that is more porous and effective in promoting tissue repair and regeneration compared to hydrogels that are currently available.

Once injected in a mouse model, the new hydrogel is shown to induce migration of naturally occurring stem cells to better promote bone healing. Current experimental applications using hydrogels and stem cells introduced into the body or expensive biological agents can come with negative side effects.

The findings, published online in the journal Nature Communications, suggest that in the near future the next generation of hydrogel systems could greatly improve current biomaterial-based therapeutics to repair bone defects.

Hydrogels are biomaterials that are made up of a 3D network of polymer chains. Due to the network's ability to absorb water and its structural similarities to living tissue, it can be used to deliver cells to defective areas to regenerate lost tissue. However, the small pore size of hydrogels limits the survival of transplanted cells, their expansion and new tissue formation, making this less than ideal for regenerating tissue.

One material that has caught on in the field of biomaterials is the naturally occurring mineral, clay. Clay has become an ideal additive to medical products with no reported negative effects. It has been shown to be biocompatible and is readily available.

The clay is structured in layers, with the surface having a negative charge. The unique layered structure and charge were important to researchers as their hydrogels had a positive or opposite charge. When the hydrogel was inserted into the clay layers, through a process called intercalation chemistry, the end result was a clay-enhanced hydrogel with a much more porous structure that could better facilitate bone formation.

Once they had their clay-enhanced hydrogel, the researchers used a process called photo-induction, or the introduction of light, to turn their new biomaterial into a gel, which would make it easier to be injected into their mouse model.

The mouse model had a non-healing skull defect, which the researchers injected with their clay-enhanced hydrogel. After six weeks, they found that the model showed significant bone healing through its own naturally occurring stem cell migration and growth.

"This research will help us develop the next generation of hydrogel systems with high porosity and could greatly improve current bone graft materials," said lead author Min Lee, professor of biomaterials science at the UCLA School of Dentistry and a member of the Jonsson Comprehensive Cancer Center. "Our nanocomposite hydrogel system will be useful for many applications, including therapeutic delivery, cell carriers and tissue engineering."

Injectable combinations of living cells and bioactive molecules using hydrogels would be a preferred medical application to treat unhealthy or damaged areas of the body rather than more invasive surgery.

Future research is planned to learn how the physical properties of nanocomposite hydrogels affect the migration of cells and their function, as well as the formation of blood vessels.

Related Links
Sechenov University
Space Medicine Technology and Systems

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