Using a magnetic field and hydrogels, a team of researchers in the Perelman School of Medicine at the University of Pennsylvania have demonstrated a new possible way to rebuild complex body tissues, which could result in more lasting fixes to common injuries, such as cartilage degeneration.
This research was published today in Advanced Materials.
“We found that we were able to arrange objects, such as cells, in ways that could generate new, complex tissues without having to alter the cells themselves,” said the study’s first author, Hannah Zlotnick, a graduate student in Bioengineering who works in the McKay Orthopaedic Research Laboratory at Penn Medicine.
“Others have had to add magnetic particles to the cells so that they respond to a magnetic field, but that approach can have unwanted long-term effects on cell health.
Instead, we manipulated the magnetic character of the environment surrounding the cells, allowing us to arrange the objects with magnets.”
In humans, tissues like cartilage can often break down, causing joint instability or pain. Often, the breakdown isn’t in total, but covers an area, forming a hole.
Current fixes are to fill those holes in with synthetic or biologic materials, which can work but often wear away because they are not the same exact material as what was there before.
It’s similar to fixing a pothole in a road by filling it with gravel and making a tar patch: the hole will be smoothed out but eventually wear away with use because it’s not the same material and can’t bond the same way.
What complicates fixing cartilage or other similar tissues is that their make-up is complex.
“There is a natural gradient from the top of cartilage to the bottom, where it contacts the bone,” Zlotnick explained. “Superficially, or at the surface, cartilage has a high cellularity, meaning there is a higher number of cells. But where cartilage attaches to the bone, deeper inside, its cellularity is low.”
So the researchers, which included senior author Robert Mauck, Ph.D., director of the McKay Lab and a professor of Orthopaedic Surgery and Bioengineering, sought to find a way to fix the potholes by repaving them instead of filling them in.
With that in mind, the research team found that if they added a magnetic liquid to a three-dimensional hydrogel solution, cells, and other non-magnetic objects including drug delivery microcapsules, could be arranged into specific patterns that mimicked natural tissue through the use of an external magnetic field.
After brief contact with the magnetic field, the hydrogel solution (and the objects in it) was exposed to ultraviolet light in a process called “photo crosslinking” to lock everything in place, and the magnetic solution subsequently was diffused out. After this, the engineered tissues maintained the necessary cellular gradient.
With this magneto-patterning technique, the team was able to recreate articular cartilage, the tissue that covers the ends of bones.
“These magneto-patterned engineered tissues better resemble the native tissue, in terms of their cell disposition and mechanical properties, compared to standard uniform synthetic materials or biologics that have been produced,” said Mauck.
“By locking cells and other drug delivering agents in place via magneto-patterning, we are able to start tissues on the appropriate trajectory to produce better implants for cartilage repair.”
While the technique was restricted to in vitro studies, it’s the first step toward potential longer-lasting, more efficient fixes in living subjects.
“This new approach can be used to generate living tissues for implantation to fix localized cartilage defects, and may one day be extended to generate living joint surfaces,” Mauck explained.
Bone is a natural complex of inorganic and organic materials (Abou Neel et al., 2016; Loi et al., 2016; Wang et al., 2020). The main component of the inorganic material is crystalline hydroxyapatite while the organic substance is mainly fibrous collagen (Loi et al., 2016). Bone has the ability to regenerate and repair itself.
Although for bone defects caused by external damage or due to bone diseases, tumors, and abnormal bone growth, the self-repairing ability of the bone alone cannot achieve the purpose of healing (Loi et al., 2016; Michalski and McCauley, 2017). It is necessary to resort to medical materials including autologous bone tissue, allogeneic bone tissue, and bone tissue substitutes. Either method requires the regeneration of local bone tissue.
In this process, external stimulations including stress stimulation, chemical stimulation, biological factor stimulation, magnetic field, and electric field are considered as necessary conditions (Abou Neel et al., 2016; Loi et al., 2016; Michalski and McCauley, 2017; Debnath et al., 2018).
The magnetic field has been proven to enhance bone tissue repair by affecting cell metabolic behavior (Iwasa and Reddi, 2018; He et al., 2019; Liu H. Y. et al., 2020). In recent research, iron is the most common material used with its para-magnetism (Luo et al., 2018; Xia et al., 2018; Yu et al., 2019).
The unpaired electrons of the outermost layer spin to make the atom maintain a certain magnetic moment. This atomic magnetic moment is arranged along the magnetic field under the action of an external magnetic field, showing a weak magnetic force that conforms to the magnetic field (Iwasa and Reddi, 2018; Luo et al., 2018).
This substance is called paramagnetic substance. Ferromagnetic substances have atomic magnetic moments composed of unpaired spin electrons (Iwasa and Reddi, 2018). In the absence of a magnetic field, the atomic magnetic moments are also neatly arranged, showing strong magnetism to the outside (Luo et al., 2018; Xia et al., 2018; He et al., 2019).
Magnetic nanoparticles (MNPs) are used as biomaterials due to their unique magnetic properties and good biocompatibility (Aliramaji et al., 2017; Brett et al., 2017). Recently, they have been widely applied in drug transportation, magnetic hyperthermia, nuclear magnetic imaging, and biological separation (Li et al., 2016; Jia et al., 2019; Nejadnik et al., 2019).
The magnetic particles are slowly deposited on the surface of the cell membrane under the action of the magnetic field. The cells engulf the magnetic particles through endocytosis. Entering the cell makes it easier to affect the physiological function of the cell (Theruvath et al., 2018; Xia et al., 2018).
If a magnetic field is applied, each magnetic particle will become a magnetic source, which will enable the magnetic scaffold material to play the role of bone tissue repair therapy. Once the magnetic particles are exposed to an external magnetic field, they will be rapidly magnetized (Yang et al., 2019).
The magnetic particles and the magnetic field work together to enhance the effectiveness of their bone tissue repair treatment (Yang et al., 2019; Zhao et al., 2019). Varieties of MNPs loaded with/without drugs have been applied in the medical industry, playing a very important role.
Especially for bone tissue repair, MNPs have been proven efficient [Singh et al., 2012a; Maleki, 2014 (Eivazzadeh-Keihan et al., 2019 #160(Eivazzadeh-Keihan et al., 2019 #160)]. This article reviews the common synthesis methods, the mechanism and application of magnetic nanomaterials in the field of bone tissue repair.
Preparation of Magnetic Nanomaterials
Preparation methods have been well-developed with immeasurable application value. Various elemental compositions have been used in magnetic nanomaterials, including Fe3O4, Fe, Co, Ni, MgFe2O4, and Co Fe2O4 (Hamidian and Tavakoli, 2016; Chen et al., 2018; Wu et al., 2019; Xue et al., 2019). The most classic and common composition of magnetic nanomaterials is Fe3O4 (Hamidian and Tavakoli, 2016; Yu et al., 2016; Huang et al., 2018).
Two main types of magnetic Fe3O4 preparation methods are the dry method and the wet method (Huang et al., 2018). Among them, the wet method is more commonly applied, mainly including the following techniques, the hydrothermal method, solvothermal method, chemical co-precipitation method, ball milling method, sol-gel method, and the atomic layer deposition method.
In the synthesis of MNPs, with different preparation conditions, different preparation methods and different catalysts, turnover number (TON), and turnover frequency (TOF) could differ widely (Singh et al., 2012b; Maleki, 2014, 2018). In the preparation of MNPs for bone repair, with the help of different catalysts, the Suzuki reaction and Heck reaction of halogenated benzene can be carried out efficiently. The overall TON and TOF can reach more than 30,000 mol and 50,000 h−1, respectively (Maleki, 2014).
More information: Hannah M. Zlotnick et al, Magneto‐Driven Gradients of Diamagnetic Objects for Engineering Complex Tissues, Advanced Materials (2020). DOI: 10.1002/adma.202005030