Regenerative medicine is defined as “an interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause, including congenital defects, disease, trauma, and aging.”
Equine regenerative medicine is an emerging field filled with exciting new developments and almost limitless potential. Unfortunately, there are significant barriers to access traditional regenerative therapies for the average horse owner.
An Emerging Field
While equine regenerative medicine has exciting applications, it is a young and rapidly evolving new field. The equine subset of regenerative medicine is an even newer field.
Depending on what branch of regenerative medicine you’re discussing, research into the world of regenerative medicine began in the mid- to late-19th century when four main events occurred:
1838 - 1839 - Schleiden and Schwann described cell theory.
1858 - Rudolf L. K. Virchow confirmed cell theory and established the idea of cells being the elementary units of life able to replicate themselves by division.
1867 - Julius Cohnheim suggested that all of the reparative cells taking part in the regeneration of wounds come from the bloodstream and bone marrow.
End of the 19th century - Barth observed that upon autologous bone transplantation in hounds the vast majority of cells die and leave a scaffolding behind to be slowly repopulated by new host cells and an adequate neovascular network.
As with many scientific theories, while early experiments were performed on animals, the field of equine regenerative medicine did not take off until much later. Many of the regenerative therapies that are used in horses today were not invented until recently. For example, PRP was first invented in the 1950s and was popularized in the 1970s for use in humans.
With a field as new and rapidly evolving as this one, results from the use of traditional regenerative therapies, such as IRAP and PRP, are varied in terms of success. Promising results that are achieved in preclinical studies, case reports, and small randomized studies, have not had the opportunity to be more thoroughly studied, as large placebo-controlled studies are scarce.
Ribitsch et al even goes so far as to say that “the field of RM faces several challenges like the lack of well-defined cells to be used as therapeutics and insufficient understanding of their mode of action… Currently, the mechanisms of the tightly regulated process, involving the interplay of growth factors, cytokines, proteinases, and cellular mediators combined with differences in cellular density, proliferation rate, inflammatory response, extracellular matrix (ECM) composition and synthetic function, are still poorly understood.”
Researchers in the field of equine regenerative medicine are undertaking pioneering work in order to create a standardized protocol for treatment and reduce variation in treatment results. Without a set and proven protocol in the use of many traditional methods of equine regenerative medicine, results are not guaranteed. This presents a significant barrier to the use of equine regenerative medicine.
Despite the ongoing research, equine regenerative medicine has the potential to save the lives of horses who would have previously been euthanized or retired due to injury, arthritis, or other such traumatic conditions.
As an example of the promise equine regenerative medicine holds: the use of regenerative therapies in the treatment of soft tissue injuries has resulted in awe-inspiring statistics. Some regenerative therapies have been shown to decrease the re-injury rates for soft tissue injuries “from 80% to 13–36% and to achieve a more tendon-like repair tissue with better histologic architecture and biomechanical properties of the healed tendon tissue compared to traditional treatments.”
Beyond management of soft tissue injuries, equine regenerative medicine provides promising new tools for equine wound management. According to Linda Dahlgren, DVM, PhD., “Regenerative therapies can function as scaffolds, cells, and bioactive factors, or a combination of these building blocks of tissue regeneration.”
In the case of human non-healing wounds, one study notes, “Regenerative medicine strategies have the potential to restore tissue, perhaps equaling or exceeding pre-damage levels, resulting in improved outcomes and quality of life.”
This optimistic and exciting result in human medicine is also applicable to equine regenerative medicine in the case of non-healing wounds. Researchers are enthusiastically studying new applications for equine regenerative medicine, as well as exploring ways to get more consistent results.
As more research emerges, it is apparent that equine regenerative medicine could be a game changer in terms of how veterinarians manage conditions that were previously thought of as life-ending.
Regenerative Medicine Helps Horses With…
Chronic or non-healing wounds are relatively common in horses. While wounds on the horse’s trunk or body heal via contraction easily, wounds on the legs of the horse are a different story.
There are several different reasons awound may become chronic. Sometimes, a wound won’t heal due to contamination with embedded foreign material, such as dirt, sticks, and various debris. In other cases, infection sets in and delays the healing of a wound. Or excessive granulation tissue develops, which has to be continually debrided.
Wounds that are more likely to become chronic are usually in a high motion area, such as the distal limb, or involve exposed bone. This second type of injury is prone to becoming chronic as the bone is slow to develop granulation tissue and is quick to die from prolonged exposure due to its poor blood flow.
Recent studies are also exploring the possibility that biofilm may be contributing to chronic wound cases. The data on biofilm and chronic wounds is quite startling. Biofilms are “a collective of one or more types of microorganisms that can grow on many different surfaces.”
A good example of a commonly seen biofilm is pond scum. In the case of equine wound management, biofilms can form over the surface of a chronic wound and prevent healing. These biofilms are more common than previously thought.
In one human study, 75 percent of samples taken from non-healing wounds contained biofilm. Due to the similarities between horse and human wounds, as well as new evidence that biofilms are in fact present in equine wounds, it is not too much of an extrapolation to assume that biofilms are common in non-healing equine wounds as well.
Equine regenerative medicine provides veterinarians with new tools to speed healing of chronic wounds and dispel biofilms. Combining nanoparticle technology with the benefits of silica, amorphous silica nanoparticle utilization, while on the cutting-edge, could be the key to chronic wounds with biofilm.
Research shows that when these T-cells are activated, they proliferate and secrete regulatory molecules such as growth factors and cytokines to stimulate production of new epithelial cells. In a recent study on wound healing, silica nanoparticles were used as a “slow release” vehicle, in order to diffuse orthosilicic acid throughout the target area. The hope was that these nanoparticles would prove beneficial in the wound healing process. The result was more than what was hoped for– silica nanoparticles were shown to promote wound closure more rapidly than soluble orthosilicic acid alone. Scientists believe that this effect is related to easy cellular internalization of these particles followed by their intra-cellular dissolution releasing silicic acid at a faster rate than its direct uptake from the medium.
The findings indicate that amorphous silica-based nanoparticles can favor the delivery and release of bioactive silicic acid to cells, promoting wound healing. While the anticipated stimulatory effect of orthosilicic acid was observed, the silica nanoparticles also stimulated fibroblast proliferation and migration.
Combining the benefits of both nanoparticles and orthosilicic acid, amorphous silica nanoparticles may help to manage chronic wounds via the regenerative properties behind T-cell stimulation.
According to the Horse Health Programme, “Arthritis is unfortunately very common in horses, especially in the ageing horse population. It is a degenerative joint disease that causes pain and inflammation. Over time, the inflammation damages the cartilage within a joint beyond repair, leading to chronic pain.”
Some surveys have estimated that up to 60 percent of all lameness in horses is related in some degree to osteoarthritis. Research into equine osteoarthritis is relatively new, with the disease first being clinically studied by the American Association of Equine Practitioners in 1966.
Horses at risk for the development of osteoarthritis fall into two different categories:
Abnormal loading on normal cartilage
Normal loading on abnormal cartilage
For example, racehorses may be more prone to osteoarthritis, as they typically have an intense career at a young age, which may place an excess amount of pressure on healthy cartilage. On the other hand, a lightly-ridden and well-managed trail horse may also develop osteoarthritis if they have genetically inferior cartilage compared to the average horse.
New equine regenerative medicine therapies have been developed specifically for the treatment of osteoarthritis in horses. For example, IRAP, which stands for Interleukin-1 Receptor Antagonist Protein, is designed to counteract inflammation in joints. The presence of pro-inflammatory cytokines in joints creates a downward spiral of inflammation and joint disease, resulting in cartilage damage and osteoarthritis.
Soft Tissue Injuries
Soft tissue injuries involve the collagen fibers in tendons that make up the connections between bones and create the “pulley system” that allows the skeletal system to move. When damaged, tendons and ligaments take a long time to heal, over the span of months or even years. The financial strain of a soft tissue injury is significant, as treatment is expensive and time-consuming, plus the horse will be unable to earn their keep during this time period.
Soft tissue injuries can be caused by mechanical overload or external trauma. Mechanical overload occurs when the fibers are stretched beyond their normal capacity during exercise. External trauma happens from either blunt trauma (i.e. being kicked by another horse) or restriction (i.e. a poorly-applied bandage).
Naturally, horse owners will attempt to do all they can to speed the healing process of these injuries. This may include the use of the regenerative therapy known as PRP, which stands for platelet rich plasma. PRP delivers a high concentration of platelets in the form of blood plasma to a lesion increasing the amount of growth factors at the site which aids in healing.
Equine Dermatologic Conditions
An area of equine medicine that isn’t often thought of as having potential for regenerative therapies is equine dermatology. The reality is that many dermatologic conditions, like pastern dermatitis, can be extremely difficult to manage and cure, particularly if the owner must refrain from steroid use. Conditions like pastern dermatitis may start off mildly, however they can progress to more severe stages and cause swelling, heat, and lameness.
While it is sometimes disregarded as “not serious,” equine dermatologic conditions can have a large impact on the horse’s quality of life and greatly impact their rideability. Some equine skin conditions, like insect bite hypersensitivity, are related to abnormal genetic factors, while other skin conditions, like pastern dermatitis, may be related to bacteria, fungi, or parasitic infestation.
Equine regenerative medicine can help these often chronic conditions resolve via the use of silica nanoparticles.
Orthosilicic acid reportedly accelerates wound cicatrisation by stimulating basal epidermal and dermal fibroblast cells. Silica nanoparticles of the right size and shape, like those found in Zarasyl Equine, are reported to stimulate T-cell receptors. These receptors are key regulators of the horse’s response to skin injuries, like the lesions associated with both pastern dermatitis and insect bite hypersensitivity.
Research shows that when T-cell receptors are activated, they proliferate and secrete regulatory molecules, such as growth factors and cytokines, to stimulate production of new epithelial cells in the vicinity of the injury. And that’s not all– T-cell receptors also recruit additional immune cells to the damaged area and activate the production of antimicrobial defense proteins.
In short, promoting healing via orthosilicic acid delivered via silica nanoparticles results in regenerated epithelial and connective tissue and boosted immune response due to T-cell receptor stimulation.
The applications for equine regenerative medicine are endless. As new research on regenerative medicine continues to emerge, there is no doubt new ways of treating old problems will develop.
Mesenchymal Stem Cells
When most people think of regenerative medicine, stem cells may be one of the first therapies to come to mind. Mesenchymal stem cells are “multipotent stem cells found in bone marrow that are important for making and repairing skeletal tissues, such as cartilage, bone, and the fat found in bone marrow.”
It’s important not to confuse this type of stem cell with those that make up our blood (haematopoietic stem cells). Mesenchymal stem cells are “adult” stem cells as they are harvested from adult bone marrow and can specialize into bone cells, cartilage cells, and fat cells.
There are two different types of stem cell therapy, allogeneic and autologous. Autologous stem cell therapy means that the cells are harvested from the same horse that is receiving them. Allogeneic means the stem cells are sourced from a donor horse. In equine regenerative medicine, nearly all mesenchymal stem cell therapies are autologous.
Because they are multipotent (able to differentiate into multiple different types of cells), mesenchymal stem cells may be useful for a variety of purposes including:
Aberrant wound healing
These stem cells are harvested while the horse is under sedation and the harvesting area is locally anesthetized. The two most common sites for mesenchymal stem cell harvesting are the sternum and ilium. After harvesting, the cells are expanded in a laboratory setting prior to re-injection.
Blood-Based Regenerative Therapy
There are a multitude of equine regenerative medicine therapies that come from blood. Perhaps the most common is IRAP, which is also known as autologous conditioned serum. This blood product contains concentrated amounts of anti-inflammatory protein and is typically used to treat osteoarthritis. Unlike other types of joint injection, autologous conditioned serum can be used repeatedly without harming the joint.
In order to create autologous conditioned serum, blood withdrawn from the patient is incubated for 24 to 48 hours prior to being injected into the joint. During this time frame, the blood is stored with medical grade glass beads coated with CrSO4, which creates the final product of enriched serum.
PRP, or platelet rich plasma, is another commonly used blood-based form of regenerative medicine. Unlike IRAP, PRP is typically used to help speed the healing of notoriously slow-healing soft tissue injuries. PRP involves withdrawing blood from the patient and running it through a centrifuge in order to concentrate the platelets. This concentrated plasma is then injected back into the damaged area of the body.
Non-Invasive Regenerative Medicine
The invasiveness of various types of equine regenerative medicine is a spectrum. Whereas the use of mesenchymal stem cells is perhaps most invasive, PRP and IRAP tend to fall in the middle of the spectrum. The least invasive forms of equine regenerative medicine are either the application of a topical ointment or the use of laser therapy.
Low level laser therapy is also called photobiomodulation. This form of equine regenerative medicine has been shown to stimulate osteogenic cells and bone tissue, as well as reduce edema and pain. Laser therapy can be used in conjunction with other forms of equine regenerative medicine, such as mesenchymal stem cells, to enhance the survival rate of the cells and improve results.
The use of silica nanoparticles is another form of equine regenerative medicine. These nanoparticles are designed to provide targeted delivery of orthosilicic acid to damaged areas of the body. An extremely non-invasive therapy, this type of equine regenerative medicine can be delivered to the body as a topical ointment or cream.
Silica nanoparticle technology has been shown to have several different effects, including:
T-cell receptors are stimulated and secrete regulatory molecules, such as growth factors and cytokines
Production of epithelial cells in the vicinity of the injury is stimulated
Additional immune cells are recruited to the damaged area
Production of antimicrobial defense proteins is activated
Barriers to Access
Unfortunately, as regenerative medicine is a new and rapidly evolving field, the barriers to access are many. Veterinarians who specialize in equine regenerative medicine are few and far between. Particularly in areas of the world where equine veterinarians are not common, vets may not have the equipment needed for these new methods. For example, some veterinarians may not have the ultrasound necessary to guide injections or access to therapeutic lasers.
Equine hospitals who are able to harvest and expand stem cells are also few and far between, with the majority in more populated areas, leaving horse owners in rural areas with fewer options. Equine stem cell banks are also uncommon.
Even practical barriers, such as whether or not a horse owner has the ability and equipment needed to transport the horse to a hospital, also limit access to equine regenerative medicine.
One of the biggest barriers to traditional applications of equine regenerative medicine is the high price tag. The cost to perform traditional regenerative therapies varies based on the type of therapy involved.
Stem Cell injection is by far the most costly, as the process requires a lot of labor. The stem cells must be harvested, expanded in a lab, and implanted. If the owner or veterinarian would like the harvested cells stored in a stem cell bank, the cost will only increase from there. Without banking the cells, the cost for stem cell therapy ranges from a minimum of $2500 and can easily get into the mid-four figures.
IRAP is significantly less expensive, however the cost is still in the range of four-figures. PRP injections are by far the least expensive, with a price tag ranging from $500 to $1000.
The average income of a horse owner in the United States is only $60,000 per year. In this day and age, this once sufficient salary is currently only moderate. Traditional equine regenerative medicine therapies are most likely out of reach for the average horse owner in the United States, based on price alone.
The benefits of non-invasive equine regenerative medicine are many, as there are much fewer barriers to its application. Whereas other equine regenerative medicine therapies cost thousands of dollars, the application of a topical cream costs less than $100 dollars. Plus, no special equipment or invasive surgeries are required.
A New Type of Regenerative Medicine
Zarasyl Equine contains a proprietary amorphous silica formula with a molecular structure tailored to provide sustained delivery of orthosilicic acid to the skin. Over a decade of scientific research has been conducted to perfect the patented, novel technology in Zarasyl Equine. Steroid and antibiotic-free, this topical ointment creates a superior moisturizing environment.