Bio101

Why We Ditched DMSO: A Look at the Safety of Dimethyl Sulfoxide

Early in the summer of 2017, I traveled to Europe to explore the Scottish Highlands. With rolling hills and an ethereal mist hanging in the air, the Highlands are easily among the most beautiful landscapes in the world.

DMSO is like the Scotland landscape

But even though I loved visiting the Highlands, I couldn’t imagine actually living there.

Why? Because there’s a flip side to such natural beauty: it has to rain nearly every day to support that amount of greenery.    

And not just a light drizzle.

I’m talking about heavy, fierce rain that can turn a pleasant afternoon hike into a jaunt through a hurricane in about five minutes flat.

It quickly occurred to me that the natural beauty of the Highlands was a double edged sword. The benefit of breathtaking scenery was overshadowed, quite literally, by nearly perpetual dark clouds and rain.

The DMSO Double Edged Sword

At Burst Biologics, we see a lot of double edged swords throughout science and medicine: Drugs can treat all kinds of conditions, but they also cause potential side effects. Surgeries carry the risk of possible complications, even as they give patients a new lease on life. Ultimately, it’s hard to get the good without a risk of the bad.

That’s probably why, in the world of regenerative medicine, it’s widely accepted that the cryoprotective agent (CPA) known as dimethyl sulfoxide (DMSO) is a necessary evil for cryopreserving graft sources prior to infusion in patients.

Many physicians simply accept DMSO as the “bad edge” of a double edged sword, with the “good edge” being the many benefits that patients enjoy with stem cell transplantation.

But this chemical can be more dangerous than doctors give it credit for.

A Brief History of DMSO

Dimethyl sulfoxide is a colorless liquid discovered in 19th century Germany as a byproduct of wood pulp when producing paper. One of its most notable properties is its ability to permeate across cell membranes. This quickly proved useful for dermatological conditions like skin inflammation or scleroderma.

DMSO is a byproduct of paper production

The year 1959 marked the first trial of DMSO usage to prevent freezing damage to living cells. Later, in 1978, DMSO received FDA approval for treating interstitial cystitis (aka chronic bladder pain).

However, all these decades later in 2017, the chemical is still only approved by the FDA for that single function. There have been rumblings about DMSO’s possible use in cancer treatment as well, but according to the Memorial Sloan Kettering Cancer Center, there are still lingering concerns over potential toxicities in DMSO. These concerns should – and do – spill over into DMSO’s use as a cryoprotectant.

Cell Preserver or Cell Killer?

On the positive side, DMSO has the ability to permeate across cell membranes, allowing it to inhibit intracellular ice formation and prevent injury in stem cell freezing. It’s also soluble in both aqueous and organic media, making it extremely useful both in the lab and in clinical applications.

But even with all these great properties, DMSO has its drawbacks. The chemical is associated with possible toxicity and a range of serious side effects, and we also know that prolonged exposure to dimethyl sulfoxide directly impacts cellular function and growth.

In fact, one of our molecular biologists explained that she uses DMSO to preserve cell lines for research, but once she’s done thawing cells, she gets rid of the DMSO as soon as possible. She’s learned from experience how quickly it kills her research cells. The same effect can occur in a clinical setting: once cells begin to thaw, they are susceptible to the cytotoxic effects of dimethyl sulfoxide.

So, with all this in mind, how exactly does this chemical affect patients in the real world?

Adverse Reactions From DMSO

As common as DMSO is as a cryoprotectant agent, there’s still a significant number of potential side effects and adverse reactions associated with the chemical. That’s why we made it a priority to completely eliminate DMSO from our products.

Here’s a brief look at the many adverse reactions (ARs) recorded after transplantation of hematopoietic stem cells in patients, as compiled in the study “Hematopoietic SCT with cryopreserved grafts” by Z Shu, S Heimfeld, and D Gao.

Types of ARs from DMSO:

  • Allergy. DMSO can induce a release of histamine. Common allergic reactions include flushing, rash, and edema.
  • Gastrointestinal. Affecting the limbic-hypothalamic pathways, DMSO can result in symptoms like nausea, abdominal pain, and emesis.
  • Renal. The incidence of kidney-related ARs is comparatively low, but includes symptoms like hemoglobinuria, proteinuria, and urine incontinence.
  • Cardiovascular. Symptoms include hypertension, arrhythmias, tachycardia, shock, cardiac arrest, and seizure.
  • Neurological. Symptoms include bilateral thalamic infarction, blurred vision, severe encephalopathy, cognition, muscle weakness, and numbness.
  • Hepatic. Symptoms include progressive jaundice.

As serious as these conditions are, this is only a partial list of the identified ARs related to DMSO, based on many studies centered around the physiological role of the chemical in ARs, from neurotoxic reactions to shock.

Studies also show that the adverse effects are cumulative. Patients receiving multi-dose therapies containing DMSO may suffer progressively more severe symptoms over time.

Even more worrisome, the scientific community doesn’t actually have a lot of data to suggest what effects the chemical may have on patients long-term. That’s why it’s problematic to inject people with the chemical – in the long run, we have no idea what may happen.

Now, to be fair, not all adverse reactions (ARs) are solely attributable to DMSO itself. In any allograft or stem cell transplantation procedure, there are many components involved. Some of these factors, such as dead cell debris after thaw or the low temperature of infused products, can also lead to ARs.

But much of the concern does lie with DMSO itself, as illuminated by a documented causal relationship between DMSO and adverse reactions. That’s why there’s been a concerted effort in the industry to remove or reduce DMSO from cryopreserved products.

What to do About DMSO

If we know that DMSO has the potential to be harmful to patients, the next question is, what do we do with that information? After all, cryopreservation is still a necessity if we want patients to enjoy the benefits of allografts and stem cell transplantation.

Well, you can deal with this problem in a few ways. One of the most common is DMSO removal through centrifugation right before delivery to the patient.

3D Model of DMSO Molecule

This is certainly a positive for many patients, but it still doesn’t fully resolve the problem. Aside from adding extra steps to the transplantation process, spinning down the product in a centrifuge still leaves trace amounts of DMSO, enough to trigger an AR in those who are sensitive to the chemical.

Plus, in the time it takes to thaw, spin, and resuspend the product, there’s also ample opportunity for cell death.

So, what else can be done? Here are four other widely discussed strategies for minimizing adverse reactions to dimethyl sulfoxide in cryopreserved grafts:

  • Reducing overall DMSO concentration
  • Administering medication before and after transplantation
  • Optimizing the infusion procedure
  • Using alternative CPAs for cryopreservation

The first three solutions hold some promise, but the bottom line is, nothing is safer than simply avoiding DMSO altogether.

A True DMSO Alternative

At Burst Biologics, we chose the fourth option: adopting a non-toxic DMSO alternative for cryopreservation in our BioBurst cellular allograft products. We developed the Progenokine Process to preserve product integrity and address the potentially harmful agent of DMSO in our cryopreservation media.

Our own lab research has demonstrated the efficacy of this DMSO-free stem cell cryopreservation medium, which enlists USP grade non-toxic ingredients. Ultimately, the products do their job well without even a hint of dimethyl sulfoxide.

In finding a quality DMSO alternative for our BioBurst products, Burst Biologics has taken a major step forward in improving the safety of regenerative medicine. While there’s still work to do, we’re proud to be moving forward on innovative new solutions that help people live healthier, more fulfilling lives.

Sources:

  1. Hematopoietic SCT with cryopreserved grafts: adverse reactions after transplantation and cryoprotectant removal before infusion
  2. Dimethyl Sulfoxide-Induced Toxicity in Cord Blood Stem Cell Transplantation: Report of Three Cases and Review of the Literature
  3. Clinical Toxicity of Cryopreserved Bone Marrow Graft Infusion

What is Regenerative Medicine Today?

Prometheus regenerating liver

We all remember Prometheus.

As you’ve probably heard us mention a time or two, Burst Biologics is in the business of regenerative medicine – and yes, it’s as cool as it sounds!

But what does regenerative medicine mean?

At its core, it’s all about helping human cells, tissues, and organs work properly. This branch of medicine focuses on the way cells live and function every day.

Compared to the whole of medicine, this is one field that’s quite new. However, forms of regenerative medicine have been practiced for more than 1000 years, and were acknowledged conceptually even in Ancient Greece. Remember Prometheus and his regenerating liver?

Of course, what we think of as regenerative medicine today is closely associated with the emergence of tissue engineering back in the late 1980s. It’s all based on the way cells work.  

The Magical Regenerating Cell

You have trillions of cells in your body, and they’re constantly regenerating. That’s the basic explanation for why you can donate blood, get a haircut, or heal from a broken bone.

Some types of cells replace themselves quickly, like the stomach cell’s two to nine day lifespan. Others last much longer, like the four month renewal rate for red blood cells.

But in any case, the concept of regenerative medicine hinges on this idea of regenerating cells.

Defining Regenerative Medicinecells can be replaced or regenerate

So, to better understand regenerative medicine, we need to consider what would happen if a group of cells in your body weren’t operating at their best. Conceptually, what could we do to fix that problem?

From the purview of regenerative medicine, it comes down to two general remedies.

 

Replacement

One clear solution is to replace the deficient cells or tissues with healthy ones. That’s essentially what an organ transplant is. If you have a failing kidney, swapping it out for a new one can rapidly restore functionality.

Replacement can be difficult, expensive, and invasive – but sometimes, it’s the only recourse available to patients with serious damage to their tissue or organs. With regenerative medicine, it’s possible to grow the new tissue that’s needed for replacement.

Regeneration

Another option is to regenerate the tissues and encourage self-healing. With this approach, you’re simply helping the body do what it normally could do, kind of like filling up the gas tank in a car that’s stalling.

One of our products is a fluid that aids and supports various mechanisms which encourage bone consolidation. Obviously, the body already knows how to heal bones, but this product aids in regulating the micro-environment to be one that encourages bone consolidation so that patients recover more quickly.

If you were to see what’s happening at a cellular level, you’d notice signaling molecules like growth factors and cytokines swooping onto the scene of an injury. These cytokines interact with cell receptors in local host cells, and can trigger a response indicative of wound healing. Basically, almost as if leading by example, these healthier cells demonstrate the way the host cells should be working, encouraging them to get back to their former, healthy selves.

Cells Themselves

The field of regenerative medicine relies heavily on advances in tissue engineering, and exemplifies plausible use cases for cellular and a-cellular allografts. But you’ve probably heard a good deal of talk about “stem cells”, and wonder how that plays a part. A good way to think of regenerative medicine is as if it’s a company, in a thriving economy. This one company is made up of different departments, and within those departments are different job descriptions and different individuals filling them.

The focus for regenerative medicine has been on “stem cells”, here at Burst Biologics we believe that’s not the best way to look at regenerative medicine. It’s so much more than that. Instead, try to think of stem cells as a single worker, in a single department, of a whole company. Yes, it does its part. Yes, it makes the whole team complete. But the rest of the team isn’t relying on the existence of that one worker to do their own jobs. 

The Future of Regenerative Medicine

The potential applications of regenerative medicine are truly profound. With tissue engineering and regenerative medicine products, physicians have the building blocks they need to change, repair, and grow damaged tissue in patients.

Previously impossible treatments are theoretically possible using regenerative medicine, reversing the effects of aging, organ failure, chronic wounds, and lifestyle diseases. The future of regenerative medicine – and the medical field as a whole – has never been brighter!