Mechanisms of Action of Polylactic Acid Matrices

Jose L. Ramirez-Garcialuna, MD, PhD:

Hi, my name is Jose Ramirez-Garcialuna. I'm a medical doctor. I earned my MD in Mexico, got certified as an emergency doctor. Worked for a few years in an emergency room, an ICU in a burn unit. Afterwards, I moved to Canada to do a PhD in experimental surgery, and I did my PhD on the immunology of wound healing, so my area of expertise is everything that's related to immunology of wound healing, inflammation, and how these can either be of benefit or not for wound healing.

Afterwards, I've been working with a few companies as a scientific advisor doing research, and I joined in January 2023 as director of Medical Affairs to PolyMedics in PolyMedics Innovations. This is German company that is doing some work in the US with PLA matrices, and we are launching this product in the US as of this year.

The polylactic acid matrices or PLA for short matrices that we use in this study are composed of lactic polymers. As they get degraded by the body, and this degradation first of all breaks the polymer into lactate monomers that get released into the wound bed, and then lactate is metabolized by the cells and surrounding tissue into water and CO2. As these matrices are degraded, the lactate that's get related to the wound bed has several beneficial effects.

So first and foremost, lactate is a molecule that is naturally occurring in the human body. It's part of the normal metabolism of the cells, and this is one of the metabolites that appears whenever the cells are in low oxygen concentrations, so this is part of the aerobic metabolism. Because of this, lactate plays a major role in signaling to the cells and neighboring cells that there is low oxygen contents.

For this reason, there's people and researchers who compare lactate to a hormone and call it a lactic hormone. The effects that the lactate itself creates in the wound bed, first and foremost, is that it enhances angiogenesis. This is very easy to understand. This molecule signals that there's hypoxia going on, so by adding external lactate into the wound bed, there is no real hypoxia. The oxygen content in the wound bed is normal, and exactly the same as before, but the cells are tricked into thinking that there is hypoxia.

This shifts their metabolism and this allows the cells to start signaling and up-regulating the expression of eugenic factors including BEGF. This in turn leads to the creation and production of new blood vessels or angiogenesis. Because this angiogenesis response is very, very intense, new blood vessels sprout, granulation tissue sprouts, and the wound bed fills up with very rich oxygen content tissue.

Second, these angiogenic effects and these hypoxia mimicking effects also affect other cells such as fibroblasts and keratinocytes. And what it does is it puts these cells into survival mode. And this survival mode is because the cell thinks that there are no oxygen content. So they turn on the genes that promote growth, that promote survival, and promote the deposition of extracellular matrix in order to feel the defect and create granulation tissue.

So taken together more granulation tissue, more blood vessels and increased survival, promote bridging of the defect than and healing of the wound. And then another effect that's very interesting in my opinion is anti-inflammatory effect.

So lactade has been demonstrated in several studies to down regulate expression and inflammatory cytokines such as IL-1, IL-6 and TNF alpha. And because of this, it effects a very powerful effect on the wound bed. We know that most chronic wounds become arrested in the inflammatory phase because there are bacterial contaminants.

The immune system is just attacking everything and destroying the tissue that is being built. So by down regulating the expression of these inflammatory markers, we are shifting the inflammatory environment from an inflammatory one into a proliferative stage.

 So this is another of the benefits of using lactate. And then finally, one that's very interesting in my opinion is the acidification of the wound bed. So lactic acid is produced whenever lactate gets in contact with water. And because there's a lot of water in the wound bed, some of the lactatw there becomes lactic acid, and this lowers the pH of the wound bed. We know that higher pHs are tied to reduced growth of cells. Cells don't like living in high pH, in ecologic pH. However, bacteria do like living there. So by having higher pHs, what we are encouraging is bacterial growth. And then also we are promoting a little bit of real hypoxia because red blood cells are something that's called the bore effect.

Whenever red blood cells are in higher pHs, the hemoglobin binds tightly to the oxygen and it does not release the oxygen into the wound bed. So there's a little bit of real hypoxia going on. By lowering the pH with lactate in this case, we remove these effects, so we put an environment where cells can thrive, we create an environment where bacteria have higher chances of growing, and then finally we remove these real hypoxia from the environments.

Taken together this effects lead to great improved closure rates as seen in our study. And something that I think is very noteworthy saying is that the matrices that we use are composed by 85% lactic acid. So that's where we see these very robust effects by using these matrices

So there are 4 cornerstones for achieving appropriate wound healing. The first one is a healthy pool of stem cells in the tissue. The second one is an adequate blood supply. The third one is enough extracellular matrix or a scaffold where cells can attach in row. And finally, the fourth one is a competent immune system that maintains an adequately balance inflammatory environment that orchestrates everything.

And so as you can see, collagen dressings and other similar products such as biological membranes do provide scaffolds where precursor cells and fibroblasts can attach and grow. However, they do not possess biologically active properties to modify any of the other wound healing cornerstones. In contrast, the matrices that we use do effect, do exert an effect on all these 4 cornerstones as we discuss, namely enhanced survival and proliferation, enhaned angiogenesis, increased extracellular matrix production and deposition, and finally immunoregulation of the wound bed.

Furthermore, because these matrices are fully synthetic, there is no risk of infection or cross-contamination with any substances that come with the material, which is normally a concern in biological tissues because as you may have heard before, there's always cross-contamination and some new viruses and new prions crossing the species barrier. So definitely by using synthetic materials, we removed these risks.

Definitely. So as you mentioned, we were actually hoping, or we were actually expecting rather than hoping the wounds treated with the matrices to heal faster because there's sound signs behind them. However, we didn't expect it to be so fast. We were really surprised to see that in average the healing rate for the PLA matrix group was half of that of the control group. And this control treatment is one of the standards of care for wound care. So this is something that is clinically being used in a lot of different places, so by reducing half the time that we require for achieving healing, this was a really interesting result.

The second one was that around 90% of the wounds healed by 12 weeks of treatment as compared to only 30% of the control wounds. So this was also something very interesting because usually for reimbursement purposes, 12 weeks marks more or less the end of the time that a lot of the agencies provide for reversing products. So we want to heal the wounds before that in order to be able to continue using products.

The PLA matrices were initially used in burns and there's like 20 years of research demonstrating that they are very effective to heal burns and to promote the healing without scarring of the tissue. Recently, we are moving now into the chronic wound space, and we're very interested in seeing other types of wounds including things like ulcers, Pyoderma gangrenosum , and pressure injuries. Actually, we have some posters being presented as the SAWC. So if the audience is interested in seeing these cases, we will encourage them to go to the poster hall and watch how these matrices also heal these type of wounds.

I am personally interested in seeing whether these lactic effects that we've been discussing can also help bridge the gap in the immunoregulatory effects of how heal wounds caused by in skin inflammation, such as in hidradenitis suppurativa, Pyoderma gangrenosum, and vasculitis, which are traditionally very hard-to-heal ulcers.

One of the things that I think really needs further research is this pH shift and the bacteriostatic effect that it causes. So there's a lot of studies, and actually that's one of the hot topics right now in wound care because there's research that has demonstrated that chronic wounds and wounds that are very hard to heal tend to have higher pH values, and these pH values tend to correlate with bacterial contamination and the progression from colonization to infection. So in theory, by adding a device that releases a weak acid into the wound in a sustained manner, these conditions can be prevented and infections can be avoided. So I am very interested in actually running a trial where we can see whether it is true and seeing if we can reduce the bacterial load in the wound beds by adding these matrices.

The other thing that we are very interested is in seeing if by using these matrices, we can prevent amputations in patients. So we have some anecdotal experience, and we're actually having a poster about that, where by using these matrices in wounds that otherwise would have been amputated because they were so severe, we are preventing these amputations. However, scientifically driven trial with hard numbers and an appropriate comparator is still required.