Wound Healing: Past, Present and Future; Is It Time for a Treatment Paradigm Shift?

May - June 2022

Wound Healing: Past, Present and Future; Is It Time for a Treatment Paradigm Shift?

Editorial Summary

‘Normal’ evolutionary wound healing processes that have been in place over time have been altered. This articles discusses an overview of the mechanisms that have caused deviation from the normal evoluionary processes. Theories are explored about the high incidence of chronic or hard-to-heal wounds.

Introduction

On the surface, wound healing as designed or evolved by nature is a rather straight forward process and the same basic principles apply to the past, present and future. The response to injury in a foetus and neonatal mammals involves very little inflammation, is primarily regenerative in nature, and leads to very little fibrosis and complete healing. In contrast, the response to injury in adults first involves significant inflammation with very little regeneration, followed by fibrosis. In animals, these same basic principles have remained consistent over time. Regardless of the tissue type, the regenerative process adheres to similar principles: first, recruitment and migration and attachment of cells, followed by cellular proliferation and differentiation, which then leads to tissue deposition, and ultimately, tissue remodeling. In nature when an animal becomes injured, the wound healing process focuses on rapid recovery as aesthetics are of no importance. Animals really don’t care what they look like, as long they are able to stay alive and defend themselves. Assuming the injury is non-critical and that there is no major infection (which is a key assumption), animals are generally successful in healing their own wounds without much/ any intervention. What happens if we now move to man? If we look at the very distant past, one can assume that these same basic principles seen in animals applied to adult humans, as survival was paramount. However, if we step forward to the present time, and see the high incidence of chronic wounds that don’t heal, we have to ask the question ‘what happened’? Why is it that today we have

such a high incidence of chronic wounds that don’t heal and why is there such a significant impairment of normal wound healing?

To answer this, I believe we have to now consider all of the complicating factors that man has introduced into and on top of the ‘natural processes’ over time. That is, the incidence of concomitant factors today is significantly higher. For example, and just to name a few, animals don’t smoke, the incidence of diabetes and hypertension is lower in animals; animals do not typically have vascular disease, animals do not take dozens of medications; animals don’t care about the aesthetic outcomes of healing (speed is of the utmost importance), they are not dependent on Centers for Medicare & Medicaid Services (CMS) or insurance carriers to approve and pay for their treatment, and they don’t have to worry about inpatient or outpatient perspective payment systems and physician fee schedules. As a result of these and many other factors, in humans today the ‘normal’ processes that have been in place over time have been altered and wound healing has become much more complicated.

If we then think about tissue engineering of new products to address this more complicated situation, while the goals of tissue engineering remain relatively the same and simple on the surface (i.e., prevent infection, prevent fibrosis and promote regeneration and incorporate tissue, signals and cells), the solution set is now multifactorial. While the three main factors that must be considered, i.e., tissue, signals and cells, remain the same, the problem is significantly compounded.

Dr Kenneth Burhop Life Sciences Advisor and Consultant San Diego CA, United States

Diabetic Foot Ulcers

If we use diabetic foot ulcers as just one clinical example, there are now a multitude of products on the market that are targeted to treat this problem. Depending on who you talk to and how you categorize the various tissue products that are currently available, there are estimates that there are well over 100 different products currently on the market. This poses a significant dilemma for care providers/ physicians who face difficult decisions on a daily basis trying to choose between this broad spectrum of options to determine which product to use, when to use it and how to use it on their patients.

As we consider diabetic foot ulcers, I would be remiss if I didn’t note that offloading is the one simple and cheap treatment that has been demonstrated to work to heal these wounds. Unfortunately, and as most readers are aware, offloading in general is not used very often by physicians and has poor patient compliance. One solution to these issues is Total Contact Casting (TCC). TCC enforces compliance of offloading, protects the wound from the external environment and diminishes friction and shear forces on the wound. However, and for some unknown reason, it too is not utilized as frequently as it could be or should be, but is a potential solution that does need to be considered.

Autographs

The menu of available products to choose from is extensive. First there are autographs. This category can include everything from a full or partial thickness skin graft to several different approaches to micrografting of tissue. At a high level and ignoring many of the technical and practical concerns of this approach (e.g., availability of grafting material, cost, injury to a secondary site on the body to retrieve the graft, etc.), these options still remain one of the standards of care today.

Amnion Membranes

Then there are other natural products that have been around for a long time in one version or another such as amniotic products. Amnion membranes have been utilized for wound healing since the early 20th century. These products focus primarily on the ‘signal’ and possibly the ‘cell’ component of the wound healing equation. At the simplest level, they have the potential to turn a chronic would back into an acute wound and ‘jump start’ the healing process. That said, there are arguably limitations in that they often require multiple applications and typically do not fill the wound void. So, now we get into the financial aspects as well. These products are not cheap and typically require multiple applications, so unfortunately, and if you are a skeptic, one could argue that there are financial incentives for care givers to utilize more of these products from a reimbursement standpoint than perhaps other products that achieve healing with less applications, thus having a potential negative impact on the health care system and the overall cost of healthcare. Yet, these products have shown remarkable efficacy and have a place in today’s treatment options.

Cellular Tissue Products

Next, there are other cellular and tissue products (CTPs) that are derived from an animal origin (xenografts) such as from bovine tendon, bovine skin, porcine Urinary Bladder Matrix (UBM), etc. The majority of these products became available as a result of research that was conducted in the 70s, 80s and early 90s. These products obviously focus primarily on the ‘tissue’ component of the wound healing triangle, as they are designed to fill the wound void. However, and depending on the product, some do help direct wound healing such that you get ‘skin and not scare’ along with more normal tissue regeneration.

“In humans today the ‘normal’ processes that have been in place over time have been altered and wound healing has become much more complicated.”

Wound Healing: Past, Present and Future; Is It Time for a Treatment

Synthetic/ Biosynthetic Products

More recently, there has been a larger number of ‘synthetic’ and ‘biosynthetic’ wound dressing products introduced into the market that utilized synthetic or biosynthetic compounds with beneficial properties, to help promote an optimal wound healing environment. The ‘pros’ of these products (as marketed) include the fact that they do not contain any animal or human derived tissues or cells, so they don’t possess the risks inherent to allogenic and xenophobic products. They are made of a wide variety of different synthetic compounds, some less toxic than others. There is certainly a place for many of these products depending on the product and the intended use (e.g., some products focus mostly on additional antibacterial attributes and can aid in infection reduction). The potential cons for some of these products include the fact that they no longer process natural biologic materials that have specific receptors or epitopes that are required for natural wound healing; depending on the composition some are viewed by the body as foreign vs. natural, so clearance mechanisms are initiated, and ultimately, the long term quality of the healing is still to be determined for some of these products. However, and similar to biologic CTPs, there are products that have great potential value in defined situations and have to be included in the ‘menu’ of options available.

I will not (cannot) go into all of the pros and cons of each of these 100+ products in this editorial. Suffice it to say however, that in almost every published clinical study examining these products to treat diabetic foot ulcers, the outcomes (complete wound closure and healing at 12 weeks) are all about the same, and with standard of care utilized as the control group, the results typically range from 40-60% of the wounds healed. To my knowledge, there is no ‘single’ product that consistently heals 100% of the wounds 100% of the time (or even close).

This then raises the question of what is different about the 40-60% of the unhealed wounds remaining in the clinical studies, and most importantly, how do we heal these wounds? There is obviously something different about these wounds that no single product available today appears to be able to address.

This then takes us to the future. As I view the problem, I like to think back on the past and of the parallel with other clinical problems like cancer and sepsis. At the beginning of my career (I won’t say how long ago), I can clearly recall clinical trial after clinical trial that failed when the trials were forced for regulatory approval reasons to compare a single treatment to a control and utilize extremely rigid predetermined endpoints (often unrealistic and crude like 28-day mortality). Unfortunately, and here is where economics come in again, each company or trial sponsor typically had only one particular product that they were willing (and able) to test in a clinical study. I think the old adage ‘when you only have a hammer, everything looks like a nail’ applies. To my knowledge, there are few large, comparative prospective, randomized and blinded trials comparing multiple products in these indications. Aside from the regulatory perspective, there was no logical financial rationale for a company to conduct an expensive comparative clinical trial with a competitive product. That said, I believe that knowing how complicated these clinical situations are, it really was (and still is) ridiculous and candidly dumb to expect to find a single ‘magic bullet’ that was going to cure these incredibly complex and deadly clinical scenarios. I believe the ‘aha moment’ came when there was a change in treatment paradigm and when clinicians began using multimodality therapies and sequential treatment protocols. The primary endpoint and goal switched to how do we reduce mortality and morbidity in these life and death situations. As a result, there has been a significant decrease in mortality in these clinical diseases over recent years.

This then leads me to ask the question, ‘isn’t this the same problem with wound healing?’ Can we, and should we, lump all wounds together and expect one of the multitude of products available today to completely heal all wounds? Why aren’t we using lessons learned from the past and thinking about the way significant advances were made in the clinical situations I mentioned above, and why don’t we consistently utilize cocktails and multiple, different, simultaneous treatments that follow variable treatment paradigms (along with enhanced diagnostics) to heal more wounds?

If one buys into this proposal, then you must also ask ‘why not’ utilize this same approach, and what are the cons and hurdles for adoption of such an approach to wound healing? I believe an approach that should be considered going forward is sequential therapy/ treatment. As one example, and reflecting back to the DFU indication, we know that most of these wounds are chronic wounds.

So should we follow a step-by-step treatment paradigm?

Jump Starting the Chronic Wound

Step one (in addition to simple debridement) should be to ‘jump start’ the wound by moving it/ converting it from a chronic wound into an acute wound. A few examples of products that might accomplish this include applying an amniotic product or powder product or even a synthetic/ biosynthetic product that focuses on the ‘signal’ and possibly the ‘cell’ component as well as healing to achieve this. Then, once you have the wound proceeding down a more normal pathway of healing, step 2 could include applying a product that fills the tissue void and simultaneously helps to drive appropriate regeneration of tissues (i.e., addresses the matrix component of wound healing). Finally, and for step 3, you still need an epithelial barrier/ cells to apply over the wound, since most of the products mentioned above still do not provide complete/ ultimate healing and closure of the wound (assuming of course that it is a larger surface area wound). Therefore, you may need to apply a skin graft or spray on a product that includes epithelial cells.

Unfortunately, even with all of these treatments, we still have not talked about the need for functions like normal neural innervation (i.e., the ability to feel and have normal sensory responses); the desire to restore other ancillary functions, like including sweat glands, etc. Perhaps this final piece of the puzzle could be

addressed via micrografting of autologous tissue, but this is still a work in progress.

Why can’t we do all of this now? I think there are some leading physicians who are already following this treatment paradigm in some fashion. They are utilizing their years of experience and clinical expertise to ‘treat the patient’ as they believe makes sense. Unfortunately, I have never seen this formally protocolized and I have never seen a flow chart protocol that is the ‘standard of care’ for all care givers to follow (if it is even possible to develop such a protocol).

The Influence of Economics

So again, why aren’t we doing this now? I believe the first and most obvious answer is economics. At the present time and utilizing the current payment and reimbursement systems around the world, these products on a singularly basis are already expensive for the hospital system. Thus, even the thought of utilizing multiple products in one patient or in one wound is usually a ‘no go’ from the start.

If one looks at the market today, and if you are a hospital system forced to control costs, you have to ask the question ‘if all of the products available produce about the same results, why wouldn’t I just purchase the cheapest product available?’ Unfortunately, I personally don’t believe adoption based purely on price is the answer since, as discussed earlier, not all products have the same mechanism of action, not all products produce the same positive long term outcomes, and different products work differently for different types of wounds.

There is no ‘magic bullet’ and you need a basket of products to select from at your disposal.

From an industry perspective, it is hard to find any single company that currently has ALL of the answers in their portfolio to offer and to

“Not all products produce the same positive long term outcomes, and different products work differently for different types of wounds.“

solve this complicated problem. That said, and I freely admit that I am certainly not qualified to conduct this analysis myself, but if you look at the ‘total cost’ to the system and to the final patient outcome with today’s standard of care compared to a new paradigm of sequential and multi-modality therapy, I think you might find that this approach makes sense. To get to the best final answer, I believe you need to add in the cost of potential amputation downstream, repeated wound incidence and treatment costs, quality of life for the patient, cost to the hospital system, etc. In the end, a new sequential treatment approach may still make overall economic sense. One economic evaluation of these costs suggested that total Medicare spending for all wound types was between $28.1 - $96.8 billion dollars1.

The Impact of Regulation

I believe the second reason we are not attempting a treatment approach like this is regulatory related. In order to get regulatory approval, there would be a requirement to perform clinical trials demonstrating the effectiveness of a multi-modality or sequential approach to wound healing. It is extremely difficult for me to envision what a clinical trial protocol would look like, even if you could do it.

How would you control for differences between patients in the timing of administration, different products utilized at different centers in the trial, different numbers of applications at each center and by each investigator, different demographics depending on the center, the variety and severity and types of wounds, the involvement of multiple companies with different technologies, etc., etc. If you attempted such a study today, I don’t know how you would get regulatory approval for a new product and what would your product label even look like? I spoke earlier in this editorial about developing all of this into a standard of

care or into a formal protocol, but there are so many unknowns and variables at the present time, I don’t know if this is even possible. That said, and as the focus of care today centers more and more towards personalized medicine, doesn’t this approach make sense?

A third factor is our current lack of understanding, measuring, and diagnosing each wound. If you were to contemplate an approach as proposed above, I don’t believe we know enough about wound biochemistry and physiology to know what product to apply to which wound, when to apply a product, how long to apply it, etc. Therefore, it becomes a bit of a guessing game, and today, treatment relies primarily on the investigator’s experience and gut feel. This is definitely an area that I believe deserves more focus and more study and funding.

A final factor may be that if we want to really treat the patient, we also need to focus more on the overall physiology of the patient and attempt to move further upstream to resolve the basic disruptions in normal physiology, vs. just concentrating on the wound itself. As an example, if we again look at DFUs and Venous Leg Ulcers (VLUs), I would contend, and I think most physicians would agree, that no matter what you do downstream to treat the wound, if you don’t resolve and correct the basic blood flow/ perfusion status of the patient (wound), and if you don’t stabilize the homeostasis of the patient and reduce comorbidities, your chances of success downstream have to be significantly diminished. The good news is that there are a few companies beginning to investigate this approach.

Conclusion

In all of the prior discussion, I admittedly didn’t even touch on a host of other contributors like infection and bioburden control, patient compliance (e.g., wound offloading and after care), lifestyle changes (e.g., smoking cessation,

“If we want to really treat the patient, we also need to focus more on the overall physiology of the patient and attempt to move further upstream to resolve the basic disruptions in normal physiology, vs. just concentrating on the wound itself.”

Wound Healing: Past, Present and Future; Is It Time for a Treatment Paradigm Shift?

obesity, etc.); these all play into the equation.

Finally, I would be remiss if I didn’t at least suggest that one solution to this problem would be the development of a product that incorporates all of the aspects of normal wound healing and includes appropriate growth factors and cells that target specific and multiple targets (chemical and cellular) into a regenerative matrix, but at this time, this does not exist. As they say ‘predictions are risky, especially about the future’ (often attributed to Yogi Berra), but this seems quite a ways off at this time.

In conclusion, I think we would all conclude that wound healing really isn’t that simple, is it? I clearly realize that if the reader looks at my proposal from the practical side of things, it sounds pretty crazy and naive. However, if one thinks about the ultimate goal that I believe everyone is trying to achieve, and certainly what patients are looking for and expecting (i.e., complete and normal regeneration of skin), don’t we have to at least start thinking about how to solve this problem differently? To quote John Lennon from the song Imagine: “You may say I am a dreamer, but I am not the only one”.

References