Ian Valerio, M.D., a plastic and reconstructive surgeon at The Ohio State University’s Wexner Medical Center in Columbus, explains how cutting-edge medicine is helping regenerate the nerves in soldiers’ limbs.
Interview conducted by Ivanhoe Broadcast News in April 2017.
I want to talk to you about nerve transplant. Can you give me an overview of what it is that you’re doing?
Dr. Valerio: Sure. For nerve reconstruction and nerve repair there’s traditionally two options that we have now available. One is what we call autologous nerve grafting which involves nerve from the actual patient. For example, if you have experienced a segmental nerve defect or have a nerve gap that’s due to either traumatic or cancer type injuries, we can use your own nerves to reconstruct the nerve defect or gap. The second option that is more recently available is that of cadaver nerve or allograft. Allograft nerve is from another person who donated their tissue after passing, and this nerve graft is decellularized to remove the donor patient’s cells. This cadaver nerve acts as a nerve transplant to reconstruct a patient’s nerve defect and can aid as a replacement regenerative nerve graft source that can replace the need to take the actual patient’s own nerves. This allograft or cadaver nerve in early studies has been shown to be an alternative to autologous nerve grafting and perform similarly to outcomes with autologous nerve cases. The allograft nerve acts as a scaffold where the patient’s own cells can repopulate the graft and allow for nerve regeneration to restore previously lost nerve and its related functions.
Are there certain areas of the body limbs primarily where this is effective and certain areas where it’s not?
Dr. Valerio: Yes, this is an area of active investigation and we have seen great expansion and application of allograft nerve to various upper extremity nerve injuries as well as to lower extremity defects. Furthermore, nerve allograft application has even expanded to certain head and neck nerve injuries including nerve defects from head and neck cancer as well as trauma. More recently, there’s also been expansion of cadaver nerve into breast cancer cases to allow for sensate breast reconstruction as well. The applications of nerve, either autologous or cadaver/allograft nerve as a nerve transplant has really shown a lot of promise for restoring nerve functions in many areas of nerve injuries spanning from head to toe.
I want to talk about this little bit if you could just describe again in layman’s terms, the process and what it is exactly that you are doing to help repair?
Dr. Valerio: A segmental nerve gap is an actual defect in a patient’s nerve. You have two nerve ends in these injuries: a proximal nerve defect/ending which is higher in the extremity and a distal nerve defect/ending which is lower in the extremity. We have to provide a “wire to span the gap” to guide nerve regeneration and re-growth of the nerve to allow for restoration of previously lost function. The cadaver nerve or nerve transplant which is currently available up to seven centimeters allows for restoring nerve continuity so that the new axons and nerve related cells from the patient can grow into the extracellular matrix and/or scaffold provided from the cadaver nerve. As the nerve regenerates it will re-innervate the muscles as well as the sensory nerve endings in the extremity, facial area, and/or breast reconstruction to restore previously lost nerve function.
How long does it take to repair that gap? Essentially, it’s a break in the pulses that senses this?
Dr. Valerio: If you think of a nerve as kind of a cable or wire that transmits electrical pulses, if someone cuts the cable or a segment out the cable, no signals can be conducted across that defect – so similar to your TV, the TV reception or signal cuts off. You have to “repair the gap or defect in the cable” to restore or see the function which is altered due to lost signal transmission. That’s what we’re using these nerve grafts for, i.e. to actually patch or repair these segmental gaps to allow for electrical or signal transmission. By doing restoring the defect in the nerve or cable, new signals will be generated as the nerves slowly grow into the replacement cable. This nerve re-growth occurs usually about a millimeter a day after about a two to three-week delay after nerve repair (this applies to both autograft or allograft cable repairs). The axons will start to grow down the cable or tube as the patient’s own cells re-populate the scaffold and restore the electrical cables or axons that will support and permit signal generation or conduction. The higher up an injury is in the extremity, the longer it takes for that nerve to grow down to the very tips of the fingers since the fingers are further away from the actual nerve injury. In nerve injuries that are lower in the extremity, a shorter timeframe is needed for restoration of nerve function given that the injury is more distal in the extremity. Thus, time is a critical factor in nerve repair and regeneration.
Can you describe what the matrix for the scaffold is? What is it essentially that’s in the arm, or in the body?
Dr. Valerio: The nerve scaffolding itself exits from two source or graft types. One graft is if you use your own nerve which has your own cellular and scaffold structure/components of the patient’s own nerve. In the allograft or cadaver nerve, the transplanted nerve is actually de-cellularized leaving only the neurogenic scaffold behind from a donor person’s harvested nerves. Certain growth factors, laminin, and extracellular matrix which is critical for nerve regeneration and growth is preserved within the transplanted nerve graft. These preserved components serve as a regenerative scaffold or “the basic bricks and mortar” needed for nerve re-growth and re-establishing nerve function to eventually occur over time. In essence, as nerve reconstruction surgeons we are re-establishing a pathway or highway for nerves to grow back down through a repaired cable to re-innervate their targets in order to get function back.
When you were talking about the regeneration of about a millimeter day, can that person feel it? How can you tell what are they feeling if anything, while it’s starting to regenerate?
Dr. Valerio: Many patients often state that they will sometimes get “shooting pains or little shooting sensations” after their nerve repair. As you tap on the area of nerve re-growth, we can cause the nerve to respond or elicit this response – which is called a positive Tinel’s sign. As the nerve regrows, this test will move further down the extremity telling us that the nerve is regenerating/growing past the repair site. When one is tapping with their finger right over where the nerve and axon re-growth is located, the patient will experience little sensations or electrical shooting up to the arm which their the brain processes that as an uncomfortable feeling because you can actually feel the nerve re-growing. After we repair a nerve injury, we can actually then trace the nerve as it re-grows down the extremity and follow this longitudinally or over time with the patient to assess nerve regeneration. As you may recall, this nerve regeneration may take a matter of many months depending on the location of nerve injury and timing of nerve repair. I just recently had a policeman who suffered a gunshot injury to the lower extremity up around his knee. He and I discussed that it may be over twelve months or a year before he potentially gains sensation back to his foot. Thus, we will follow his progress by assessing the Tinel’s sign elicited by tapping the area of expected nerve re-growth as well as with nerve conduction studies/EMGs to make sure nerve regeneration is occurring. We’ve had a number of individuals that have now benefited from our military experiences and background in nerve repair and complex reconstruction, using such nerve reconstruction strategies for both our wounded warriors as well as civilians and veterans to achieve successful nerve repair and regeneration via nerve transplants in various traumatic, oncologic, and other injury types.
Can we talk a little bit about Jeffrey Cole? Do you remember when you first met him?
Dr. Valerio: Yes, Cpl. Cole was injured back around August 2010.
What do you remember about him when you met him?
Dr. Valerio: Jeffrey was a young man who was deployed to Afghanistan in 2010. He was on foot patrol and involved in a mission overseas, specifically in Helmand, Afghanistan. That was a heavy Taliban and insurgent hotbed area. Cpl Cole was engaged in a firefight with the enemy when he was struck many times by enemy fire. For his efforts, Cpl Cole achieved a number of Medals and accolades for his valor and honor in battle. He suffered multiple gunshot wounds including a gunshot wound to his left upper extremity which completely severed or caused a segmental injury to his ulnar nerve. I met him at National Naval Medical Center which was the precursor to Walter Reed Bethesda (renamed after BRAC). Upon meeting Cpl Cole we talked about limb salvage options given his soft tissue and specific nerve injuries. After talking about the options of using either his own nerve versus using this cadaver or transplant nerve option, he carefully considered the pros and cons of the two nerve repair options before electing for the cadaver nerve option. He strongly felt that he did not want to sacrifice any other parts of his body given the nature of injuries and multiple injures he had already suffered and did not want to have an additional nerve defect from the donor nerve source taken from his own body. He had an approximately seven centimeter nerve gap after debriding his injured nerve to a healthy nerve level – specifically the ulnar nerve in his case. Then we used an Avance cadaver nerve graft to reconstruct his segmental ulnar nerve defect.
You said seven centimeters, just for my references, how big of a gap?
Dr. Valerio: That’s a sizeable nerve gap of over 2.5inches which cannot be repaired directly and without a nerve graft.
He had a pretty sizable injury.
Dr. Valerio: Yes, and very high ulnar nerve injury which is a difficult nerve to sometimes achieve successful nerve regeneration and recovery of function after injury.
What other options would he have had prior to having this kind of the option?
Dr. Valerio: Use of his own nerve would be another option to repair this nerve. Those are really the two nerve repair options you have for his particular nerve injury. It’s not uncommon for injuries of a high ulnar nerve nature like Jeffrey had to require distal nerve transfers and/or tendon transfers to address the injured ulnar nerve associated deficits in hand form and function. For the sensory and motor functional deficits, there are some newer nerve transfer options that are more commonly performed today, but they weren’t as common back when Jeffrey was initially injured. The other option which we hope to avoid of course is amputation, especially given the nature of injuries he also had which included a significant vascular injury (brachial artery grafting) and accompanying severe soft tissue injuries. Thus, limb loss or limb amputation was a potential risk or threat in Jeffrey’s case. Fortunately, we were able to do limb salvage procedures and nerve repair to save his arm. He has had nerve regeneration through this nerve transplant which was one of the longest and earliest cadaver nerve transplants performed in the U.S. He regained a lot of his proximal ulnar nerve motor function, some minimal intrinsic function of his hand, and he has regained sensation back which continues to improve even today seven years after his initial injury and nerve repair surgery.
Is that unusual to still have improvements so far out?
Dr. Valerio: It’s not as unusual as we’re seeing now, as we follow nerve injuries long-term you’ll see they continually improve slowly over time. Even in our hand transplant patients these are patients that have lost their limbs that receive a cadaver hand that becomes functional over time. That nerve regeneration as well as improvement occurs over time. That’s probably a multitude of factors. One is the way that your brain interacts with the peripheral nerve as its going to the extremity or to its end targets with muscle and sensory functions. Part of it is the continue remodeling and reintegration that’s going on as nerve re-grows and a scar is broken down and allows for improvements. Then also the plasticity of the brain, where the way that the body and the patient can interact with the environment in order to improve these things.
Because this is a cadaver transplant does he need anti-rejection medication does he need anything to take?
Dr. Valerio: No, that was the big advance for this new nerve allograft or cadaver nerve graft source. Back in the eighties, a few nerve transplants from cadavers were performed but because they included the donor patient’s cells, immune suppression was required for at least 9-12 months given the threat of rejection. Dr. McKinnon’s work from Toronto and St. Louis provided alot of groundbreaking early work that she did and others had done on transplanted nerve grafts. Previously, immune anti-rejection drugs were necessary because of the cellular components within the actual allograft or cadaver nerve tissue. Overtime, decellularized options have risen in various soft tissue allograft or cadaver sources of tissues which allow for patients to benefit from these valuable alternative tissue alternatives. Through various proprietary techniques, soft tissue and nerve allografts provide decellularized scaffolds that are more inert or non-immunogenic but retain certain biologically active components. The body can thus regenerate and repair the nerve defect through these cadaver grafts lacking cells and not have to worry about having to take anti-rejection medicines.
When you saw Jeffrey last month, what goes through your mind when you see this young man continuing on?
Dr. Valerio: First, Cpl Cole is a Marine. Marines are typically very driven and determined individuals who strive for optimal performance. I saw quite a few such remarkable individuals during my time at Bethesda treating many wounded warriors – Marines, Soldiers, Sailors, and Airmen. Jeffrey is a great example of where regenerative medicine has come to impact patient care, because his story is so much more than just his nerve graft surgery. He’s now a national park ranger, still serving the U.S. government and helping our citizens. While he has been medically retired from his military service due to the compilation of injuries he suffered, he is doing quite well. He has found love again. He’s has a new girlfriend in his life and they’re happily dating and together in DC. Jeffrey and I have spent quite a few times together now after both of us transitioned from our active duty military careers. I have followed up with him as well as a number my patients that have had nerve or other type of reconstructions so it’s just great to see him and so many other wounded warriors living their lives. Despite the various significant injuries many of these wounded warriors have suffered and encountered, each and every one of them has successfully moved on to many satisfying and productive lives and have provided many rewarding examples of how we as surgeons can contribute in their recoveries and life success stories.
I just want to ask for background on you Dr. Valerio, little bit about your service and your connections with these wounded warriors? You still work with the military?
Dr. Valerio: My background is that I’m a native Ohioan, from Ashtabula, Ohio. After growing up in my hometown, I transitioned to Case Western Reserve University to complete my undergraduate and graduate school training. I then completed medical school at the University of Kentucky College of Medicine before entering my residency training at the University of Pittsburgh Medical Center which is one of the premier plastic and reconstructive training programs in the country. After additional fellowship training in microsurgery and craniofacial surgery overseas in Taiwan and India, I entered my active service duty service to the military and the U.S. Navy. As a prior health profession scholarship program (HPSP), the military provided a scholarship for my medical school in which I incurred 4 years of service obligation to the Navy. I entered active duty service in 2010, which was during the surge in Afghanistan as the Global War on Terror and Operation Enduring Freedom had been an ongoing conflict. When I started at Bethesda, this was a very busy time for treating a high number of complex war related injuries. While at National Naval Medical Center and then Walter Reed Bethesda soon after the merger, I treated a number of Sailors, Soldiers, Airmen, and Marines that were injured in combat. Additionally, I also experienced a deployment as a trauma and plastic surgeon at the NATO Role 3 Hospital in Kandahar which was one of the busiest trauma receiving hospitals in Afghanistan at the time. I was there for about eight months serving as a trauma as well as a reconstructive surgeon. After my overseas tour of duty, I returned to Bethesda to serve the reconstructive needs of many of our injured service members. At the end of 2014 I transitioned from active duty status to active reserve status in the Navy as I decided to come to Ohio State University Wexner Medical Center in order to resume a dedicated academic medical career and train future generations of reconstructive surgeons to hopefully further advance our field.
You are in active reserve now?
Dr. Valerio: Still active reserve yes.
What branch?
Dr. Valerio: I’m a sailor or in the U.S. Navy. I do one weekend a month of service related duties plus at least 2-4 additional weeks for annual training requirements. I typically go back to Walter Reed Bethesda to perform my annual training which I usually go during July or August every year.
Is there anything I didn’t ask you that you want people know?
Dr. Valerio: With every major war related conflict there have been certain advances within the field of medicine. We’re seeing that as well with this most recent series of conflicts involving the Global War on Terror. As I reflect on the many hundreds of wounded warriors I’ve personally treated, we’ve seen great advances in various reconstructions of extremity injuries in which regenerative medicine applications have aided in definitive reconstruction that weren’t available during other periods of war. It is our collectively responsibility to translate and expand our experiential and knowledge base we have experienced during these recent conflicts to our civilian sectors and then bring back further advances when called upon in the present ongoing conflicts and those to be encountered in the future.
END OF INTERVIEW
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