Advanced treatment of diabetic foot ulcers

It will be difficult to achieve healing without using more advanced techniques, especially when a diabetic foot ulcer is deep and has exposed bone or tendon in the wound bed. These challenging diabetic wounds should be treated at the highest accessible level to prevent amputations. We present here some of the available modalities; sometimes, these have to be used in combination.

Subchapters

Negative Pressure Wound Therapy (NPWT)

Platelet Rich Plasma (PRP)

Hyperbaric Oxygen Therapy (HBOT)

Topical oxygen therapy

Dermal skin substitutes

Surgery: Flexor tenotomy

Surgery: Limb saving amputations

 

Negative pressure wound therapy (NPWT)

Negative pressure wound therapy is a versatile tool to stimulate the wound bed to promote granulation tissue faster.  We have written a separate chapter on NPWT and will not repeat all the basic principles here. You will find the chapter under "Menu"- "Tools" - "NPWT."  

We use NPWT in diabetic foot ulcers when we have large or deep ulcers close to bone or tendon structures.  Be aware that NPWT most often will not be able to provide granulation tissue over an exposed tendon unless only a small part of the tendon is exposed.  The same is true of exposed bone.  If there is a small area of exposed bone- about 1cm2, NPWT may be able to stimulate the surrounding tissue to granulate over the exposed area. If there are large areas of exposed bone, the situation can be quite hopeless and may warrant the excision of the exposed bone.

While using NPWT to treat, for example, venous leg ulcers can be a reasonably straightforward procedure, things are quite different when treating diabetic foot ulcers with this modality. Using NPWT on diabetic ulcers should only be done by experienced hands aware of all the potentially catastrophic pitfalls.  Using NPWT in an incorrect manner can lead to serious infections, which can lead to septicemia or amputation! Use extreme caution here. NPWT is a fairly safe modality- but when we see serious complications, they almost always occur with NPWT used on diabetic foot ulcers. 

It is essential that the wound is thoroughly debrided beforehand and that the microbial concentrations in the wound are as low as possible. We like to prepare the wound by using iodine-soaked gauze changed daily for about a week before we consider applying an NPWT dressing. 

When treating a diabetic foot ulcer with NPWT, we have to monitor the patient closely. In other words, this modality is not safe if the patient lives far away or shows low levels of compliance. If the NPWT pump shuts off for some reason or there is a leakage, this can lead to severe complications.  Since diabetic foot ulcers often are around the foot, it can be difficult to achieve a good seal, and leakages are common. If the pump is not working correctly or there is a leak, a negative pressure dressing will act as a greenhouse for microbes, and the risks of severe infection are very high! 

In the image below, we show you an example of using NPWT on a relatively large ulcer on the medial aspect of the first MTP joint.  The patient was quite young and had good arterial circulation but had already developed severe sensory neuropathy.  The ulcer developed during a hike with inadequate shoewear - he didn't feel any pain as he was walking, and the ulcer was the result.  Upon debridement, the joint capsule appeared in the base of the wound bed.  Although this type of ulcer has fairly good healing potential with off-loading, we knew it would take at least about six months to heal.  This was a good case for applying NPWT. After only 12 days of NPWT, the wound bed had granulated so well that we could do a partial thickness skin graft over it, and the wound had entirely healed by day 37. This is a star example of how NPWT can be applied. However, many patients also have impaired arterial circulation, and in those cases, NPWT will often not work as well.

Figure 1 In patients with good arterial circulation and a clean wound bed, NPWT can sometimes provide rapid healing.  these images show the foot of a 40-year old diabetic patient who developed the ulcer after a hike with inadequate footwear.  He had severe sensory neuropathy and felt no pain from the ulcer.  The wound was debrided and in the upper left image, you can see whitish tissue in the wound bed which is the joint capsule of the first MTP joint. The capsule was intact.  After 12 days of NPWT, the wound bed had granulated very well and a split-thickness skin graft was applied which took well.  On day 37 the wound had healed completely.  This case shows what is theoretically possible to achieve with NPWT but far from all diabetic foot ulcers will respond this well to NPWT treatment. 

Concerning diabetic foot ulcers, NPWT works best in those patients who only have sensory neuropathy but have retained good arterial circulation. We sometimes try NPWT on patients with impaired arterial circulation but the results are often not as good.  If you have tried NPWT for about two weeks without the ulcer showing any improvements and alternative treatment should be started. 

The possibility of using negative pressure with regular instillation of saline or preferably antimicrobial fluids has opened up new possibilities for where we can use NPWT.  By using both negative pressure and lavage at the same time we are less concerned about the microbial burden of the wound.  At our clinic, we routinely use NPWT with installation on all diabetic foot ulcers where we consider NPWT.  In our opinion, this is significantly safer and we have seen very few adverse events when we use this type of NPWT.   The drawback of NPWT with installation is obviously the cost of the pump and the single-use equipment.  The pump is also quite large and heavy making out-patient treatment with this modality quite challenging. 

No matter which type of NPWT is used, you have to be aware of the fact that NPWT does not promote epithelialization. It does not help skin cells to migrate over the granulated wound bed!  Once the wound is nicely granulated there is no use to continue the NPWT treatment.  We routinely use a split-thickness skin graft to cover the granulated wounds to shorten the healing time as much as possible.  Diabetic foot ulcers are usually not very large in surface area and we often only need a small bit of donor skin to cover this. There is some discussion about whether split skin grafts should be used on the plantar side of the foot.  the argument is that the area where the split-thickness skin graft is placed remains very thin afterward increasing the chance of recurrence.  Letting the skin close naturally may lead to thicker and more resistant skin in that area. In our experience, this has not been a major issue. We believe that as long as you protect the newly developed skin well enough for a few months, also split-thickness skin grafts will become quite resistant to new mechanical forces. 

With the combination of NPWT and split-thickness skin grafting, we can often close diabetic foot ulcers within 2-3 months, where we would have otherwise used 6-9 months or longer to achieve the same result.  Used correctly, NPWT is actually a cheap method of treating a diabetic foot ulcer compared to traditional dressings, at least in a western setting.  If we have a patient with a diabetic foot ulcer in Europe where home care nurses come to change the dressings 2-3 x a week for half a year, the labor costs alone will be higher than using an NPWT pump for a few weeks!  The socio-economic gains from using NPWT in the right manner are very high. 

Because NPWT poses a risk for serious infection or other adverse events, the patient needs to be well informed about what to look out for, especially if NPWT is used in an out-patient setting.  Who should the patient contact if an alarm on the pump goes off?  Does your clinic provide 24/7 help to deal with a pump that is not working properly? These are considerations you will have to make before administering NPWT to a patient.  In an outpatient setting, it is often safest to inform the patient to remove the entire NPWT dressing and replace it with a regular dressing if the pump is not working correctly. This policy will prevent you from getting calls in the middle of the night and the patient can return to the clinic at regular office hours the next day. 

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Figure 2  When treating diabetic foot ulcers, it is our opinion that NPWT with installation is the safest modality as the risks of infection are greatly reduced. In many countries, it is possible to loan the pumps from the distributors and only pay the costs for the single-use items. In this way, NPWT is a very cost-effective treatment even for areas with low resources. However, hands-on training is required to use this sort of equipment correctly and safely. image copyright: 3M/Acelity

Platelet-rich plasma (PRP)

When we have a situation with a deep ulcer with exposed bone or tendon, it is important to achieve tissue coverage as soon as possible. Granulation tissue will unfortunately usually not develop over larger areas of exposed bone or tendon.   As a rule of thumb we should have some sort of tissue coverage over these structures within a week. A plastic surgeon may in selected cases be able to do  a rotational flap or even a free flap in a few selected cases. But often this is not possible due to lack of resources or because many of these patients do not have good enough arterial circulation to allow for these flap procedures. 

 

Using platelet-rich plasma can be an excellent alternative to achieving tissue coverage in difficult situations.  This is an autologous product - that means, it is derived from the patients own blood.  20-50ml of blood are drawn from the patient and centrifuged for some minutes to separate the platelets from the rest of the blood constituents. The result is a platelet clot or a patch which then is placed directly onto the wound bed. The woundbed has to be very clean, have very low levels of microbes and signs of some granulation tissue so that the platelets can hold on to the wound bed.  We will not repeat all principles of PRP treatment here. We have written a separate chapter on PRP discussing in detail the different modes of preparing PRP from the patients blood.   This chapter is found under "Menu"-"Tools"-"PRP".

Figure 3  An example where we managed to salvage a complex and quite hopeless situation.  This patient had severe osteomyelitis and soft tissue infection in the greater toe of the left foot.  Amputation of the toe had to be performed, but there was not enough tissue left to cover the exposed metatarsal head.  The patient had impaired arterial circulation, and a flap was not a realistic alternative.  Instead, a PRP clot was applied three times over two weeks and managed to cover the exposed bone, and the wound granulated quickly after that and healed. 

PRP is not a magic modality that solves all of our challenges with diabetic foot ulcers.  Like any wound treatment modality, it will not always work.  This can be due to unfavorable conditions in the wound like necrotic tissue or a high microbial load. If there is a lot of exudate the platelets will not be able to attach properly.  In elderly patients their platelets may lack the "vitality" to work properly.  medications that affect platelets can also impair their wound healing properties. 

 

PRP is a very cost-effective and limb saving modality when used correctly. there are ready-made kits to make platelet products from the patients blood. It is possible to make PRP with very cheap resources as long as you have a high-speed centrifuge available to you, but results are often more consistent using commercially available kits. 

 

In most cases the patient will need two or three PRP treatments to fill the wound cavity. Each application is usually done with about a one week interval. Once you see that the platelets remain attached to the woundbed at the dressing shift you can almost be sure that the wound will heal - provided you have a good off-loading regime!

 

Hyperbaric oxygen treatment (HBOT)

 

Exposed tendon, bone, osteomyelitis or severe soft tissue infection are indicators increasing the risk of limb amputation.  In these cases, we have to consider using HBOT where available to save the limb. If the patient does not have serious co-morbidities and has reasonably good arterial circulation. HBOT may significantly speed up the healing process. There is some discussion in the scientific communities as to how effective HBOT actually is i diabetic foot ulcers. In our experience, however, we have seen consistently good results with this treatment modality for diabetic foot ulcers.  Our patients have, however, been thoroughly pre-screened to select those who will most likely benefit most from this treatment.  We will not repeat all principles of HBOT here- we have written a separate chapter on this which you find under " Menu"- "Tools"- "HBOT".  

For most African patients HBOT is not a realistic alternative.  However, in larger cities in Africa some university hospitals have HBOT chambers available.  We are also aware of an increasing number of private clinics offering this treatment, particularly in South- Africa. 

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Figure 4  HBOT treatment is not accessible for most African patients with diabetic foot problems. At some university hospitals, however, this treatment is available. In southern Africa in particular there is a growing number of private clinics that provide HBOT as well.  If the patient has to pay for the treatment themselves it is a very costly treatment and many patients will simply not be able to afford this.  On the left, we see a large chamber that has space for several patients at a time. On the right is a monoplace chamber to treat one patient at a time. 

Even in many western countries where many resources are available, patients often have to wait for several months before getting a space in a hyperbaric chamber.  Therefore, it is essential to refer the patient at an early stage- do not wait until the catastrophe is all too apparent.  As we mentioned earlier- not all patients with diabetic foot ulcers are necessarily good candidates for HBOT treatment.  The patient will have to go through a pre-screening test where the patient inhales oxygen at a higher pressure, and transcutaneous oxygen measurements on the foot will determine whether HBOT treatment is indicated. 

Video 1  A video by Dr. Gregory Weir with a presentation that was held at the WUWHS in AbuDhabi in 2022 about hyperbaric oxygen treatment in resource-challenged regions. copyright: Dr. Gregory Weir

Topical oxygen therapy

Topical oxygen therapy differs enormously from one device to another. It isn't easy to look at this group of treatments as one.  There has been an ongoing discussion for decades as to how effective the topical delivery of oxygen actually is.  In the last few years, however. we have seen the emergence of some reasonably good documentation about the effectiveness of topical cyclical delivery devices, particularly the TWO2 device is of interest here. Many of the studies have focused on the treatment of diabetic foot ulcers.  We will not go into details of topical oxygen therapy here- instead, we will write a separate chapter on this treatment modality.  We have to date not tried this treatment ourselves but will start doing so soon. It is obviously far cheaper than HBOT and is a product that could actually be made available to many regions in Africa. 

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Figure 5 An overview of different topical oxygen delivery systems - Epiflo, EO2. Natrox, GWR Medical, and TWO2.  The TWO2 system has several controlled studies to show its efficacy in the treatment of diabetic foot ulcers. image copyright: Robert Frykberg

Video 2  If you are interested in learning more about the scientific evidence behind cyclical topical wound oxygen therapy, click on the image above to get to a youtube video. 

Skin substitutes

There is an ever-increasing number of dermal substitutes available on the market today.  The choice is downright confusing for many clinicians. 

 

The theory behind dermal substitutes is to stimulate the wound to heal faster and promote quicker epithelialization.  Some of these products can be directly applied to exposed areas of bone or tendon but more often they are used in the end phase of healing when only epithelialization is lacking. 

As we mentioned earlier - there is a confusing number of such skin substitutes on the market today.  We will present here the three most established products on the market.  They are mainly used in the USA and many of these products are not readily available in all western countries. At most African centers these will not be available but we mention these products briefly here to broaden your horizon of knowledge. 

Some advantages of using such "artificial" products are that we do not need to harvest skin from the patient. A normal skin transplant can not be placed over exposed tendon or bone in most cases.  The downside of these products is obviously the price.  Furthermore, there are logistical challenges as some of the products are delivered in frozen condition and have short stability at room temperature. 

TheraSkin®

TheraSkin® is an allograft ( made of human skin) and is prepared in such a way so that it is not rejected by the wounds celles immediately. It contains both dermis and epidermis layers. It will not grow into the wound bed but will gradually dissolve. The theory is that as it gradually dissolves it releases collagen, growth-factors and cytokines which stimulate the wound healing process. TheraSkin® needs to applied several times -  anew application every two weeks or so is recommended.  the product is sent in frozen state at -70 C and can be stored for up to  6 months.  The manufacturer states on their own webpage that in a study 63% more patients achieved healing within 12 weeks compared to Apligraf, and 91% more patients achieved healing in the same time compared to Dermagraft.   

Figure 6 TheraSkin®  looks like a typical split-thickness skin graft, but it will not integrate into the wound bed because it is an allograft.  It will gradually dissolve, slowly relasing collagen, growth factors and cytokines into the wound ebd to stimulate healing. Theraskin can be applied to smaller areas of exposed tendon or bone.  image copyright: theraskin

Apligraf®

 

Apligraf® is a living, two-layered skin substitute consisting av a bovine dermal layer and a epidermal layer made of human keratinocytes.  The product has very short shelf-life and from the point of shipment it has to be used within 2-3 days.  In the USA it is approved by the FDA for the treatment of venous- and diabetic foot ulcers. It is one of the products with longest documentation and has been used in the USA for over 20 years. 

Figure 7 Apligraf® has been on the market for over 20 years and has good scientific documentation for diabetic foot ulcers.  The product consists of living cells that have been cultivated in a culture medium.  Therefore it has a very short shelf-life.  image copyright: Organogenesis

Figure 8 An example of the use of Apligraf® on the dorsum of the first MTP joint.  Note the small incisions in Apligraf®, which are important such that wound exudate does not accumulate beneath the graft.  Some caregivers fixate the graft using sutures or staples, others use steristrips or simply a dressing that compresses the product into the wound bed. image copyright: Organogenesis

Video 3 A demonstrtaion of the use of Apligraf®  Click on the image above to get to a youtube link of the video. 

Demagraft®

Demagraft® is a dermal substitute consisting of human fibroblasts placed on a layer of absorbable material. Dermagraft® is approved by the FDA for the treatment of diabetic foot ulcers. Like Theraskin, it has to be transported and stored at -70C but can be stored up to 6 months at that temperature.

Figure 9 Application of Demagraft® on a diabetic foot ulcer beneath the first metatarsal head on the plantar side.  As with the other skin substitutes, it needs to be re-applied over the course of a few weeks for best results. image copyright: dermagraft.com

Video 4  A short video showing how easy it is to apply Demagraft®. A regular foam dressing is used to keep it in place. 

Our presentation of dermal substitutes is far from complete. In the past years, there has, for example, been an increased focus on the use of amniotic membrane for this purpose.  We will write a separate chapter on dermal substitutes later to give you a complete oversight of what products are available.  

Surgical procedures: flexor tendon tenotomy 

When an ulcer develops at the end of a toe because of a hammer- or mallet toe deformity, we should first try to offload the area using, for example, self-adhesive wool felt, silicone, or other appropriate materials.  If a patient has these deformities and experiences recurrences of the ulcers, we should consider doing a flexor tendon tenotomy.  The same applies to younger patients with these deformities, where we, with a fair amount of certainty, can predict that ulcers will develop in these areas of the foot. There is an international trend with increased documentation for this practice. 

 

A tenotomy means to cut a tendon.  With tiny incisions, which can be done under local anesthesia in an out-patient setting, the tendons causing the deformity can be cut, thereby improving the toe's position. However, this procedure should only be performed in patients with flexible deformities.  This means we have to test the affected joint - if it can be moved somewhat, we will most likely achieve an improvement by cutting the tendons.  If the joint already has become very stiff, a tenotomy will most likely not do any good.  Also, the patient should, of course, not have critical ischemia.  In our experience, this procedure has proven to be very safe and effective.  We make only tiny incisions that we do not suture. Our theory is that any hematoma that may develop can freely drain out of the incision by avoiding sutures, thereby reducing the chance of infection. 

You may wonder whether the tenotomy will negatively impact the functioning of the toes afterward. Remember that the tendon, in effect, was not functioning because of the hammertoe deformity - thus, the patient will not miss it after we cut the tendon. 

Figure 10 If a patient with a flexible hammertoe ( or mallet toe) deformity has recurrent ulcers at the end of the toes, consider doing a flexor tendon tenotomy.  Usually only the flexor digitorum longus tendon needs to be cut, smetimes we cut the flexor digitorum brevis also.  If the patient has severe impairment of the arterial circulation this procedure is contraindicated. 

Video 5 A video explaining how a flexor tendon tenotomy is performed. Click on the image above to get to the youtube link of the video.

Surgery: Limb saving amputations

 

In difficult situations, an amputation may be the only correct choice.  If possible we will try to amputate as little of the foot as possible - preferable only a toe.  We are working on a chapter dedicated only to amputations.  Until then we will share a few key concepts with you here.  

Especially in the elderly diabetic population we almost always see impaired arterial function with diabetic foot ulcers.  Whenever possible we should try to revascularize the foot before we attempt an amputation of even the little toe. In other words, when possible refer the patient to a vascular surgeon if these resources are available to your patient.  For many African patients this is not a realistic option.  In some situations we also do not have the time to wait for a vascular surgeon and may have to amputate a toe immediately to prevent the gangrene from spreading further. 

Unless the patient is young, you will almost always experience some sort of complication after amputating a toe.  Most often you will see some necrosis at the suture site. often this resolves on its own over several months. Sometimes a small fistula will remain which heals very slowly - see image below.  It is important to inform the patient/other caregivers about this.  An amputation of a toe is not a minor procedure for a diabetic patient - it can lead to serious complications and almost always heals quite slowly. 

Figure 11 Even under optimal conditions, there is often delayed healing at the suture site after toe amputations in diabetic patients. In our hands only about 30-40 heal uneventfully. Quite often a part of the suture line will open and heal slowly over time. This is not generally a major challenge but it is important that you are aware of this phenomenon.  A toe amputation in diabetic patients is not a straight forward procedure. 

There is general agreement internationally that local anesthesia at the toe's base should be avoided in patients with impaired arterial circulation. The needle can itself puncture the digital arteries and destroy what little was left of the circulation in the digit. Furthermore, the pressure from the injected fluid itself can cause irreversible harm to the already impaired arteries. If possible, you should get an anesthesiologist to perform a popliteal blockade or ankle blockade with local anesthesia. Incidentally, regional blockades are thought to ( temporarily) improve the blood flow below the blockade, which is beneficial. This effect is at best temporary, but any improvement of the arterial circulation, no matter how short, must be seen as positive. In an off-the-grid clinic, you will not have access to anesthesiology services. Here you either have to learn such techniques yourself. If you do not have acquired such skills, you will have to opt for a ring blockade at the toe's base. Try not to stick the needle as deep as where the digital arteries go, use the thinnest needle you have ( 28G is excellent), and use as little local anesthesia as possible. Usually, not more than 3ml lidocaine is needed to give adequate anesthesia to a toe. Do not use lidocaine with adrenaline!

It is equally important that the surgeon treats the tissue with the utmost respect. Any unnecessary pressure from forceps on the edge of the skin can cause poor healing afterwards. Avoid dissecting the tissue layers. "Stick to the bone" is an important principle. Instead of dissecting through layers of soft tissue we try to dissect at the level of the bone to avoid causing unnecessary damage to vascular structures. 

 

In situations where there are serious ulcers in the metatarsal area with perhaps osteomyelitis there may be a need for a resection of the entire metatarsal bone. In this way it may be possible to save the limb. It is easier to do this in the first and fifth metatarsal bone because they are easier to access anatomically.  The same rules apply her as to amputations of  toes.  Avoid unnecessary dissection of soft tissues and stick to the bone to avoid damaging blood vessels.  Since the arterial circulation often is impaired in these patients be prepared for wound complications after the amputation.  If negative pressure therapy is available this is a very useful modality in these cases. 

Figure 12 An example of an amputation of the fifth ray ( fifth metatarsal bone inclusive the fifth toe). The patient had a deep ulcer and severe osteomyelitis of the metatarsal bone beneath. The upper right image shows the bone cleanly excised, and the soft tissue looks well circulated. It was not possible to close the skin without much tension. Here we opted for using negative pressure therapy to promote granulation. After two weeks, a split-thickness skin graft was applied, and the wound healed well. After such an amputation, regular shoes do not fit properly, and the patient should get custom-made orthopedic shoes where this is available. 

While it may be feasible to do a toe amputation or even metatarsal amputation in patients with impaired arterial circulation, a mid-foot amputation will most certainly fail. To put it another way: if we attempt a toe amputation or even metatarsal amputation in these patients, we often end up with some wound problem at the amputation site. These challenges can, however, usually be dealt with. If you attempt a midfoot amputation in these patients, you will end up with complications that cannot be salvaged. Do not attempt a mid-foot amputation unless the patient is very young ( < 40 years) and has good blood circulation.

 

The series of images below reinforces this statement. A diabetic patient with apparently only moderate arterial disease was amputated mid-foot by experienced surgeons. The postoperative image shows what seems like well-perfused skin flaps. However, only a few days later, the skin edges turned necrotic, and the patient ended up with a leg amputation. 

 

As we mentioned earlier, we are working on a separate chapter on amputations in general, where we will discuss these issues in more detail.  

Figure 13 An example of attempting a midfoot amputation in a  diabetic patient with wet gangrene. The skin flaps look well-perfused immediately postoperatively. After only five days, however, necrosis had appeared because of impaired arterial circulation. This example illustrates that we, in most cases, have an amputation at the leg- or thigh-level to avoid repeated amputations.  image copyright: Håvard Dahle.