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A Novel Approach to Using Flowable Human Amniotic Fluid for DFUs in High-Risk Patients
Diabetes mellitus is a vicious metabolic disease with consequences including peripheral neuropathy, ischemia, callus formation, deformities, edema, and peripheral artery disease.1 Unfortunately, as a result of these comorbidities in various combinations, patients living with diabetes are at increased risk for developing diabetic foot ulcers (DFUs). The global prevalence of DFUs is 6.3%, with males affected more often than females, in addition to Type 2 being more prevalent than Type 1.2
DFUs also place a financial burden on the health care system. As of 2013, the cost of diabetes-related foot ulcers and amputations accounted for up to $17 billion in the United States health care system.3 On a global scale, predictions cite that the expenditure of diabetes would reach $850 billion.4
Currently, the standard of care (SOC) involves 4 established principles: pressure relief, debridement, infection management, and revascularization when indicated.2 When the standard of care does not result in wound progression, one may consider advanced care such as biologics, surgical intervention, or a combination.
The concept of using amniotic tissue is not a novel idea, but dates back as far as 1910 when human amniotic membranes had multiple surgical applications, including temporary wound dressings, burn care, and leg ulcer treatment.5 The use of amniotic fluid also has shown great potential for DFUs due to their antimicrobial properties and promotion of re-epithelialization of wounds.6
In this case study, we look at three separate high-risk patients treated for DFUs. Each patient had a different anatomical location of their wounds, clinical presentation, and past medical history. While standard of care was utilized for each patient, the timeline for application of flowable amniotic tissue was approached individually. This series hopes to open a discussion regarding the novel use of topical application of human amniotic tissue as an advanced wound care option for those who may have failed conservative therapy or may be looking for alternative methods to help heal pedal ulcers.
A Closer Look at the Cases
Each examination and evaluation took place in a clinical setting either in the outpatient clinic or on the hospital ward floors. The team carefully undressed the wounds, followed by cleansing via available wound cleansers. All wounds underwent evaluation for maceration and/or hyperkeratotic formation. Debridement was carried out via sterile scalpel blades and sterile dermal curettes. The team took final wound measurements prior to application of amniotic tissue products. Amniotic tissue consisted of either PalinGen® SportFlow (Amnio Technology), or PalinGen® Hydromembrane (Amnio Technology). In order to assist in maintaining contact with the wound surface area, Promogran Prisma™ (3M) was utilized off-label as a vehicle for the topical amniotic fluid. Once in contact with the wound bed, the wound was secured with a non-adherent layer followed by a sterile dressing. Appropriate offloading was gained via an offloading postoperative shoe, walking boot with offloading modifications, or offloading Prevalon boots (Stryker) while patients were non-weight-bearing.
DFUs were treated via topical application of PalinGen SportFlow, a human allograft tissue matrix that is chorion-free and derived from human amnion and amniotic fluid. Tissue is obtained from healthy donors who voluntarily offer their placentas following elective Caesarian delivery. PalinGen SportFlow is indicated for any sized wound; however, a common range includes 1cm to 3cm per the manufacture guidelines.
Case Study 1: Digital Infection in a Patient With Diabetes
The first patient was seen as an emergency department (ED) consult for a right second digit infection. Past medial history includes hypertension, mixed hyperlipidemia, diabetes mellitus type 2, hypothyroidism, and iron deficiency anemia. Upon examination, there was a large blister filled with purulence plantarly with additional erythema coursing proximally to the midfoot.
We performed a bedside incision and drainage with saline flushing, followed by a betadine dressing and admission with IV antibiotics. Plain film radiographs were ordered with a final impression of no active osteomyelitis. An additional magnetic resonance image (MRI) of the toes was ordered due to purulent drainage being found on clinical exam. Final MRI findings demonstrated superficial and deep soft tissue edema, and focal signal alteration within the plantar soft tissues at the proximal phalanx of the second toe. Ankle brachial indices (ABIs) were also conducted and demonstrated a right sided value of 0.97 at the posterior tibial and 0.85 at the dorsalis pedis. Based on clinical examination, there was still evidence of purulent drainage and the digit being cold to the touch. Despite antibiotic therapy, it was decided to proceed with a second digit amputation and debridement to the level of the metatarsophalangeal joint in the operating room. Four days postoperatively, negative pressure wound therapy was initiated via Vacuum Assisted Closure (VAC) (3M). VAC changes took place every 3–4 days either by the on-call resident or the wound care nursing team.
Ten days postoperatively, we initiated the the first topical application of PalinGen SportFlow while maintaining negative-pressure wound therapy. The patient underwent topical amniotic tissue therapy for 1 month in conjunction with VAC therapy while inpatient. Of note, wound measurement documentation changed from 1 continuous surgical incision to separate dorsal and plantar wound measurements. With the plantar wound healing progressing, amniotic therapy focused primarily on the dorsal aspect of the wound.
Following 1 month of amniotic therapy, a 1-week trial of PalinGen Hydromembrane–only therapy was applied to the dorsal wound. VAC therapy was maintained as well. After the 1 week of PalinGen Hydromembrane therapy, it was decided that Flow therapy would be restarted for 1 additional week. Due to skin maceration from the VAC, VAC therapy halted for 2 weeks; amniotic therapy continued.
Based on clinical presentation of purulence during a dressing change 7 weeks following second digit amputation we conducted a further work-up for osteomyelitis despite no evidence of constitutional symptoms. Radiographs demonstrated bony erosion to the second metatarsal head, which led to the decision to return to the operating room for a partial second metatarsal amputation with the implantation of antibiotic-impregnated beads and iodoform packing for delayed closure.
Once the infection had been removed based on pathology results and lab results had stabilized, a new therapy of PalinGen SportFlow with Prisma was initiated 5 days postoperatively along with reinitiating VAC therapy 6 days postoperatively. This therapy was carried out for 1 week before officially discontinuing VAC therapy. Prisma and PalinGen SportFlow therapy was conducted for another week before transitioning to 3 applications of singular membrane therapy over the span of 5 weeks. At the conclusion of the final PalinGen Hydromembrane therapy, the patient presented clinically with fully epithelialized skin and no further open wounds.
In total, the wound was treated over the span of 20.5 weeks with 6 applications of PalinGen SportFlow, 8 applications of PalinGen Hydromembrane, and 2 applications of Prisma. The patient has remained healed to date with no evidence of reulceration per chart review.
Case Study 2: A Patient With Lower Extremity Cellulitis
The second patient was seen in the ED as a consult for cellulitis to the left foot. Past medical history included hypertension, diabetes mellitus type 2, left hallux amputation, peripheral neuropathy, history of methicillin-resistant Staphylococcus aureus (MRSA), hypokalemia, and tinea pedis. This patient was seen in the ED 16 days status post–left hallux amputation from a community hospital and was lost to follow-up with the community surgeon. The patient presented to the ED to have the surgical site evaluated and possible suture removal.
The surgical site demonstrated erythema coursing proximally to the midfoot with probing to both the first and second ray. There was a mild amount of purulence expressed along with a small of necrosis dorsally. There were also various social circumstances at home (i.e., lack of electricity, lack of wound care support at home), which made postoperative care difficult and unrealistic for this patient. The patient was admitted with IV antibiotics with recommendations for a vascular consult as well as ordering ABIs. The ABI results found the right posterior tibial and left dorsalis pedis artery to have monophasic wavefroms. The right dorsalis pedis and left posterior tibial artery were found to have biphasic to triphasic wavefroms. Vascular services were consulted for an assessment to heal and they determined the patient to be very likely to have adequate blood supply for wound healing.
Following 10 days of local wound care and antibiotic tailoring with the help of the infectious disease department, it was decided to proceed with an incision and drainage with debridement of all non-viable tissue and bone. An intraoperative decision was made to place a Penrose drain for secondary closure. Two days postoperatively, the Penrose drain was removed, and the first topical application of Flow was initiated in conjunction with negative pressure wound therapy via Wound VAC.
Following 1 week of treatment, we decided to discontinue the VAC therapy due to the clinical healing progression. We elected to proceed with a second round of PalinGen SportFlow, this time applied in combination with Prisma. This therapy was maintained for 1 week; with the following 2 weeks of treatment consisting primarily of PalinGen Hydromembrane. Upon physical examination prior to discharge, the patient was completely healed.
In total, the wound was treated over the span of 6 weeks with 2 applications of PalinGen SportFlow, 2 applications of PalinGen Hydromembrane, and 1 application of Prisma. The patient has remained healed to date with no evidence of reulceration per chart review.
Case Study 3: Treating a Chronic Plantar Ulcer of the First MTPJ
The third patient was an inpatient consult for a chronic lower extremity wound. Past medical history includes diabetes mellitus type 2, peripheral neuropathy, venous insufficiency, cellulitis, stage 3 chronic kidney disease, essential hypertension, heart transplant recipient, and gout.
Of note, this patient was known to the podiatry clinic dating back to October 2019. The patient had a history of previous wounds, which had been healed and re-ulcerated. Prior to the beginning of this case series, podiatry had been consulted twice in the span of 1 month. At the time of the case series, the patient was still suffering from a chronic ulcer to the plantar surface of the first metatarsophalangeal joint on the left foot. The patient was treated previously with conservative wound care, but the wound had yet to fully heal. Imaging was conducted with two views plain radiographs with a final impression of degenerative joint changes and vascular calcifications. Previous ABIs wound vessels to be noncompressible but did state there were adequate toe pressures. On examination, there was a negative probe to bone test and no purulent drainage, therefore leading to a decreased suspicion of osteomyelitis.
Based on the chronicity of the wound in addition to conservative measures being ineffective despite appropriate offloading, it was decided to pursue an advanced conservative care plan. One day following initial consult, therapy was initiated via PalinGen SportFlow soaked in Prisma with the addition of PalinGen Hydromembrane. Following 1 week of therapy, the wound had decreased by 50%, so it was decided to commence a second round of PalinGen SportFlow soaked in Prisma. Two weeks later, the wound continued to decrease in size, and a third and final round of PalinGen SportFlow soaked in Prisma was applied. Following discharge from the hospital, the patient was seen in clinic for routine wound monitoring.
Based on the nature of the wound depth decreasing, but the wound edges slightly increasing, it was decided to focus on reapproximating the wound edges and therefore proceed with a final application of a membrane. Upon physical exam 2 weeks later, the wound had healed with fragile epithelium and was treated with a simple non-adherent bandage for added protection. The patient was referred out to the outpatient wound clinic due to additional wounds not cared for by podiatry. However, based on chart review, the patient’s pedal wound was absent upon first presentation to the wound clinic within 2 weeks from being referred out of the clinic.
In total, the wound was treated over the span of 9 weeks with 3 applications of PalinGen SportFlow, 2 applications of PalinGen Hydromembrane, and 3 applications of Prisma. The patient has remained healed to date with no evidence of re-ulceration per chart review.
What These Cases Suggest About Amniotic Tissue for DFUs
At the conclusion of the series, it was determined that all 3 patients were able to fully heal their diabetic foot ulcers with the assistance of advanced wound care via amniotic fluid. While each patient had their own respective past medical history, wound etiology, and treatment course, this study aids in the consideration of using amniotic tissue for treating DFUs.
The literature demonstrates various justifications on the effectiveness of amniotic tissue when treating wounds. Biologic dressings, such as human amniotic membranes, have the capability to reduce bacterial contamination and prevent further contamination, reduce pain, reduce the loss of fluid, protein, heat and energy, promote healing, and protect underlying structures.7 When assessing amniotic fluid, researchers have said that trophic factors act in order to stimulate cell differentiation, as well as cell movement and proliferation which may ultimately lead to the re-epithelialization of a wound.6 Additionally, amniotic fluid was found to activate mitosis, angiogenesis, and increase the rate of wound closure in patients with diabetes.6
Further consideration should also be given regarding the complexity and high-risk nature of having a DFU. DFUs were found to double mortality and heart attack risks while simultaneously increasing the risk of stroke by 40%.8 When assessing mortality, patients are at twice the risk of death at 10 years with a DFU as a patient with diabetes and no DFU.9 As of 2007, the relative 5-year mortality rate following limb amputation was 68%, second only to lung cancer at 86%.10
The cost of treating is not something to be ignored either. Patients who suffer from DFUs are twice as costly to US Medicare as those with diabetes mellitus alone.11 In 2013, the cost of a DFU was greater than the 5 most costly forms of cancer.3 To add to the heavy financial impact, $1 million is spent on diabetic foot complications every 30 seconds in the USA alone.3
In Conclusion
The use of amniotic tissue when treating wounds has dated back to 1910 and to this day in this new century, there is still justifications and new avenues where this type of treatment may be utilized. This case series was able to examine 3 different patients, all with diabetic foot ulcers, and demonstrated that topical flowable amniotic tissue may be useful for healing high-risk patients with diabetic foot ulcers. This is likely due to the use of amniotic fluid and its ability to reduce and prevent contamination, reduce pain, promote cellular movement and proliferation, and most importantly, promote healing. The use of amniotic tissue as an advanced method for wound care in patient who suffer from DFUs continue to show clinical promise and should be given full consideration for utilization in the future.
Dr. Glover is a third-year Chief Resident at the Tucson VA Hospital in Tucson, AZ.
Dr. Walters is the Research Director of Podiatric Surgery at the Southern Arizona VA Healthcare System in Tucson, AZ
Dr. Samoy is the Residency Program Director of Podiatric Surgery at the Southern Arizona VA Healthcare System in Tucson, AZ
Dr. Dancho is the Chief of Podiatric Surgery at the Southern Arizona VA Healthcare System in Tucson, AZ.
References
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9. Iversen MM, Tell GS, Riise T, et al. History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag Health Study, Norway. Diabetes Care. 2009;32(12):2193-2199. doi:10.2337/dc09-0651
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11. Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers [published correction appears in Diabetes Care. 2014 Sep;37(9):2660]. Diabetes Care. 2014;37(3):651-658. doi:10.2337/dc13-2176
