Fully Synthetic Bioengineered Nanomedical Scaffold in Chronic Neuropathic Foot Ulcers

Introduction. Chronic ulcerations on weightbearing surfaces of the lower extremities are uniquely challenging and can lead to complications such as infection or amputation. Objective. This 3-patient case series of 4 chronic wounds of various etiologies outlines the use of a fully synthetic bioengineered nanomedical scaffold that exhibits durability and allows for cell migration and angiogenesis while resisting enzymatic degradation. Materials and Methods. The nanomedical scaffold was rehydrated in sterile saline at room temperature for 3 to 5 minutes until translucent and pliable, then it was fenestrated with a scalpel. Following sharp debridement, it was affixed to the ulcer. A nonadherent dressing was applied, followed by applying a moist sterile dressing in a bolster fashion. Results. All 4 ulcers reached the primary endpoints of granulation, as well as decreased wound size, using the nanomedical scaffold. Conclusions. The nanomedical scaffold successfully reduced the ulcer depths, stimulated granulation tissue while preventing necrosis, and helped the wounds remain infection free. The outcome of this case series suggests a fully synthetic bioengineered nanomedical scaffold can be used as an alternative to human or animal extracellular matrix in chronic, hard-to-heal neuropathic ulcers.

Skin substitutes can be employed to transition chronic wounds beyond the stalled inflammatory phase and promote wound healing. Extracellular matrix (ECM) products provide a scaffold for cellular ingrowth and promote tissue regeneration.^1,2 An ideal skin substitute would temporarily reproduce the function of dermis or epidermis, exhibit durability and flexibility to conform to any wound contour, and limit infection while promoting healing. An implantable nanomedical scaffold that exhibits structural similarities to native ECM and possesses features conducive to wound healing offers a novel approach for the treatment of these chronic wounds.³ The nanomedical scaffold (Restrata Wound Matrix; Acera Surgical, St. Louis, MO) is composed of nanospun polyglactin 910 poly(lactic-co-glycolic acid) (PLGA) (10:90) and polydioxanone, materials commonly used in sutures and that fully hydrolyze in about 1 month.^4,5 The synthetic nature of the nanomedical scaffold helps avoid the possibility of contaminations or reactions to transplanted tissues.^6,7

This case series outlines the use of the fully synthetic durable nanomedical scaffold for the treatment of recalcitrant neuropathic foot ulcers with the primary goal of achieving granulation.

This case series was conducted at a single treatment center (Southern Arizona Veterans Affairs Health Care System, Tucson, AZ). Patients with a history of recalcitrant neuropathic foot ulcers were included. Comorbidities included neuropathy, diabetes mellitus, obesity, lymphedema, and peripheral vascular disease. All data collection were conducted in strict accordance with institutional procedures. Wound observations were performed weekly.

Before each treatment, the clinically noninfected wound was cleansed (CarraKlenz; Medline Industries, Mundelein, IL) and sharply debrided of any nonviable tissue. Measurements then were taken with single-use paper rulers. The wounds were treated with the implantable nanomedical scaffold weekly or as deemed appropriate based on physician assessment of the wound. The nanomedical scaffold was rehydrated in room temperature saline for 3 to 5 minutes until pliable and mostly translucent then fenestrated with a scalpel. The nanomedical scaffolds were affixed to the ulcers in 1 of 3 ways: 3-0 chromic gut suture, skin staples, or a nonadherent dressing (Mepitel; Mölnlycke Health Care, Gothenburg, Sweden) with adhesive strips (Steri-Strips; 3M, St Paul, MN). Secondary dressings consisted of a nonadherent dressing and adhesive strips, moist gauze, rolled gauze, and a cohesive dressing.

Patients were instructed to leave the dressings fully intact for the first 7 days, and proper offloading was provided as clinically indicated.

This case series included data from 3 patients with 4 chronic wounds of varying etiologies and sizes treated with the implantable nanomedical scaffold. All 4 ulcers achieved granulation tissue formation and decreased in wound area with the use of the nanomedical scaffold.

Case 1

A 71-year-old Caucasian man with neuropathic diabetes presented with lymphedema, multiple myeloma, venous insufficiency, and obesity with Charcot neuroarthropathy of the left ankle and subsequent ulcer lasting about 50 years (Figure 1A). The weightbearing surface of the patient’s foot was the area between the medial calcaneus and medial malleolus. He had been admitted twice in the last year for infections to the area secondary to immunosuppression from multiple myeloma treatment. The patient was admitted to a skilled nursing facility and transitioned from full weightbearing to non-weightbearing status with pivot transfer at the beginning of the treatment with the nanomedical scaffold.

In week 1, the medial ankle ulcer was treated with the implantable scaffold, and the matrix was secured using 3-0 chromic gut (Figure 1B). A secondary dressing and soft splint were applied. The wound decreased in size, and a second application was performed in week 3, affixed with skin staples, and the soft splint was continued (Figure 1C). In week 5, a skin island had grown centrally.

At week 7, a third nanomedical scaffold was applied to an ulcer that showed a percent area reduction (PAR) of 68.4% from initiation of treatment (Figure 1D). With adjunctive therapy, the wound healed in 28 weeks (Figure 1E).

Case 2

A 73-year-old Caucasian man with neuropathy presented with right Charcot neuroarthropathy and right partial first ray resection with failed split-thickness skin grafting and subsequent dehiscence 13 months prior to treatment (Figure 2A). The patient had been prescribed an offloading shoe, walking boot, and custom offloading orthotics, which he had been noncompliant with in the past. The ulceration was a recurrence at the same location as previous ulcerations.

At the beginning of week 1, the patient was placed in a total contact cast (TCC), which was changed weekly. The initial application of the nanomedical scaffold from week 1 was secured with 3-0 chromic gut suture (Figure 2B). A second application of the wound matrix was applied in week 4, debridement was performed in week 5, and a third nanomedical scaffold was performed in week 6 with a PAR of 56.0%.

With adjunctive therapy, the wound healed in 17 weeks (Figure 2C).

Case 3

A 67-year-old African American man with a plantar calcaneal ulcer of the left foot of 8 years’ duration developed a right fifth metatarsal base ulcer that probed to the bone. The patient presented with diabetes, neuropathy, severe lymphedema, chronic kidney disease, Charcot neuroarthropathy of the left foot, and obesity. The left foot underwent partial calcanectomy 2 years prior. The patient was not a good candidate for surgical reconstruction and was at high risk for amputation.

Eight months after initial development of the right foot ulcer, the ulcers on both feet underwent hydrosurgical debridement with the implantable nanomedical scaffold in the operating room (Figures 3A, 4A). By week 4, the material in the right foot was fully hydrolyzed, and a second application of the nanomedical scaffold was performed bilaterally (Figures 3B, 4B).

Previously exposed bone was completely covered with granular tissue prior to the third application of the material on the right foot at week 6. In the left foot, notable improvements were seen at week 7 following a third application (Figure 4C).

At week 13, the right foot achieved complete healing (Figure 3C) and the left ulcer achieved a PAR of 94.9% (Figure 4D). Attempts for limb salvage were thus far successful, and the patient had 2 functional legs to transfer and walk.

The initial endpoint of this case series was to use the nanomedical scaffold to cover deep structures and fill in tissue defects to achieve granulation and decrease the risk of infection, thereby avoiding amputation in these patients. It also demonstrated successful reduction in wound area, achieving granulation in all 3 cases when used to treat their recalcitrant neuropathic ulcers.

Case 1 showed a PAR of 68.4% after 7 weeks and case 2 showed a PAR of 56.0% in 6 weeks. Once the goal of granulation was achieved, clinical decision-making was employed and amniotic products were used until closure.⁸ The TCC used in case 2 provided offloading, but due to chronicity of the ulcer and previous failure of similar modalities, it did not account for the healing seen. The nanomedical scaffold provided durability and safety as there is a very low risk of graft reactivity under the cast.

Case 3 achieved a PAR of 94.9% on the left foot and complete closure of the right foot in 13 weeks. These results are especially important when taking into account the risk factors and comorbidities of the patients included in this case series. People with diabetes (cases 1 and 3) are 15 times more likely to experience a lower extremity amputation than those without diabetes.⁹ Furthermore, patients > 65 years with Charcot neuroarthropathy (cases 2 and 3) are at a 12-times higher risk of amputation than a patient with a foot ulcer alone.¹⁰ African American veterans, such as case 3, have a 1.4-fold higher risk for lower extremity amputation than white counterparts.¹¹

Although the results of the present case series are encouraging, this is only an initial assessment of the implantable nanomedical scaffold for the use of chronic neuropathic ulcers. A small number of patients were evaluated, and additional work with longer-term follow-up is needed to further confirm its clinical benefits.

A fully synthetic bioengineered nanomedical scaffold was used to treat recalcitrant neuropathic foot ulcers and resulted in improvements in wound healing, including reduction in ulcer area and depths, stimulation of granulation tissue, and successful limb preservation in high-risk patients. The present case series suggests the nanomedical scaffold can be used as an alternative to human or animal wound matrices in chronic neuropathic ulcers of the subcutaneous tissue and as an adjunctive therapy for limb preservation in complex chronic ulcerations.

Affiliation: Southern Arizona VA Health Care System, Tucson, AZ

Correspondence: Jodi L. Walters, DPM, Podiatrist and Director of Podiatric Research, Southern Arizona VA Health Care System, Podiatry, 3601 S 6th Avenue, Tucson, AZ 85723; jodi.walters@va.gov;
jlwalt44@gmail.com

Disclosure: The Southern Arizona VA Health Care System provided the facilities and support for this research. The authors disclose no financial or other conflicts of interest. Portions of this paper were presented as posters at the Symposium on Advanced Wound Care Spring and Fall 2018 meetings.