Successful Upper Extremity Limb Salvage Using Cellular- and Tissue-based Products in a Patient With Uncontrolled Diabetes

Type 2 diabetes is an endocrine disease in which altered metabolism of glucose leads to chronic hyperglycemia due to insulin resistance. Approximately 1 in 10 people in the United States are affected by type 2 diabetes.¹ Patients with type 2 diabetes have increased rates of soft tissue infections, which are compounded by impaired wound healing, microvascular changes, and chronic inflammation. The management of diabetic infections, wounds, and ulcers requires a multidisciplinary approach involving good nutrition, glycemic control, debridement, and antimicrobial therapy.

The impaired angiogenesis of patients with type 2 diabetes strongly contributes to the chronic, nonhealing nature of many diabetic wounds.² Wound healing normally progresses in a linear fashion beginning with hemostasis, followed by inflammation and proliferation, and ending with remodeling. In patients with type 2 diabetes, however, healing does not properly progress through these stages, and delayed healing leads to chronic wounds. Additionally, normal healing relies on angiogenesis to transport necessary growth factors, nutrients, and other substances to the site of injury; wounds in patients with diabetes exhibit lower capillary densities and overall decreased vascularity compared with wounds in patients without diabetes.³ Thus, patients with the microvascular changes associated with type 2 diabetes are at increased risk of developing nonhealing wounds.² The literature suggests there is a 25% to 39% upper-extremity amputation rate owing to infection in patients with diabetes.^4,5 However, the rate of upper-limb amputation in patients with osteomyelitis is not significantly different between patients with diabetes and patients without diabetes (1.7% and 1.6%, respectively).⁶

To facilitate prompt closure of chronic, nonhealing diabetic wounds, it may be necessary to use CTPs. The 3 categories of CTPs are ECMs, human amniotic tissues, and composites that combine living cells and a collagen matrix. Currently, the 3 broad categories of ECM products that are available off-the-shelf are xenografts, allografts, and bioengineered products. The concept behind the use of ECMs is to provide a biological scaffold to facilitate wound healing. Additionally, ECMs modulate the wound environment and subsequently become incorporated into the wound bed.⁷

One group of ECMs is derived from human amnion. These products have been used in many settings, including for tendon and nerve wrapping. For those applications, data indicate there are fewer adhesions and less scar formation with use of human amnion, resulting in improved functional recovery.⁸ Additionally, ECM derived from human amnion has antimicrobial properties, making it ideal for nerve wrapping.^8,9

A second commonly used product in reconstruction is bilaminate neodermis. These products have been used in wounds with exposed critical structures and have become an essential tool in reconstructive surgery.^10-17 After incorporation of the neodermis, the wound is recategorized from a critical wound to one suitable for skin grafting.

The third product described in this report is an acellular fish skin. This material has been described for use in burns and DFUs, and data indicate that it offers more antimicrobial resistance than human amnion/chorion.^15-17 There are relatively limited reports on the use of acellular fish skin and, to the authors’ knowledge, no study to date has used these products to cover exposed critical structures in a wound bed.

The current case report demonstrates the use of 3 ECMs—meshed dermal regeneration template (Integra Dermal Regeneration Template; Integra LifeSciences), minimally processed human umbilical cord membrane (Avive Soft Tissue Membrane; AxoGen, Inc), and acellular fish skin (Omega3; Kerecis)—in the reconstruction of a chronic diabetic upper extremity wound. This intervention ultimately led to limb salvage in a previously nonfunctional upper extremity.

A 51-year-old right-hand dominant female with a history of hypertension, peripheral neuropathy, and severe uncontrolled type 2 diabetes (HbA_1C level, 16.1) was admitted emergently for a significant right upper extremity soft tissue infection. Over a 4-month hospitalization period, the patient underwent multiple rounds of debridement for recurrent infections of the volar forearm, including open carpal tunnel release, forearm fasciotomy, and drainage of flexor tenosynovitis. This resulted in a complex right forearm wound with exposed median nerve and flexor tendons (Figure 1A).

Upon consultation for limb salvage with the plastic surgery team, the patient was found to have a nonfunctional upper extremity. One week after undergoing debridement for flexor tenosynovitis of the right hand, the patient received excisional debridement along with placement of a single application of dermal regeneration template over the entire volar forearm wound. At the same time, minimally processed human umbilical cord membrane was wrapped around the median nerve. At the postoperative clinic visit 3 weeks later, the patient exhibited the return of some sensation in a median nerve distribution and started to regain the ability to flex the fingers (Figure 1B). One month later, the patient underwent split-thickness skin grafting of the right forearm and hand over the dermal regeneration template. On postoperative day 6, the graft was partially lost along the distal radial forearm (Figure 1C). This resulted in exposed flexor tendons and median nerve at the base of the wound (Figure 1D).

On postoperative day 20, acellular fish skin was applied to the distal radial forearm over the exposed flexor tendons and median nerve (Figure 1E). The patient was followed up in the wound clinic, and the previously exposed vital structures remained covered throughout the healing process (Figure 1F). Of note, the patient regained protective sensation and some motion in the hand in a median nerve distribution, which she had lost completely before reconstruction. The patient was followed up weekly, although inconsistently, for 4 months postoperatively. This also included an admission to the authors’ hospital (University of New Mexico) for nonketotic hyperosmolar state, at which time the patient’s blood glucose level was 763 mg/dL and the HbA_1C level was 14.2. The patient’s wounds ultimately healed by secondary intention with local wound care, which was used after critical structures were no longer exposed.

In the setting of complex diabetic wounds, the physiologic response is abnormal and often results in significant morbidity. Patients with such wounds are often poor candidates for complex reconstruction owing to the underlying type 2 diabetes. As a result, these patients often experience failed reconstructions, from primary closure to skin grafts and even free flaps. This is further complicated in the setting of exposed critical structures, such as tendons and nerves. Often, these patients are treated with local wound care; however, in the case of exposed underlying structures, local wound care is not enough.

For patients with exposed critical structures, a free flap is often the primary option. However, patient factors must be strongly weighed before considering free tissue transfer. Donor site morbidity, wound healing potential, and the patient’s ability to adhere to the postoperative protocol, along with appropriate social support, must be considered. Additionally, ECMs can be used to help avoid the need for free flaps in patients who are not good surgical candidates. As demonstrated by the readmission for nonketotic hyperosmolar state of the current case, this patient had extremely poor glycemic control before admission and after discharge. In addition, the patient had limited access to care due to low resources. Although tight glycemic control is possible in the inpatient setting, it is not feasible for every patient to remain inpatient (or in a skilled nursing or long-term acute care facility) in an urban hospital system that is overwhelmed at baseline. Given these factors, in this clinical scenario a simple solution that does not require long-term hospitalization is ideal.

ECM is an essential tool in the reconstructive armamentarium that enables the use of off-the-shelf products with no donor site morbidity and no need for extended hospitalization. When deciding between different tissue products in the setting of complex wounds, it is essential to align the wound characteristics with the most appropriate ECM available. The 3 products used in the current case were human amnion, dermal regeneration template, and acellular fish skin.

Human amnion has been shown to have a plethora of uses, including in the settings of burns, acute wounds, chronic wounds, and dural repair, as well as for tendon wrapping and nerve wrapping. Previous studies have demonstrated that wrapping the tendon and nerve with amnion can reduce adhesions and improve functional recovery.⁸ In general, amnion functions as a physical barrier, which prevents desiccation of the wound bed.⁸ This ability to physically exclude fibroblasts makes it ideal for nerve wrapping. It is also reported to have an analgesic effect by protecting exposed nerve ends from the environment; additionally, it is known to have immunomodulatory effects, inhibiting fibrosis and scar formation, and to have intrinsic antimicrobial properties.⁸ The umbilical cord membrane used in this case is 8 times thicker than other commercially available amniotic membranes, and it has been shown to be safe and effective for use as a nerve wrap in the setting of upper extremity reconstruction.⁹

The dermal regeneration template used in the current report is a skin regeneration system that has become an essential tool in the reconstructive armamentarium for addressing wounds with exposed critical structures. It has an outer silicone layer, which substitutes epidermis, and an inner cross-linked matrix composed of pure bovine collagen and glycosaminoglycans that promotes dermal skin cell regeneration.¹⁰ The matrix allows the patient’s native cells to incorporate into the template.¹¹ Following the incorporation of the dermal matrix, a skin graft is conducted after the outer silicon layer is removed.¹⁰

Perhaps the most appealing application of the dermal regeneration template involves the ability to apply it directly on tendons, nerves, and other underlying structures. In addition to creating a vascularized wound bed that will accept a skin graft, this matrix promotes less fibroblast migration than split-thickness skin grafts, making it less likely to cause significant wound contraction and adhesion formation.¹¹ This product has been used in burn reconstructions for full-thickness wounds.¹² Another well-researched application of this dermal regeneration template involves traumatic hand wounds. Weigert et al¹³ studied 15 patients with traumatic hand wounds with exposed tendons, joints, or bone. The matrix was used on all 15 patients, followed by skin grafting. Of those patients, 13 experienced functional and definitive coverage of the hand wounds. The dermal regeneration template has also been used in the management of DFUs. Although research on the use of this product on DFUs is more limited, studies have demonstrated that it has a role in the promotion of healing in small-sized DFUs. Clerici et al¹⁴ found that 26 of 30 patients (86.7%) with diabetic foot wounds with exposed tendon or bone experienced complete healing with the application of the dermal regeneration template. Few studies have been published on the use of the dermal regeneration template specifically in diabetic upper extremity wounds; however, it is generally accepted as an option in the setting of exposed critical structures.

The use of acellular fish skin harvested from North Atlantic cod has shown promise in the management of lower extremity diabetic wounds and in patients with chronic vascular insufficiency.¹⁵ Positive effects have also been seen in healing acute wounds; data suggest that wounds treated with acellular fish skin heal faster than wounds treated with porcine membrane and human amnion/chorion.¹⁶ Additionally, use of acellular fish skin in the setting of both adult and pediatric burns has been reported.¹⁷ To the knowledge of the authors of this report, there has not been any discussion of using this product in the setting of exposed critical structures.

Because there is no risk of virus transmission from cod to humans, the piscine dermis requires minimal processing for medical use. As a result, the piscine dermis maintains its natural structure and elements, including omega-3 fatty acids. The gentle processing allows cells to migrate into the piscine dermis within a preserved scaffolding that does not have any unintentional cross-linking due to processing, a known inhibitor of fibroblast and endothelial progenitor cell migration.¹⁶ The characteristics of the product enable the body to incorporate the acellular fish skin and ultimately, self-epithelialize; in the appropriate setting, this alleviates the need for skin grafting. Skin grafting often remains necessary for larger wounds. Compared with a dehydrated human amnion/chorion graft, the acellular fish skin graft was shown to have better 3-D ingrowth.¹⁶ In addition, this product has a bacterial barrier that is maintained for 24 to 48 hours after application. As demonstrated in this case report, acellular fish skin is an effective option to cover exposed critical structures in the upper extremity, and it has become an integral tool in the authors’ reconstructive practice.

This study is limited because it is a single case report. More studies are needed to evaluate acellular fish skin in the reconstruction of critical wounds.

The patient discussed in this case report benefited from appropriate use of multiple CTPs to manage a complex upper extremity diabetic wound, which resulted in successful wound reconstruction and improved function. This report demonstrates that CTPs are important adjuncts in the management of complex wounds and that they have a place in the modern reconstructive algorithm. The optimal application of such products in this case facilitated wound closure and ultimately, successful coverage of critical structures (ie, median nerve, flexor tendons), thereby restoring function and salvaging the dominant upper extremity.

To the authors’ knowledge, the current case is the first described use of acellular fish skin in the setting of upper extremity reconstruction with exposed tendon and nerve.