The Basics of Integra Dermal Regeneration Template and its Expanding Clinical Applications

Abstract

First developed for coverage of burn wounds, Integra (Integra LifeSciences) is a synthetic acellular dermal regeneration template that provides a base for revascularization and neodermal formation. The use of Integra has slowly grown and has now become an important consideration along the reconstructive ladder. This article reviews the basic science of Integra and provides an overview of the many expanding applications based on anatomic location.

Integra (Integra LifeSciences, Plainsboro, New Jersey) is a manufactured acellular dermal regeneration template composed of a bilaminate sheet of cross-linked bovine tendon collagen and shark glycosaminoglycans (chondroitin-6-sulfate) with a silicone sheet cover. It was developed by the joint efforts of Massachusetts General Hospital, Boston Shriners Burns Center, and Massachusetts Institute of Technology in the 1970s. In the 1980s, Yannas and Burke published the design, composition, and control of this polymer. ^{1 2 3}

Integra was initially created out of necessity to provide temporary coverage for patients with extensive burns. Those who benefited most from this technology were patients with severe full-thickness burns in whom donor sites were severely limited or nonexistent. However, since its initial application in burn treatment, its clinical applications have broadened significantly. This article will describe the biologic basis for Integra, provide a basic primer on its clinical use, and review the current specialized uses which have been studied in the extremities, trunk, and head and neck.

Basic Science

Integra serves as a scaffolding for the growth of a neodermis. Blood vessels and other cells migrate into the matrix and begin to lay down a new layer of dermis. The impermeable silicone layer serves to close the wound and prevent fluid egress.

Histology of Integration

Four distinct phases of dermal regeneration have been observed—imbibition, fibroblast migration, neovascularization, and remodeling and maturation. ⁴ Imbibition occurs within minutes and the initial take of the matrix is enhanced via fibrin in the wound exudate. Swelling of the matrix during this period is expected.

Around day seven, fibroblasts begin migration into the matrix. ⁴ In the third week, myofibroblasts arrive and begin depositing native collagen within the matrix. By week four, host collagen is dominant and replaces the matrix collagen. During this stage, the neodermis is thicker than host dermis, but through maturation, the neodermis thins and gains pliability.

By the end of week four, the neodermis is fully vascularized. This can be appreciated clinically by the color progression from pink to pale yellow to peach. Other groups have found vascularization to be complete after two weeks; however, these studies were in patients with acute burns and the earlier vascularization may be attributed to increased metabolism and systemic inflammatory response. ⁵ It is important to note that once the neodermis has formed, no adnexa, nerve endings, or elastic fibers will be present. After the neodermis is fully vascularized, it is ready to receive a graft. Once the graft is placed, the dermal–epidermal junction will develop rete ridges.

Primer on Product Use

Preparation of Product

The product is prepared in sterile basin with 1 L of sterile saline. Integra is packaged between two polyethylene sheets which must be peeled away from one another. The matrix should be washed for 2 minutes and kept in the basin until it is needed.

Wound Bed Requirements

The wound bed should be meticulously prepared in order for Integra to take. All nonviable tissues should be debrided. The wound bed should be clear of contamination and infection with adequate vascular supply, pristine hemostasis, and a uniform bed to facilitate complete contact of the wound bed with the matrix. Once the wound bed is debrided to punctate bleeding, hemostasis should be achieved and may be facilitated by epinephrine, pinpoint electrocautery, thrombin spray, or thrombin-soaked gauze. Fascia, fat, dermis, muscle, and bone will all receive Integra provided the above conditions are met.

Application of Product

To facilitate the best take of Integra, begin by applying the sheet at the wound edge. If the matrix is being placed over a joint, be sure the joint is in full extension and be mindful there is an increased chance of the Integra not taking in this area. Once the sheet has been placed on the bed, staple the Integra parallel to the wound edges and trim the excess. Alternatively, the sheet can be placed and then stapled perpendicular to the wound bed and trimmed to size. Fixation of the sheet can be achieved using either staples or sutures. If using more than one sheet, fix the sheets independently and overlap them by 2 to 3 mm.

Sheet Dressing

Dressings are most important to guarantee complete contact between the Integra matrix and the wound bed. This can be accomplished with a bolster, negative pressure wound device, or tie over dressing. An antimicrobial layer may be added using either Acticoat (Smith & Nephew), silver nitrate 0.5%, or Sulfamylon solution (Mylan Pharmaceuticals) 5%. Avoid using Dakins, petroleum-based products, or enzymatic debridement agents.

Use of Negative Pressure Wound Therapy

Negative pressure wound dressings have become a common method of bolstering Integra. It can be applied in a manner similar to its use in bolstering skin grafts and helps to improve fluid egress, decrease edema, protect from shear stress, and promote vascular in growth. They can be particularly useful in difficult anatomical areas, such as the groin or axilla.

Complications and How to Treat Them

Hematoma and Fluid Collection

A common early complication is seroma and hematoma formation. ^{6 7} If this occurs, the fluid collection should be evacuated using a 20-gauge needle. If a hematoma is not able to be evacuated with a needle, cut the Integra over the aspect with the hematoma and evacuate the clot with a sponge or tongue blade. Bleeding should then be controlled, and the matrix can be reapplied. If fluid accumulates under the matrix within the first five postoperative days, evacuate the fluid using a 20-gauge needle so as to prevent infection and formation of granulation tissue.

Infection

A common cause of loss of Integra is infection. ^{6 7} This can be reduced by ensuring the wound bed is debrided of necrotic tissue and any hematoma or fluid collection are evacuated. For local areas of infected Integra, aspirate the purulent drainage and treat with topical antibiotics while irrigating five times daily. Cultures should guide antibiotic therapy. If these steps do not work and the Integra begins to “float,” remove the area in question and do not replace Integra until the infection has been treated adequately.

Poor Take

Those areas which have not taken after 5 days should be addressed to ensure viability of the rest of the Integra. Areas of poor take are characterized by “poor color and lack of adherence.” If the area is under 2 cm ² , do not remove but rather ensure it is not infected. If the area is greater than 2 cm ² , remove the sheet and replace with either a new sheet of Integra or a STSG. However, caution is advised in this assessment as color change does occur during the process of inosculation and neovascularization.

Premature Silicone Separation

If the silicone separates from the neodermis, determine the cause of separation and address it. If the neodermis shows good take, cover the neodermis with an allograft, xenograft, or epidermal autograft.

Timing of Grafting

Within one to two weeks, the neodermis will have formed. After 3 weeks, the silicone is ready for removal and the neodermis can receive a graft. To remove the silicone, first remove the sutures and/or staples holding it in place. With forceps and a spatula or other blunt instrument, lift the silicone starting from the edge and gently peel back. If met with resistance, the neodermis is likely not fully formed and not ready to receive a graft. This can be re-evaluated in one week's time.

Once the silicone has been removed, the neodermis should then be prepared to receive a graft. Excessive granulation tissue in the bed should be gently removed with the back of a forceps. Bleeding can be controlled with epinephrine soaked gauze pads. A split thickness skin graft (STSG) can then be harvested in standard fashion as thin as 0.006 inches. As these grafts are thinner than conventional STSG, care must be taken in positioning it. It can be floated into position with saline. Once secured, the STSG should be dressed in standard fashion with a bolster.

Clinical Uses

FDA Approval

In 1996, Integra was approved by the Federal Drug Administration (FDA) for use in patients with extensive burns with insufficient donor tissue for coverage. In 2002, Integra was approved for use in reconstruction of burn scars. In 2016, Integra was approved for use in certain diabetic foot ulcers that last for longer than six weeks and do not involve exposure of the joint capsule, tendon or bone. This must be used in conjunction with optimal diabetic foot ulcer care. ⁸

Alternative Uses

Despite its FDA approval for burns and diabetic foot ulcers, Integra has found increasing use all over the body for coverage of wounds that are not amenable to direct skin grafting. ^{6 7 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24}

Extremities

Integra use has been increasingly studied for upper and lower extremity wounds where coverage of bone, tendons, and joints is a common problem. ^{9 10 11 12 13 14 15 16} Wounds previously thought to have an insufficient vascular bed for grafting, and therefore in need of flap coverage, have been shown to have reliably successful outcomes with Integra. Vascularized paratenon or periosteum are classically considered a prerequisite for successful skin grafting, however Integra has been shown to help overcome this limitation. Shores et al prospectively examined 42 patients with upper and lower extremity wounds with exposed tendon without paratenon, with an average wound size of 65 cm ² . They found 92.5% successful coverage and active range of motion of 91.2% when compared with the uninjured side. ¹⁴ On smaller wounds in the hands, Reynolds et al looked at the use of Integra in hand wounds from nonburn trauma and cancer resection and found excellent results with 97% success over wounds, an average of 19 cm ² . ¹⁵ They also noted additional benefits, including in office placement of initial Integra under local anesthesia for clean wounds. In the digits, Taras et al have further utilized Integra to cover wounds with exposed bone, joint surfaces, and even hardware, with 95% success. ¹⁶ However, this was an observational study and it is difficult to know which wounds may have gone on to heal secondarily without intervention. The authors do note that they only applied Integra in situations they did not feel would be amenable to dressing changes and or skin grafting alone. Nevertheless, in the extremities many of the classic teachings on the limitations of covering poorly vascularized surfaces have been tested, and Integra has been shown to be successful in multiple studies, particularly for smaller wounds of the hands. Figs. 1 2 to 3 show a case of Integra use over small volar digital wounds over exposed tendon, highlighting the expected appearance prior to grafting.

Fig. 1.

Left hand after Integra placement over index and long finger wounds over exposed tendon. Initial appearance after removal of silicone sheet after 3 weeks with an oversewn foam bolster.

Fig. 2.

Left hand after Integra placement over index and long finger wounds over exposed tendon without paratenon. Appearance after superficial debridement in preparation for skin grafting.

Fig. 3.

Left hand after Integra placement over index and long finger wounds over exposed tendon without paratenon. Appearance after placement of split thickness skin graft.

Trunk

On the trunk, Integra has found applications for large wounds where thicker durable coverage is desired but thin autografts are necessary for large areas, similar to the treatment of burns. ^{17 18 19} These types of wounds have been frequently described in case studies in patients with giant congenital melanocytic nevi (GCMN). ^{17 18} While tissue expansion is the usual initial consideration, the complications and time required for multiple procedures has spurred interest in Integra for use over large truncal defects. Su et al report a case of a 1,932 cm ² GCMN spanning the entire back of a 23-year-old male. In this case, reconstruction with Integra was noted to provide good neodermis formation with adequate elastic response to pinch and shear stress allowing full range of motion. ¹⁸ In other cases, Integra has been described for large keloids not amenable to primary closure. The use of Integra allows for the excision of diseased dermis, predisposed to keloid formation, and facilitates neodermal reconstruction with regenerative rather than inflammatory healing. Moreover, the use of Integra allows for ultrathin skin graft harvesting, which helps prevent the formation of keloids at the donor site. ^{19 20 21}

Head and neck

The most widely studied role for Integra in the head and neck has been for coverage of full-thickness scalp wounds. ^{22 23 24} In a review of 34 studies, 32 showed success rates > 90%, with wounds described as large at 610 cm ² . ²³ Within these studies, the use of burring the outer table was frequently described to improve graft vascularization over denuded calvarium. While preoperative radiation was not considered a strict contraindication, graft take was expectedly noted to be less reliable over previously irradiated wound beds with an increased incidence of postoperative breakdown. However, when placed and allowed to heal prior to radiation, Integra based reconstruction was noted to be tolerant of postoperative radiation with good durability. In a comparative cost analysis of patients with full-thickness scalp defects with exposed denuded calvarium treated with Integra or flap reconstruction, the overall hospital costs were found to have no significant difference, with Integra-based reconstruction being more cost effective in cases of wounds > 100 cm ² . ²⁴

In other areas of head and neck reconstruction, Integra has been described in case reports to augment local and free flap reconstruction after tumor excision. Patel et al describe its use for the lining of an orbital exenteration defect. The primary benefits of Integra were noted to be quick recovery and progression to radiation therapy, as well as improved tumor surveillance. ²⁵ Gravvanis et al have also utilized Integra for intra-oral lining with permanent durable coverage. In this case, Integra was used to line the intra-oral defect of the floor of the mouth over the neomandible, after free-fibular reconstruction. The Integra was noted to have 100% take at removal of the silicone layer at 2 weeks, with subsequent spontaneous mucosalization that was sufficiently robust to support dental implants. ²⁶

Antibiotic Delivery Device

An augmentation to these uses of Integra, utilized by the senior author (ER), is the addition of focused antibiotic delivery at the time of Integra placement called the “Gottlieb technique.” Proper surgical debridement must be performed, and this is not a method for treating gross infection but can help to clear bacterial or fungal contamination. After adequate debridement the Integra is removed from its packaging and the underside of the Integra is patted dry. The antibiotic therapy is then applied to the underside of the Integra as seen in Figs. 4 and 5 . The antibiotics can be tailored to prior cultures. If the antibiotic is in powder form, then this can be dissolved in a few milliliters of saline to create a concentrated slurry. Typical antibiotic mixtures include 1 g of vancomycin with 240 mg gentamicin. In the setting of fungal contamination, 50 mg of amphotericin can be used. In our experience this has not led to issues with the integration of Integra and has enabled wound coverage with antibiotic delivery in patients who were not flap candidates.

Fig. 4.

Application of amphotericin slurry to underside of Integra prior to placement.

Fig. 5.

Placement of Integra with amphotericin slurry on the dorsum of the foot after debridement of invasive fungal infection.

Conclusion

Integra is being more widely used within reconstructive surgery as it slowly finds its place within an expanding number of clinical applications. In no way do these newer technologies suggest that the surgeon jettison clinical judgment and trusted surgical practice. Free, local, and regional flaps remain vital for the coverage of exposed structures, and yet, dermal regeneration templates have added a new rung to the reconstructive ladder and can provide an intermediary between grafting and flap coverage. As studies increasingly reveal the capability of dermal regeneration templates for coverage of wounds previously requiring larger complex operations, the modern plastic surgeon must be familiar with these products and be able to consider their use to minimize surgical and donor site morbidity when indicated. Integra has paved the way with dermal regeneration templates and has proven to be a versatile instrument in the plastic surgeons' armamentarium.