Introduction
Product Description
Indications for Use
Scientific Abstracts
Clinical Studies

Introduction
The first and only FDA approved tissue engineered product for burn and reconstructive surgery

An inspired new approach to dermal regeneration

• INTEGRA® Dermal Regeneration Template is an innovative bilayer matrix that provides a scaffold for dermal regeneration
• INTEGRA® Dermal Regeneration Template is a biodegradable template that induces organized regeneration of dermal tissue by the body
• INTEGRA® Dermal Regeneration Template provides immediate wound closure
  
  

Increases wound management options

• An alternative to allograft or standard STG autograft
• Minimal donor site morbidity
• Able to reserve available donor sites for sheet grafts
  
  

The only approved skin substitute that regenerates dermis

• Allows early wound excision
• Immediate closure of the wound
• Controls fluid loss
• The patient is physiologically improved, allowing for early ambulation and rehabilitation
  
  

Proven in extensive clinical trials*

• The safety and effectiveness of INTEGRA® Dermal Regeneration Template were evaluated in 444 patients in four clinical trials with the following results:
  • No scar formation appeared in the histological specimens in the pivotal trial¹
  • The median take of INTEGRA® Dermal Regeneration Template was comparable to conventional autograft²
  • The median take of INTEGRA® Dermal Regeneration Template was 95% overall in the anatomic site study³
  • Epidermal autograft had successful take in 90.5% of the sites²
  • No reports of rejection of INTEGRA® Dermal Regeneration Template⁴

Worldwide experience

• Almost 1,000 patients treated with INTEGRA® Dermal Regeneration Template
• Regulatory approval in over 30 countries, with approval in additional countries pending
• CE Mark certification in Europe awarded in March 1998
  
  

Experts discuss INTEGRA® Dermal Regeneration Template
"In our burn center, INTEGRA® Dermal Regeneration Template has replaced allograft in major burns and has produced long-term results as good as sheet autografts, using very thin meshed autografts from donor sites which heal within a week. Hypertrophic scarring doesn't occur with successful application of INTEGRA® Dermal Regeneration Template."
- David Heimbach, MD, Director
University of Washington Burn Center Harborview Medical Center
Seattle, Washington

"Think donor sites. The ultra-thin epidermal autograft allows the donor site to heal in five or six days. Dermal tissue is not needed in the epidermal autograft and is in fact, undesirable and should be minimized."
- Arnold Luterman, MD, Director University of South Alabama Mobile, Alabama

References
1. Stern R. McPherson M, Longaker,MT. Histologic study of artificial skin used in the treatment of full thickness thermal injury. J Burn Rehabil. 1990; 11:7-13
2. Heimbach D, Luteman A, Burke JF, et al. Artificial dermis for major burns: a multi-center randomized clinical trial. Ann Surg 1988; S208:313-320
3. Data on file, Integra LifeSciences Corporation
4. Michaeli D, McPherson M. Immunlogic study of artificial skin used in the treatment of thermal injuries. J Burn Care Rehabil. 1990;11:21-26.

Product Description: Back to top
INTEGRA® Dermal Regeneration Template is a bilayer membrane system for skin replacement. The dermal replacement layer is made of a porous matrix of fibers of cross-linked bovine tendon collagen and a glycosaminoglycan (chondroitin-6-sulfate) that is manufactured with a controlled porosity and defined degradation rate. The temporary epidermal substitute layer is made of synthetic polysiloxane polymer (silicone) and functions to control moisture loss from the wound. The collagen dermal replacement layer serves as a matrix for the infiltration of fibroblasts, macrophages, lymphocytes, and capillaries derived from the wound bed. As healing progresses an endogenous collagen matrix is deposited by fibroblasts; simultaneously, the dermal layer of INTEGRA® Dermal Regeneration Template is degraded. Upon adequate vascularization of the dermal layer and availability of donor autograft tissue, the temporary silicone layer is removed and a thin, meshed layer of epidermal autograft is placed over the "neodermis." Cells from the epidermal autograft grow and form a confluent stratum corneum, thereby closing the wound reconstituting a functional dermis and epidermis.

INTEGRA® Dermal Regeneration Template Function
INTEGRA® Dermal Regeneration Template is a skin replacement system for the treatment of deep partial-thickness or full-thickness thermal injury to the skin. INTEGRA® Dermal Regeneration Template is applied following excision of the burn wound to viable tissue. It serves two critical functions:

• It is available without delay and functionally closes the excised wounds immediately without the need to create donor site wounds. Following application, it functions as an "artificial skin" that provides immediate postexcisional wound homeostasis, facilitating patient recovery and relieving metabolic stress.
• It serves as a template to generate "neodermis," a dermal-like tissue that readily accepts very thin epidermal autografts. Formation of the neodermis typically takes 14-21 days. After the neodermis is formed, the silicone layer is easily removed and a very thin meshed and widely spread epidermal autograft can be applied over the neodermis. These thin epidermal autografts result in less donor site morbidity than conventional split-thickness autografts. The cosmetic results are excellent, exceeding the results for conventional meshed autograft. Since the epidermal autograft can be applied immediately after the neodermis has formed (usually 14-21 days after application), the application of the epidermal autograft can also be scheduled at a time when sufficient donor sites are available and/or the patient's condition is suitable for the grafting procedure. In a multicenter clinical trial, INTEGRA® Dermal Regeneration Template remained in place successfully for up to 73 days prior to epidermal autografting.

The neodermis tissue formed by INTEGRA® Dermal Regeneration Template is distinct from granulation tissue, which is not a desirable bed for epidermal autografts. Granulation tissue, which may form at joints between INTEGRA® Dermal Regeneration Template sheets or in areas affected by infection or other problems will typically have a deep red, granular appearance and bleeds easily. In contrast, the neodermis that is visible under the silicone layer, or that is exposed after removal of the silicone layer, is typically yellow to orange in color with patches of light red. After final healing of the wound, the neodermis tissue histologically and functionally is similar to normal dermis.


Indications for Use Back to top
INTEGRA® Dermal Regeneration Template is indicated for the postexcisional treatment of life-threatening full-thickness or deep partial-thickness thermal injuries where sufficient autograft is not available at the time of excision or not desirable due to the physiological condition of the patient.
Examples of situations where the use of conventional autograft may not be desirable are:

• Elderly patients where sparing of the donor sites is desirable due to the thinness and friability of the skin, and/or because creating new wounds may cause undue stress on the patient;
• Infants where the skin is also thin and where there may be limited areas to harvest grafts; and
• Any other patient populations in which there are multi-system injuries or there would be significant added stress to the patient from creating additional donor site wounds.
  
  

INTEGRA® Dermal Regeneration Template is also indicated for the repair of scar contractures when other therapies have failed or when donor sites for repair are not sufficient or desirable due to the physiological condition of the patient.

Scientific Abstracts Back to top

Histological Study of INTEGRA® Dermal Regeneration Template Used in Thermal Injury
R. Stern et. al, Journal of Burn Care & Rehabilitation, Vo. II, No. 1, January, February, 1990.

This section is based on a report on the INTEGRA® Dermal Regeneration Template Multicenter Clinical Trial by Robert Stern, MD, From the Department of Pathology, School of Medicine, University of California, San Francisco, CA, Michael McPherson, PharmD, Marion Laboratories, Inc., Marion Park Drive, Kansas City, MO, and Michael T. Longaker, MD, Department of Surgery, School of Medicine, University of California, San Francisco, CA.

Abstract
An artificial skin has been devised (INTEGRA® Dermal Regeneration Template) which is an effective treatment for third-degree burns. When extensive body surface is involved in burn injury, such skin substitutes may become the treatment of choice. The INTEGRA® Dermal Regeneration Template consists of a dermal substitute developed through the co-precipitation and lyophilization of bovine collagen and chondroitin-6-sulfate and an epidermal layer of synthetic, polysiloxane polymer. After a specified period following application, usually 7-14 days, the artificial epidermis is removed, and an ultrathin epidermal autograft (.003 - .005 inches thick) is placed on the burn area. Serial biopsies were obtained from 131 patients participating in this multicenter clinical trial ranging from seven days to two years after application of the artificial skin. A histologic study of the stages of wound healing in the burn areas is presented here. Six sequential phases of repair were discerned using conventional hematoxylin and eosin staining and light microscopy. In addition to the six phases, there were occasional, unusual histologic features. There was eosinophilic infiltration or macrophage-derived giant cell formation in the wound area; however, such findings did not correlate clinically with a negative response. Good repair was obtained with rare exceptions. An intact dermis was achieved with regrowth of apparently normal reticular and papillary dermis. Definitive closure of a complete epidermal layer was obtained with a minimum of scarring. Even though epidermal autografts were applied, there was no reformation of rete pegs even two years after application.

Clinical Studies Back to top

Multicenter Safety and Efficacy Clinical Trial (Pivotal Study)
In the pivotal multicenter clinical trial, 149 patients were evaluated for safety and 106 patients (with 136 comparative wound sites) were included in an assessment of efficacy. The demographic profile was: mean age 32.0, age range <1 to 88 years, gender: 112 males and 37 females and a mean %TBSA burn of 45.7% with a range of 14.5%-88.5%. Take, which was defined as the median fractional area of the wound site to support epidermal growth, was the main efficacy variable and was bimodally distributed. In the multicenter trial, INTEGRA template had successful take (take >10%) in 69% of the wound sites (94 of 136). For this group of wound sites with successful take, the mean take was 81%, and the median take was 90%. Over 80% of the wound sites in this successful take group had greater than 60% take. INTEGRA template failed to take (take ?10%) in 31% of the wound sites (42 of 136 comparative wound sites). For this group, the mean take was 1.7% and the median take was 0%.

The INTEGRA template neodermis provided a viable surface for the successful transplantation of thin, meshed and spread epidermal autograft. The take of epidermal autograft was bimodally distributed. In the multicenter trial, epidermal autograft had successful take (take >10%) in 90.5% of the sites (95 of 105 comparative wound sites). For this group of wound sites with successful take, the mean was 84% and the median take was 90%. Over 80% of the wound sites in this successful take group had greater than 65% take. Epidermal autograft failed to take (take <10%) in 9.5% of the sites (10 of 105 comparative wound sites). For this group, the mean take was 1.7% take and the median take was 0%.

No significant difference was seen between the total time for burn healing for wounds treated with INTEGRA template and for wounds treated with temporary wound covers. The healing time of thin epidermal autograft on the INTEGRA template neodermis was comparable to that of conventional autograft. Donor sites for thin epidermal autograft healed faster and allowed for more cycles of reharvesting than conventional donor sites.

Histological Evaluation
Three hundred thirty-six serial biopsies were obtained from 131 patients participating in the multicenter clinical trial ranging from 7 days to 2 years after application of INTEGRA template. A histological study of the wound healing in the burned areas was conducted. An intact dermis was achieved with regrowth of apparently normal reticular and papillary dermis. No scar formation appeared in the biopsies of patients examined.

Anatomic Site Study
In the noncomparative single-center anatomic site study, 59 patients (130 wound sites) were evaluated for safety and 41 patients (104 wound sites) were evaluated for efficacy parameters. The demographic profile was: mean age, 49.2, age range 19-93 years, gender: 33 males and 26 females and a mean %TBSA burn of 49.8% with a range of 1%-97%. The mean take of INTEGRA template was 77.6%, and the median take was 95%. The mean take of the epidermal autograft was 77.8% and the median take was 85%. Median take was similar for the various anatomic locations evaluated. However, the small number of patients and noncomparative nature of the study prevented conclusions from being made.

Meshed vs. Sheet Study
A pilot study was conducted on 20 patients (59 wound sites) to compare 2:1 meshed (but not expanded) and sheet INTEGRA template. The demographic profile was: mean age, 30.1, age range 4-59 years, gender: 16 males and 4 females and a mean TBSA of 53.6% with a range of 30-90%. The mean take of INTEGRA template in this study was 80.6% and the median take was 100%, while the mean take for the epidermal autograft was 86.5% and the median take was 95%. However, due to the small number of patients and study design, statistical conclusions could not be drawn.

Postapproval Study
A Postapproval Study of INTEGRA template evaluated the safety and effectiveness in 216 patients, 841 wound sites. There were 222 patients enrolled in the study, however 6 patients did not meet entry criteria (3 did not sign the patient informed consent form, 3 did not receive INTEGRA template) resulting in 216 patients entered into the study. The demographic profile was: mean age 34.7, age range 4 months to 87 years, gender: 151 males and 65 females and a mean %TBSA burn of 36.5% with a range of <1% to 95%. Effectiveness was measured by graft take. Overall mean percent take for INTEGRA template was 76.2% and the median percent take for INTEGRA template was 98%. The mean take of epidermal autograft was 87.4% with median take of 95%. The rate of infection in the study patients was 16.3% (13.2% superficial and 3.1% invasive). Patient mortality was 13.9%. Data analysis indicated that mortality was related to patient age, percent total body surface area burned, presence of inhalation injury, and presence of infection at a non-INTEGRA template treated wound site. Invasive infection at an INTEGRA template wound site was not a significant risk factor for mortality.

SUMMARY OF CLINICAL STUDIES
Contracture Reconstruction

Patients Reconstructive Surgery Study
This study evaluated the clinical and histologic outcomes in 20 consecutive patients (30 anatomic sites) whose scars and contractures were treated with INTEGRA template. Patients' mean age was 27.6 years, with an age range of 4-54 years. Patient follow-up ranged from 3 to 24 months. The mean take was derived from the adverse event data and was calculated to be 94.2% for INTEGRA template and 86.3% for epidermal autograft. Efficacy was evaluated using the Vancouver Burn Scar Assessment scale by an independent review panel, a visual analog scale of patient satisfaction and histological evaluations of patient biopsies.
The Vancouver Burn Scar Assessment scale ranges from 0 (normal) to 15. The mean preoperative Vancouver Burn Scar Assessment was 13.3 and the mean postoperative score was 9.0. For the patient satisfaction assessments, patients or their parents completed a questionnaire at least 3 months after the second stage of the reconstruction. A visual analog scale was used in which a score of 0%=preoperative scar and a score of 100%=normal skin with no scar. Patients/parents reported mean scores of 72% for range of movement, 62% for softness, 59% for appearance, 27% for pruritis and 14% for dryness.

Retrospective Contracture Reconstruction Survey
This survey requested information from physicians already using INTEGRA template on the use of the product for contracture reconstruction. Information was received from 13 of 19 physicians surveyed who reported on 89 patients and 127 anatomic sites. The demographic profile for the reported patients were: mean age 24.8, age range <1 to 72, gender 52 males and 37 females. The safety results of this survey are provided in tabular form in the adverse event section.

Part Number: 32021, 32025, 34051, 34055, 34101, 34105, 38101, 38105

For more information, please contact Integra Customer Service at 877-444-1122 or 609-275-9004.