Successful Management and Surgical Closure of
Chronic and Pathological Wounds Using Integra®
Marc E. Gottlieb, MD, FACS
Jennifer Furman, BS
Arimedica version, 2005.
published in Journal of Burns and Wounds, Vol 03, #02, 2004.
Copyright © 2004, 2005, Marc E. Gottlieb, MD
Content may be used for non-commercial educational purposes.
Content may not be republished, nor used for commercial purposes without prior license or permission., except as permitted as “fair use” under United States copyright laws.
Marc E. Gottlieb, MD, FACS
Integra Dermal Regeneration Template® is a bilaminate material, a collagen-chondroitin sponge overlayered with silicone. It serves as a high quality artificial skin and as a matrix for dermatogenesis. Developed for burns, it has since been used for many acute illnesses and reconstructive purposes. It is also ideally suited to chronic and pathological wounds. It survives adverse conditions where grafts would die. In performs the essential coverage duties of flaps without donor sites. It heals wounds and salvages extremities where conventional methods of repair fail or are too risky. This study analyzes Integra’s use for chronic and pathological wounds in 111 patients. Results are stratified by underlying diagnosis and anatomical location. Major outcomes were: 71% of patients completely healed by Integra; 20% of patients almost completely healed by Integra, with small residual wounds closed by secondary procedures (14%) or left open for chronic wound care (6%); 9% of patients unhealed or amputated, usually attributable to disease. Extreme arterial insufficiency and diabetic plantar ulcers were the two prominent profiles of failure. Excluding those patients as poorly selected, 92% of patients healed completely by Integra alone or with small subsidiary flaps. Of 166 instances of exposed internal structures that are ordinarily closed with flaps, Integra closed 90 % of them. Lengths of treatment, from time of Integra until completely healed, averaged 7 months across all diagnoses, a relatively short interval by the standards of managing refractory pathological wounds. These intervals were acceptable to patients because the care was successful and because it was nearly all outpatient. Integra is a superior method of closing select chronic wounds. Study data and conclusions are supplemented by: a review of Integra histogenesis, illustrating the biological reasons for Integra’s properties and performance; a set of case studies which illustrate the indications and use of Integra; a discussion of indications and how-to details.
Integra Dermal Regeneration Template® (manufactured by Integra Life Sciences, Plainsboro, New Jersey; marketed by Ethicon, Somerville, New Jersey, USA) is a spongy material made of collagen and chondroitin, manufactured as thin sheets overlayered with silicone rubber. It has two interrelated modes of use, first as an effective acute skin substitute, and then as a matrix for autogenous skin regeneration. It is used by applying the artificial skin to a prepared wound. Cells invade the matrix and gradually generate a lamina of dermis-like tissue. The process is observable through the silicone “epidermis”, and when it is complete (typically 3-5 weeks), the silicone is peeled off and thin skin autografts are placed to restore epithelium.
Integra’s chemical composition, material structure, biological properties, and clinical methods are mostly unique among current wound and surgical products. Applied to acute wounds, Integra controls inflammation and physiological reactions to injury, it protects the wound and preserves tissue, it minimizes symptoms and nursing requirements, and it fosters a rapid return to activity and rehabilitation. The regenerated tissue is also comparable to real dermis and is distinct from scar. While originally developed for burns 1 - 7, it’s properties make it useful for a variety of acute wounds (degloving, fasciitis, excisional defects) and for skin reconstruction (controlling keloids, correcting contractures). Integra can also be used to close pathological wounds and chronic ulcers. It’s advantageous properties make it not only effective for this task, but oftentimes superior to conventional surgical methods (repair, flaps, grafts), and sometimes the only permissible option. The relevant biological properties of Integra, the rationale for its use on chronic and pathological wounds, and its results in 111 chronic wound patients are presented here.
The data are a retrospective analysis of 111 patients in whom Integra was used to close or manage chronic and pathological wounds of months or years duration. All patients were cared for in the six years June 1996 to June 2002, representing the entire interval between Integra’s approval by the United States Food and Drug Administration and the collation of this data (latter patients whose staged reconstruction straddles the termination date were excluded). All patients were cared for and operated on by the primary author. Their management followed the scheme of care applied in principle to all wounds: Phase 1, preliminary essential care included evaluation and diagnosis, establishment of good hygiene, control of injury, inflammation, and edema, and correction of underlying disease and risks (e.g. control of rheumatoid inflammation, revascularization across occlusive atheromas, pressure offloading by orthotics). Phase 2, subsequent discretionary care to close or otherwise resolve the wound, with surgical closure by Integra opted based on criteria discussed below. Phase 3, long term maintenance care to keep underlying illnesses controlled and to prevent future ulceration. Care was administered in customary venues, office or clinic, home with home nursing services, hospitals, and outpatient surgical centers, with nearly all care being outpatient. Integra was used exclusively in the operating room, using standard methods of wound preparation and Integra application (detailed in the Discussion). Post-operative wound and graft care continued until the reconstruction was healed or until alternate methods of closure superceded the original plan. Data were analyzed by reviewing available records from the venues of care (office, hospital, outpatient wound clinic). Telephone calls to patients were made to verify long term outcomes.
During the 72 month study interval, Integra was used in 132 patients. Acute uses of Integra (19 patients) are not included in this study, and 2 chronic wound patients with missing records were excluded. The other 111 patients with chronic wounds are the subjects of this study. Integra was the method of wound closure in 107 patients having 158 documented individual ulcers. In the other 4 patients, Integra was used as an adjunct to chronic wound surgery, mainly for closing donor sites when flaps were used for primary closure. Data and results are presented in four groups. The first three are numerical data presented in tabular form. Detailed explanations of all tables accompany them in the table legends.
Data set 1. The first set of data profiles the patients, diseases, and wounds. It documents the types of problems for which Integra is suited. Table 1 presents patient demographics and diagnoses. Tables 2a - 2d profile the wounds by their history (duration, prior failed procedures) and by their anatomy (location, exposure of structures). Because the underlying causes of chronic wounds have substantially different implications for age distribution, ancillary treatment, and complications and outcomes, patient and ulcer data are stratified by diagnostic category.
Data set 2. The second set of data documents outcomes or success rates. Tables 3a – 3d detail outcomes by type of outcome, diagnosis, anatomical site, and closure of exposed internal structures. All 111 patients are included in the descriptive data of tables 1 and 2. The results in tables 3 exclude 8 of these patients who either died before the reconstruction was complete or for whom late status or outcomes were not verifiable.
Data set 3. The third data set assesses management, logistical, and economic aspects of Integra. Table 4 studies duration of care. Direct costs of care were not tabulated, but economic impact was estimated in Table 5 by analyzing venues of care, inpatient versus outpatient.
Set 4. The fourth group is neither analytical nor descriptive data, but rather a selection of case studies meant to illuminate Integra’s properties and its place in the schema of caring for chronic and pathological wounds. These cases were selected based upon the wide spectrum of issues that they illustrate and the availability of a suitable (but often incomplete) set of photographs.
General results. Integra was successful in closing the wounds in 71% of patients. In 20%, Integra contributed to a successful outcome, supplemented by other operations. Integra failed to close the wound or resolve the clinical problem in 9% of patients. Failures were largely on the lower extremity in association with severe arterial insufficiency and a few other problematic diagnoses. Integra successfully closed and healed 90% of the exposed bones, joints, tendons, and other structures to which it was applied. For chronic ulcers, inpatient services were nearly eliminated.
Table 1. Diagnoses and Patients
Table 1. This table profiles the patients and the underlying diseases and risk factors causing their chronic ulcers. The causes are organized into generalized categories. Many patients had multiple risk factors, such as: some rheumatoid patients also had atherosclerotic arterial insufficiency, some venous patients had a hypercoagulable disorder responsible for their original venous thrombosis, and “diabetic ulcers” were a syndrome of risks related to biomechanics and arterial insufficiency. In all patients, each underlying risk or diagnosis was managed as required, but for nearly all, one diagnosis predominated as the most immediate or problematic factor. All 111 patients are stratified accordingly under “primary diagnosis.” The diagnostic categories are ranked in order of incidence. Sex and age distributions are given for each of these diagnostic categories. “Secondary diagnosis” lists the number of additional patients for whom that diagnosis was a subsidiary risk. “Specific diagnoses” list the individual disorders or circumstances that occurred in each group.
Table 2a. Ulcer History, duration and prior surgery
Table 2a. This table profiles the ulcers and their history, specifically duration and incidence of prior failed surgery. The absolute number of ulcers is ignored, considering each patient to have a single ulcerative condition. Data are again stratified by diagnostic category (underlying disease). Duration, presented as range and mean, is subdivided by whether the ulcers are relatively young or old, less than 2 years duration (listed in months, italics) or greater than 2 years (listed in years). Note that for each diagnosis, that patient numbers in the younger-older subgroups do not necessarily sum to the total patients (e.g. 27 arterial patients, but only 9 and 1 patients are in the <2 and >2 year groups), and that some cells are empty. This is because duration of the ulcers and other retrospective data were not complete for all patients, and only verifiable data was used to complete the table. However, since missing data was presumably a random event, the available data does reasonably reflect the longevity of the ulcers for the whole group. Standard deviations of the means are considered irrelevant for the brief durations of the short-group, and undefined for the small numbers of the long-group, but they are presented for the long term venous patients and for the groups as a whole to give a measure of the spread of the data within these groups. The incidence of failed prior procedures is listed as number of patients who had them (not as the actual number of procedures). The true incidence of prior procedures was higher than listed, but analysis was limited to verifiable information in the available medical records.
Table 2b. Ulcer Anatomy, site and complications
Table 2b. This table profiles the anatomy of the ulcers, their site and complications. Data are again stratified by primary diagnosis. Unlike the previous tables which analyzed the 111 patients, this table focuses on the 166 ulcers that were managed with Integra in those 111 patients. These 166 ulcers are partitioned by major anatomical region. “Anatomical complications” refer to exposure of internal structures, including bones, joints, tendons, and internal organs, their incidence listed as number of patients who had these conditions (rather than the number of individual anatomical structures exposed). The incidence of exposed structures was higher than listed, but analysis was limited to verifiable information in the available medical records.
Table 2c. Ulcer Anatomy, detailed
Table 2c. This table shows more detailed information about the location of the ulcers. All of the 166 documented ulcers, “instances”, are partitioned by anatomical location. Note that the sum of “number of patients” having ulcers at a given location is undefined, exceeding the 111 study patients because some had ulcers at multiple locations.
Table 2d. Ulcer Complications, detailed
Table 2d. This is a more detailed profile of the exposed internal structures (in 78 patients) that were covered by Integra. The posted data are again limited to only those exposed structures explicitly documented in operative and clinic records. Exposed bone is partitioned by whether only cortical bone was covered, or if debridement or ostectomy had exposed cancellous bone. “Open joint” refers explicitly to joints in which there was an arthrotomy with loss of joint capsule and synovium and exposure of the joint space. Major / minor tendons are classed based on physical size or functional significance. Grouped tendons such as the finger and toe extensors are counted only once for each instance, even though multiple individual tendons might have been exposed. Many of the treated wounds had additional undocumented exposure of minor tendons. Integra also covered many joint and retinacular ligaments, structures which also might ordinarily be closed by flaps, but the incidence of these situations was undocumented in the available records. Many pieces of Integra were applied directly to large areas of muscle, but because of the dependably good results, there was no special attention to this condition, neither clinical nor analytical, and instances and results are not tabulated. Coverage of viscera and hardware are presented in the case studies. The 173 instances of exposure occurred in 111 individual ulcers ( 67% of all ulcers) in 78 patients (71% of all patients), reflecting the severity or complexity of most of these problems.
Table 3a. Outcomes, by outcome category and complications
Table 3a. Patient survival and available data permit outcome analysis in 103 of the 111 patients. Outcomes are divided into three general groups. Group 1 are those patients in whom Integra resolved the chronic ulcer, subdivided into 4 scenarios. Group1a is the nominal uncomplicated Integra reconstruction (excise the wound, place Integra, place skin grafts when regenerated, healed). As with any skin graft, a few weeks of topical care may be required for complete healing, but in some patients, group 1b, persistent open areas after the epidermal overgrafts required more than 8 weeks of care, usually with additional topical modalities such as PDGF (platelet derived growth factor) to coax complete reepithelialization of the regenerated Integra. In group 1c, incomplete skin graft take and reepithelialization prompted a second skin graft over the original Integra in order to complete the reconstruction. In group 1d, Integra reconstruction was successful but incomplete, and residual open areas or areas of lost Integra were successfully closed with a second application of Integra (and subsequent skin grafts).
Group 2 are those patients in whom Integra incompletely healed the wound but nevertheless contributed to a successful wound and patient outcome. Most of these patients had successful closure of part or most of the wound with Integra, but a more conventional wound closure (repair, skin grafts, flaps) was needed to finish select areas or persistent open structures (group 2a). Integra’s ability to suppress inflammation and ameliorate adverse or pathological conditions in the wound was important in three patients, leading to a stable asymptomatic non-pathological wound that could be managed or closed by other means (2b). In two patients (2c), skin grafts over Integra were unstable, leading to persistent open regenerated Integra, but the wounds and patients were still substantially improved because wound pathology and symptoms were controlled and manageable by chronic topical care.
Group 3 are the failures, including loss or failure of the Integra with a persistent wound (group 3a), persistence or progression of ulcerative wound pathology (group 3b), and failure of the reconstruction leading to amputation (group 3c, 2 above knee, 3 below knee). One infection occurred (inflammation, pain, suppuration, graft lysis, fever), but it is not formally tabulated because it occurred in one of the 8 patients with an unassessable outcome. Integra performed properly in some of the amputation patients, but they are tabulated as failures anyway because the Integra reconstruction did not contribute to an ultimate good outcome.
Table 3b. Outcomes, by diagnosis
Table 3b. In this table, the 103 outcomes in three general outcome categories are stratified by underlying diagnosis. In the incompletely healed Group 2, Integra was of greater or lesser success from one patient to another. The relative success is ranked by the approximate area, in thirds, of the original wound which was successfully closed (note that Group 2 subdivisions x, y, z are distinct from the outcome types a, b, c, d in table 3a). The predominant cause of failure was atherosclerotic arterial insufficiency.
Table 3c. Outcomes, by site
Table 3c. In this table, the 103 patient outcomes in three general outcome categories are stratified by anatomical site. Recall from table 2c that many patients had multiple ulcers. The entry “multiple” refers to patients that had ulcers at more than just one of the sites listed in the other rows (all of these combinations were on the lower extremity, e.g. leg and ankle, or leg and foot).
Table 3d. Outcomes, closure of internal structures
Table 3d. There were 173 exposed structures among all 111 study patients, of which 166 occurred in the 103 patients included in the outcomes analysis. This table lists the results of Integra applied over internal structures for those 166 instances. The number-of-patients column reflects that some patients had multiple exposed structures. Of the 166 instances of exposed structures with known outcomes, 90% were successfully closed by Integra. Ten structures (6%) were eventually closed with secondary surgery, but Integra functioned as a competent artificial skin, keeping those structures safe, thereby permitting late closure and salvage.
Table 4. Length of treatment
Table 4. This table shows the duration of treatment. “Integra-to-skin grafts” is the regeneration time in weeks, the mean times between placing Integra and placing the first set of skin grafts, precise information available for 99 patients. The intervals were counted in days, then converted to weeks for display. Since this parameter was largely controlled by the surgeon and the basic physiology of Integra, the values and distributions are relatively uniform. The exception is the malignancy category, where, as would be expected, the radiation patients caused a high end bimodal spread.
“Integra-to-healed” is the interval, in months, between placing Integra and when the wound was fully epithelialized. This information could be ascertained accurately for 70 patients. Patients in the Group 2 partial success category are also included, their interval measured by when secondary grafts or flaps were healed. Data is presented for patients, not ulcers. For patients with multiple wounds, the times for individual ulcers were averaged, and that was used as the value for each patient. Patient values were then averaged within each diagnostic category. In four groups, there was a clear outlier which was excluded from the averages (the parenthetical values under “range” are the four outliers). The total value is the direct average on all 70 patients.
Table 5. Inpatient versus Outpatient
Table 5. This table estimates the economics of using Integra by counting the number of patients who had inpatient hospitalization versus those whose care was entirely outpatient. The first data column is the number of study patients each year (because the study covers only 6 months of 1996 and 2002, the numbers in parentheses are pro rata annualizations so that the overall trend can be more easily visualized. The second column is the number of inpatients who had an inpatient admission at any time related to their Integra reconstruction, either with the primary excision and Integra or the skin grafts. “Inpatient admission” is defined as a formal hospitalization of greater than 24 hours duration subject to the legal and administrative criteria of inpatient reimbursement, and does not include overnight stays of less than 24 hours. The last column is the percentage inpatients, the ratio of the first two columns. The group inpatient rate was 36% over 6 years, but there was an important trend. The inpatient rate was a linear decline to zero (linear regression on the last column has r2 = 0.9698). The problems and severity of the patients were not obviously changed, and this decrease reflects multiple factors as described in the discussion.
Case Study 1, Outcome type 1a, nominal reconstruction, healed. A 65 year old woman with Wegener’s granulomatosis and severe related pulmonary disease developed an achilles ulcer. (Figure 1a) A period of wound care and stabilization of disease induced some “granulation tissue”, a proliferative wound module, indicative of wound healing competence. However, because of tendon shearing, this wound cannot heal easily, even in a healthy person, and with active disease, risks to wound and patient are high. (Figure 2b) In surgery, the wound was excised, and the tendon was decorticated until only healthy fibers remained. The blue lines are the design for a reverse sural nerve flap and donor site skin grafts, considered then rejected in favor of what was safest. (Figure 1c) The material is shown here regenerated and ready for skin grafts. (Figure 1d) Two months later, the tendon is healed and stable.
Figure 1 a (top left), b (top right), c (bottom left), d (bottom right)
Case Study 2, Outcome type 1b, healed after ancillary care. A 69 year old woman with severe rheumatoid arthritis developed an ankle ulcer following prosthetic knee arthroplasty. (Figure 2a) There was periwound inflammation and lytic necrosis of the margins, typical of rheumatoid and hypercoagulable ulceration. Laboratory diagnosis revealed Factor V Leiden heterozygous, low proteins C and S, and high homocysteine. Arterial ankle-brachial index was 0.93, and periwound transcutaneous oxygen pressures were 4 – 50, increasing to 200 – 330 breathing 100% O2. These studies confirm a hypercoagulable disorder without arterial macrovascular disease. (Figure 2b) It failed to improve significantly after 6 weeks of basic wound care, anti-inflammatory therapy, and warfarin. (Figure 2c) In surgery, excision of the wound and surrounding calcinosis cutis exposed muscles, ligaments, and tendons. Integra was opted for closure for reasons of disease stability and essential coverage. (Figure 2d) After placement of Integra, overt inflammation completely ceased, and the material regenerated. (Figure 2e) Two months after skin grafts, epithelialization was retarded, with only small islands of epidermis scattered over the regenerated Integra. Platelet derived growth factor was initiated, after which the skin closed. Note that even though not yet completely healed, that the regenerated Integra is a healthy tissue, without necrosis-lysis-ulceration nor periwound inflammation. (Figure 2f) One year later, the patient had a severe rheumatoid flare-up, with multifocal new foot and leg ulcers. The original left leg reconstruction remained healthy and uninvolved. Integra was used on the new ulcers, seen in the back over the right achilles.
Figure 2 a (top left), b (top right), c (middle left), d (middle right), e (bottom left), f (bottom right)
Case Study 3, Outcome type 1d, healed after second Integra. A 69 year old woman presented with a small ulcer over a varicose vein, right medial leg. Arterial circulation was normal. Failing to heal with basic care, it was excised and sutured. (Figure 3a) The sutured wound became necrotic. Active ulceration at the margins progressed in spite of good topical care. (Figure 3b) Workup for pathology revealed protein C deficiency and cryoglobulins, corroborated by histology which showed stasis, thrombosis, vascular necrosis, and only sparse inflammation, findings typical of microthrombotic ulcers. Warfarin anticoagulation was started. (Figure 3c) When the ulcer still did not improve, the wound was excised. Skin grafts and local flaps were contraindicated because they would have the same complications that caused the ulcer in the first place. Integra closed the wound and controlled pathology, with no further necrosis. (Figure 3d) By the time the Integra was ready to lose its silicone, it had not yet regenerated over the flexor digitorum longus tendon. Because the matrix can conduct tissue, the tendon will close, but it needed more time. This is not a failure, but merely the time to apply a second serial piece of Integra. (Figure 3e) Three months after skin grafts, all was healed. The contours of the tibialis posterior muscle and the flexor digitorum tendon are easily seen. (Figure 3f) Two years after that, the reconstruction remains healthy.
Figure 3 a (top left), b (top right), c (middle left), d (middle right), e (bottom left), f (bottom right)
Case Study 4, Outcome type 2a, partial success, healed after secondary flap. An 86 year old woman presented with chronic right medial ankle ulceration of several years duration, probably just venous, but complicated by exposure of major tendons and the ankle joint. (Figure 4a) After excision, Integra was used to close the wound and its various exposed structures. (Figure 4b) Integra healed the wound except for a small perforation into the tibialis posterior tendon sheath. Unepithelialized surfaces seen here would have healed within a few weeks, but the shearing tendon (its excursion marked by blue dots) requires explicit closure. (Figure 4c) The reconstruction was completed by using a small flap from the dorsum of the foot to cover the tendon. Note the normal quality of the Integra skin, soft, compliant, wrinkling and folding with ankle motion.
Figure 4, a (left), b (middle), c (right)
Case Study 5, Outcome type 2c, persistent open Integra. A 75 year old man had extensive chronic venous disease and ulceration of both legs, unresponsive to all treatments over many years. (Figure 5a) The right medial leg has the usual stigmata of severe long standing venous hypertension and chronic stasis dermatitis, with pronounced dermatosclerosis and ulceration. (Figure 5b) All pathological skin, fascias, and wounds were excised, veins were stripped, and skin was reconstructed with Integra. Seen here shortly after skin grafting, the Integra is completely regenerated. Small areas of incomplete skin graft are healthy, with prompt complete reepithelialization expected. (Figure 5c) Due to special circumstances, the patient had to return quickly to his usual work, and he was unable to continue complying with all prescribed care. Although complete closure was anticipated (especially since this was just venous disease), stasis effects recurred, and some areas never healed. Even the Integra reconstructed skin developed venous pigmentation, shown here one year later. His care has capitulated to a program of long term maintenance for the remaining open areas. While this is not an ideal result, patients are much more accepting of big improvements than their physicians are of anything not perfect. Integra was successful, because compared to what he had, he is much improved, with chronic inflammation, drainage, and pain eliminated, and daily function preserved.
Figure 5, a (left), b (middle), c (right)
Case Study 6, Diagnosis, venous. A 77 year old man with chronic venous ulceration presented after yet another failed skin graft. Most venous ulcers will heal within the traditional scope of management: good topical care and compression, followed by venous interruption, and then excision and skin grafts if needed. However, when disease is persistent, other care has failed, and there are essential coverage needs, then excision and skin reconstruction is required. (Figure 6a) Upon presentation, the right medial ankle ulcer was surrounded by extensive eczematous dermatitis and edema. Necrotic recent skin grafts were still present. (Figure 6b) After two weeks of basic hygiene, topical steroids, and compression, acute conditions were controlled. Because of the given history, healing was not expected with topical care and compression alone. (Figure 6c) Ulcer excision exposed the posterior tibial neurovascular bundle, posterior compartment muscles, and the achilles fat space. Integra was opted for closure for all of the reasons mentioned: chronicity, a history of failed care, and the presence of exposed structures and adverse biomechanics which would prevent successful skin grafting. (Figure 6d) In conjunction with continued elastic compression, the reconstruction has remained healed and healthy, seen here at one year.
Figure 6 a (top left), b (top right), c (bottom left), d (bottom right)
Case Study 7, Diagnosis, immunopathic. A 71 year old woman had an ulcer of the lateral left leg and ankle. (Figure 7a) She was treated for 4 years for “venous ulceration”, but multifocal lytic ulceration, exposure but sparing of muscles and tendons, distribution along tendon sheaths, absence of venous pigment and edema, and various musculoskeletal symptoms are all paradigm features of rheumatoid and similar immunopathic wounds. (Figure 7b) After making and confirming the diagnosis of rheumatoid arthritis, anti-inflammatory and antimetabolic treatments were started. The wound was excised and closed with Integra, including coverage of bare fibular cortex and multiple muscles and tendons. (Figure 7c) The involved area healed quickly and has remained healed ever since, seen here at 6 months. (Figure 7d) Two years later, the patient became very ill with disease flare-up. Rheumatoid panniculitis and multifocal ulceration occurred on both lower extremities, seen here on the medial side of the left leg. Topical wound care, compression and edema control, intralesional steroids, and increased systemic therapy brought the acute problems under control, but left multiple open wounds. (Figure 7e) This image is simultaneous to figure 7d. Whatever else has happened nearby, the original lateral leg reconstruction remained healthy throughout the acute flare-up. (Figure 7f) The new ulcers on the medial side of the leg did not heal after a suitable period of topical care and observation. Integra was then used, and all healed, seen here 9 months later.
Figure 7 a (top left), b (top right), c (middle left), d (middle right), e (bottom left), f (bottom right)
Case Study 8, Diagnosis, hypercoagulable. A 61 year old woman had left leg ulceration of many years duration and a history of multiple venous thrombosis, pulmonary embolism, and warfarin resistance. These are hallmark features of a hypercoagulable disorder, but long standing warfarin therapy precluded making the exact pre-thrombotic diagnosis. (Figure 8a) In spite of the history, the usual stigmata of venous disease, pigment, edema, and dermatosclerosis, were not very severe, and there was never any improvement by compression and topical care alone. This was a hypercoagulable rather than a venous ulcer, further confirmed histologically by microthrombi. Granulation tissue at the base of the wound indicated intrinsic wound healing competence, but there was chronic active dermatitis, panniculitis, and necrosis in the margins and periwound soft tissues. (Figure 8b) After a few weeks of hygiene, good topical care, compression, and increased warfarin, the wound and periwound were improved, but nevertheless, inflammation and active necrosis-ulceration persisted at the margins. (Figure 8c) In surgery, the ulcer was excised, including a tangential fibular ostectomy for hyperplastic osteophytes (common under chronic inflammatory ulcers, due to the effects of transforming or pro-proliferative growth factors which are perpetually in the wound). The wound was closed with Integra. Seen here at 6 days, periwound inflammation, erythema, and edema have completely subsided. (Figure 8d) The ulcer remained healed during a 4 year follow-up period, seen here 9 months after skin grafts.
Figure 8 a (top left), b (top right), c (bottom left), d (bottom right)
Case Study 9, Diagnosis, mechanical. A 79 year old woman presented with an ankle ulcer of several years duration. (Figure 9a) The right lateral malleolar area was inflamed with eczematous dermatitis. The wound base had granulation tissue indicative of sufficient arterial circulation and intrinsic wound healing competence. However, there was persistent active ulceration and failure of epithelial ingrowth. Workup for all of the usual culprits failed to make any diagnosis other than chronic pseudarthrosis at an old malleolar non-union directly under the ulcer. The significance of tissue mechanics and their influence on mesenchymal differentiation, repair, and pathology should never be overlooked. The cardinal signs of pseudarthrosis are inflammation and pain, and in a susceptible elderly person, it can create enough local pathology to maintain an active ulcer. (Figure 9b) The ulcer did not close with improved topical care and splints, so surgery was done. It was excised, including bone fragments and the arthrosis, and Integra was used to close the wound and the structures underneath. Seen here 11 days later, periwound inflammation is gone. (Figure c) The wound healed and has remained so, seen here a year later.
Figure 9, a (left), b (middle), c (right)
Case Study 10, Location, upper extremity. A 42 year old woman with diabetes and upper extremity atherosclerosis developed ischemic ulceration of the left long finger. Progressive necrosis and ray amputation resulted in a mid hand wound and partial necrosis of the ring finger. (Figure 10a) After a few weeks of good wound hygiene, silver sulfadiazine, and debridement, the wounds stabilized, and necrosis and further ulceration were arrested. Arterial pressure and circulation were not as bad as first thought, evidenced by the completely healed central hand. Granulation tissue attests to active wound healing and a potentially salvageable ring finger, as long as essential coverage issues over the skeletal structures can be fulfilled. The usual flaps from adjacent fingers cannot be done in this high risk arteriopathic hand. (Figure 10b) After excisional debridement, specific structures needing coverage were the web space, the proximal interphalangeal joint, and the flexor tendons and their sheath. (Figure 10c) The hand healed. Integra closed the flexor tendons, and it reconstructed a fully compliant web space free of scar and contracture. The interphalangeal joint had a persistent small ulcer which was closed with a small secondary flap from the dorsum of the joint. Joint motion is limited, but the patient eschewed therapy and is very happy to have a healed hand without having lost the ring finger.
Figure 10, a (left), b (middle), c (right)
Case Study 11, Location, trunk. A 51 year old woman, with dialysis dependent renal disease and tertiary hyperparathyroidism, developed multifocal necrosis and ulceration of the trunk. (Figure 11a) The history, pattern of involvement, and the debilitating ischemic pain were all typical of systemic calcinosis (calciphylaxis). The diagnosis is easily made by clinical features, but histology of debrided material confirms it. Medial arteriosclerosis of all small order arteries and arterioles is characteristic, often accompanied by microthrombosis. (Figures 11b,c) The patient had numerous infarcted lesions on the trunk. The right breast and right flank (lower abdomen) are shown. This condition is refractory to usual topical and surgical care. Progressive necrosis is common, and attempts to debride can cause more necrosis (pathergy). Managed by good topical care alone, many months may be required for closure. Skin grafts and customary repairs are likely to fail or cause more problems. (Figures 11d,e) All necrotic areas were excised and closed with Integra. Pain and progressive ulceration immediately ceased. All areas healed quickly, seen here 3 months after excision and Integra. This is the paradigm Integra reconstruction, complete success without delays. Integra’s ability to close and control the wound without donor sites nor risk to the patient is ideally suited to this diagnosis.
Figure 11 a (left), b (top middle), c (top right), d (bottom middle), e (bottom right)
Case Study 12, Location, leg. A 77 year old woman had a 40 year history of continuous leg ulceration and progressive systemic illness. In spite of classic symptoms of Sjögren’s disease, the diagnosis was missed countless times. When seen in consultation, the diagnosis was made, anti-inflammatory and antimetabolic treatments were started, and the patient’s general health status improved substantially. (Figures 12a,b) The leg ulcers are shown just prior to excision. Proper excision means thorough fasciectomy, removing all pathological tissues, including the fibrotic, ulcerated, and inflamed sural fascia. This means that muscles, tendons, retinacular ligaments and other structures will all be exposed when excision is complete. Skin grafts will not cover these structures, and even if they could in principle, here they would be at risk for recurrent pathological lysis and ulceration. (Figures 12c,d) The legs and ankles are shown one week after excision and Integra. Note the wrinkling in the Integra, a common occurrence due to control of inflammation and edema, thereby decreasing limb volume and surface. All care was outpatient. (Figures 12e,f) The legs healed and have stayed stable, shown here two years later. Note the bandaging imprints, attesting to the patient’s diligent efforts to control edema and care for her skin. Consistent rheumatology management has kept the patient healthy, and lifestyle has been restored. (Figure 12g) A close-up view shows the quality and texture of the regenerated material and how comparable it is to normal skin.
Figure 12 a, b (left column), c, d (middle column), e, f (right column), g (bottom)
Case Study 13, Location, foot & ankle. A 77 year old man with long standing rheumatoid arthritis developed a right lateral ankle ulcer. (Figure 13a) The wound was a typical rheumatoid lesion, characterized by multifocal lysis of skin and fascias. (Figure 13b) After a month of various care, the wound did not improve, with inflammation and marginal necrosis still active. With spontaneous improvement not expected, surgery was required. In a healthy patient, skin grafts or dependable local flaps would have been best. In this situation, challenged by active rheumatoid disease, and given the contiguity with mechanically active structures, Integra was the safest and surest option. (Figure 13c) The Integra reconstruction healed quickly, seen here after a few months. In this image, there is some contact dermatitis due to prolonged use of dressing materials after everything was healed. The Integra reconstructed skin is inherently healthy, and dermatitis cleared promptly with topical steroids.
Figure 13, a (left), b (middle), c (right)
Case Study 14, Exposed structure, bone. A 33 year old man had chronic recurrent venous ulceration of the leg following femur fracture and femoral vein injury at age 14. (Figure 14a) Surgery was opted after repetitive cycles of disease made it clear that the skin and scars were unstable and would be perpetually ulcerated in spite of care. All pathological tissues were excised, exposing inflammatory dysplasia of the tibial cortex. (Figure 14b) The tibia was planed back to architecturally normal bone. Integra was used to cover the tibia and reconstruct healthy new skin over the entire wound. (Figure 14c) At 5 months, the reconstruction is almost completely healed (it has since healed and has remained stable for 5 years).
Figure 14, a (left), b (middle), c (right)
Case Study 15, Exposed structure, joint. A 43 year old man developed multiple complications of rapidly progressive scleroderma. (Figure 15a) His hands had skin atrophy, sclerosis, and telangiectasias typical of scleroderma. There were multiple contractures and skin lesions. The largest ulcer was on the dorsum of the index finger metacarpophalangeal joint, where loss of the dorsal joint capsule caused direct wide exposure of the joint space and dorsal bone surfaces. As one of the few fingers not contracted and still functional, salvage was important for rudimentary activities. This view, in surgery, shows the open metacarpophalangeal joint and degenerated bone at the base of the phalanx. (Figure 15b) These open structures required suitable coverage. Sclerotic skin made local flaps a technical impossibility. Histology showed stenotic fibrotic arteries typical of immunopathic angiopathy, and impaired circulation made any surgery risky. Conventional options for closure, including topical care, repair, flaps, grafts, and amputation, were all too risky, doomed to fail, technically unfeasible, or too destructive of remaining function. Only Integra offered a safe, dependable, sensible solution. (Figure 15c) Integra healed the open bones and joint and preserved a functioning finger, shown here at 6 months. The material is compliant enough to allow full flexion. Threats to the finger are gone, and daily function is possible.
Figure 15, a (left), b (middle), c (right)
Case Study 16, Exposed structure, hardware. A 50 year old woman had a distal tibia fracture treated by plate and screw fixation. Skin dehiscence was managed by rectus abdominis and latissimus free flaps, both of which died. (Figure 16a) When seen in consultation, the first jobs were to stop all other surgery, clean up the wound, and work her up for autoimmune and hematological disorders as suggested by the history, pathological wound behavior, and necrotic skin margins (an explicit diagnosis was not established). The tibialis anterior tendon, the metal plate and screws, and the fracture underneath were all exposed and needed a solution for coverage and salvage. Options for surgical closure of an open distal tibia are already limited, and in this case, all choices, local flaps and free flaps, carried substantial risk of further failure. The patient was averse to any other elaborate surgery which carried risk. Rather than take these risks, Integra was opted. (Figure 16b) Integra was not intended to be the means of final skin closure. It was used to take advantage of its role as a high quality artificial skin. The goal was to stay ahead of silicone separation, replacing a new piece every 4 weeks until the fracture was healed and the plate could be removed, probably after 3 or 4 months. The first piece of Integra is seen here at the first 4-week exchange. It has regenerated over non-essential soft tissues, and it is regenerating over the tibialis tendon. The leg is otherwise healthy, free of edema and necrosis, showing edema-reduction wrinkles in skin and Integra. (Figure 16c) This image shows the matrix after removing the silicone. The matrix over the plate is intact, filled with yellow serum. At the margins of this zone, tissue is starting to grow inward, tangentially across the matrix. Skin grafts were placed on peripheral regenerated areas, and new Integra was placed over the central zone. (Figure 16d) Tangential histogenesis as a means of complete regeneration was not the original surgical plan, but that is what happened. There were no complications nor setbacks of any kind. The patient became quite skilled with the required care, permitting her to take an out-of-country holiday vacation for three weeks while the third piece of Integra was in place. After the third Integra (and skin grafts), the leg was healed, seen here 11 months after starting the reconstruction. It has remained healed for two years, the hardware uncomplicated and still in place. (Figures 16e,f) The patient is fully ambulatory and active, with no restrictions of any kind. The fracture is healed, and the plate and screws remain in place. Ankle dorsiflexion is off by 20 degrees, but this is a consequence of trauma, not the reconstruction, and it is better than having the whole foot off. Plantar flexion is normal. (Figure 16g) This image is a close-up view of the matrix at the time of the first exchange. Opacified new tissue is diffusing inward across the matrix from the living margins. This centripetal growth will continue until the entire matrix has generated tissue.
Figure 16 a (top left), b (top middle), c (top right), d (middle left), e (center), f (middle right), g (bottom)
Case Study 17, Adjunct use, flap delay and donor site. A 14 year old boy had a back ulcer of several years duration following radiation for a spinal tumor. Reconstruction was to be done by staged transfer of a regional random (non-irradiated) flap. Integra was used not as the primary wound closure but instead as an adjunct to the flaps. (Figure 17a) A large random flap from the non-irradiated left lumbar area was elevated and transposed to cover the ulcer and part of the dystrophic irradiated skin on the right. Remaining dystrophic lumbar skin will be replaced when the base of the current flap is elevated and moved, after the forward part of the flap is healed. (Figure 17b) Integra was used to close the flap donor site, opted in lieu of skin grafts to minimize pain, drainage, and nursing requirements, and to limit skin grafts to only one subsequent procedure. Part of any good flap delay is to keep the elevated pedicle from healing and revascularizing on its deep surface. Integra can also be seen buried underneath the flap to prevent this. (Figure 17c) Fourteen days later, a delay was done, consisting of division of the base of the flap, trying to force more robust vascularization at the front end. The Integra has a normal two-week appearance, still a transparent window on underlying structures, but just starting to opacify from histogenesis. The buried Integra cannot be seen, but its presence under the flap continues to ensure flap revascularization at the distal end rather then the middle or base. (Figure 17d) Three weeks later, the delayed flap is healthy, uncomplicated, and ready for transposition. The Integra is fully regenerated and ready for skin grafts. (Figure 17e) Taken at the same time as image 17d, this image shows the back end of the flap, elevated and ready to move. The buried Integra is healthy. It has done its job, keeping the flap unconnected in that area, making the flap easy and bloodless to elevate, without creating new vascular stresses on the flap. The tail of the flap was moved across the midline to replace the remaining dystrophic irradiated skin. Skin grafts were placed over both pieces of regenerated Integra. (Figure 17f) A year later, everything is healed. The flap is healthy, Integra regenerated skin is soft and compliant, and there has been no skin dystrophy nor ulceration. All components of the reconstruction healed without complication, and the problem was managed entirely as an outpatient with little pain and no disability.
Figure 17 a (top left), b (top middle), c (top right), d (bottom left), e (bottom middle), f (bottom right)
Case Study 18, Arterial disease. A 64 year old man with unreconstructable aortoiliac atherosclerosis developed toe ulcers. The patient went through progressive levels of amputation, each complicated by further necrosis. (Figure 18a) Necrosis of the thigh amputation illustrates a prime dilemma in operating on severely ischemic parts. Suturing wounds and flaps creates tension which can diminish circulation. In the presence of prior hypoperfusion, the reduction is enough to kill tissue. However, you also cannot reliably leave the wound open, because highly ischemic tissues are intolerant of desiccation, bioburden, inflammation, and injurious topical medicaments. This wound was sutured, and adjacent tissues died. If it is now simply debrided and left open, it will likely die some more. Most surgeons avoid this dilemma by simply doing a higher level amputation, but in this case, that option has run out. (Figure 18b) Integra solves this dilemma, allowing one to debride the wound and then immediately close it without stress or tension on the tissues. By arresting inflammation, it controls yet another factor which threatens the ischemic wound. Seen here two weeks after debridement and Integra, the wound is healthy, and there is no necrosis at any of the margins. Because surgical revascularization was not possible, hyperbaric oxygen was used as an adjunct therapy for two weeks after Integra placement. (Figure 18c) The Integra and skin grafts healed without problems, and the reconstruction remained stable.
Figure 18, a (left), b (middle), c (right)
Case Study 19, Arterial disease and diabetes. A 74 year old man with diabetic atherosclerosis developed forefoot ulceration leading to necrosis and abscess. (Figure 19a) Transtarsal amputation was done through cuboid and cuneiforms. This is a competent amputation because all major tendons to the ankle are still inserted, and the ankle is motored and stable. However, osteotomies and intertarsal joints are exposed and require cover. (Figure 19b) There is insufficient skin for closure, but “creating” enough skin by further bone recession will detach tendons and destabilize the ankle warranting below knee amputation. There are no local flaps, and arterial disease precludes a free flap. Integra is the simple, safe, and reliable solution. (Figure 19c) The Integra healed without problems. All care was managed as an outpatient. By using a posterior “wedge shoe”, the patient remained ambulatory during latter parts of the reconstruction. (Figure 19d) This lateral view of the foot demonstrates active dorsiflexion through the tibialis anterior tendon, confirming that major tendons remain inserted and active. (Figure 19e) Using an insert at the front of a regular shoe, and a thin ankle-foot orthosis for some additional stability, this patient has led an otherwise normal life. Two years later, he remains completely ambulatory and active. Integra has been consistently successful in closing and salvaging midfoot amputations. There should no longer be any need to throw away an extremity only for the want of a good flap. Integra should be the preferred option for salvaging complex foot wounds in high risk patients.
Figure 19 a (top left), b (top middle), c (bottom left), d (bottom middle), e (right)
Case Study 20, Select problem, achilles. A 44 year old woman had a spontaneous achilles tendon rupture. Several failed operations resulted in multiple wound complications and necrosis of the tendon. The area was eventually closed with a rectus abdominis muscle free flap and skin grafts. (Figure 20a) The patient presented for consultation at two years because the old flap and grafts were chronically dysplastic, with recurring ulceration, pain, and dysfunction. The graft and scar dysplasia were attributed to local flexion-extension mechanics, and an attempt was made to excise and revise them. This resulted in acute skin necrosis and new ulceration. This overall history is pathognomonic of an underlying immune or thrombotic disorder. Along with a history of retinal artery thrombosis, laboratory workup confirmed a hypercoagulable antiphospholipid antibody syndrome. (Figure 20b) Closure of this wound has challenges which defy conventional surgery, as already proven by her history. Any incision risks more necrosis and ulceration. A free flap already failed, and more donor sites are unjustifiable. New skin grafts will develop the same dystrophy and ulceration. The reconstruction must be mechanically compliant and thin enough to accommodate normal footwear. Integra overcomes these obstacles with complete safety. Wound debridement and warfarin anticoagulation were followed by Integra. A second piece of Integra was placed after the first one regenerated, in order to get a thicker neodermis in this area of significant mechanical load. There were no adverse events. (Figure 20c) The area healed without any of the pathological changes that affected the original skin grafts, seen here at one year. The reconstructed skin is thin, soft, and compliant. It has developed the transverse dermal creases that are expected in this area. Underlying old rectus muscle had been sculpted to shape and preserved, and with subsequent therapy and activities, applied load induced tendinous metaplasia, and the patient now has normal ankle mechanics and normal function.
Figure 20, a (left), b (middle), c (right)
Case Study 21, Select problem, heel. An 84 year old woman developed multiple leg and foot ulcers related to diabetic vascular disease and disabling senile illnesses. Dependent on her family for physical assistance, foot preservation was required so that she could stand and assist with wheelchair transfers. (Figure 21a) All ulcers were debrided and closed with Integra, including large defects over the right achilles and heel. The extent of posterior calcanectomy can be seen from the missing heel contour. (Figure 21b) A close up view of the heel shows stable skin. Reconstruction was uncomplicated, and all wounds healed. Care was outpatient, and good results occurred with no risk to the patient nor any dependence on living autogenous tissues which most likely would have failed. Lifestyle was preserved.
Figure 21, a (left), b (right)
Case Study 22, Select problem, stump salvage. A 53 year old man had below knee amputation for diabetic vascular complications. (Figure 22a) Most surgeons seeing a stump complication indiscriminately do an above knee amputation, most of which are unnecessary. This wound had granulation tissue and other wound module elements indicative of sufficient circulation and competence to heal. Necrosis was a consequence of avoidable technical factors. With patience, good wound care, and suitable surgery, this below knee amputation can be preserved and healed. (Figure 22b) After a period of debridement and good daily care, the wound met criteria for reclosure. Note the exposed necrotic tibial surface which needed excision. (Figure 22c) In surgery, the prepared wound was excised and anterior tibia was decorticated. For closure, the conventional choices of grafts and flaps were either not available or not likely to work. Had they been the only choices, higher amputation might have been considered. However, Integra solved this problem with no risk to the stump nor to the patient. Without Integra, there simply were no reliable options. Integra is not an alternative nor substitute for classic surgery, but rather an independent surgical modality that works where conventional methods cannot. (Figure 22d) The stump healed. Throughout the reconstruction, a rigid posterior platform splint maintained an extended knee, permitting expeditious rehabilitation. This image is three months after skin grafts. The patient had fallen, causing a tangential avulsion laceration of the newly healed epidermis. Treated and rehealed like any similar laceration. this minor traumatic injury illustrates that Integra requires some time to develop sufficient strength to bear up to the requirements of daily life. Appropriate caution and care should be taken for several months after reconstruction.
Figure 22, a (left), b (second), c (third), d(right)
Case Study 23, Select problem, limb salvage. A 67 year old woman developed foot necrosis due to complications of atherosclerosis. (Figure 23a) The foot was managed by basic topical care and debridement. Operative revascularization was done (saphenous vein graft to dorsalis pedis artery), and the wound responded with rapid proliferation of granulation tissue. After that, even skin grafts would have healed readily on the simple areas, but complex areas of exposed bones, joints, tendons, and ligaments complicated the coverage issues. Flaps are conventionally needed, local or free, but in an arteriopathic foot wound of this size, they are either not available or have too many potential risks. Integra bypasses all of these dilemmas. It solves the coverage issues with no risk. (Figure 23b) The wound was debrided and closed with Integra, shown here 6 weeks after placement and ready for skin grafts. (Figure 23c) The foot healed and remained stable, seen here 6 months later.
Figure 23, a (left), b (middle), c (right)
Case Study 24, Select problem, superiority to conventional choices. A 60 year old man with severe diabetes, vascular disease, and previous left below knee amputation developed a large heel ulcer while hospitalized. He was offered, and refused, right leg amputation. The issues of arterial disease and anatomical location once again make conventional grafts and flaps unworkable, but Integra reliably solves what conventional modalities cannot. (Figure 24a) A large posterior calcanectomy was performed. The osteotomy and achilles insertion were closed with Integra, seen here as a face on view of the healed reconstruction. (Figure 24b) His toes were also missing from previous vascular problems, but enough foot remained to permit stable weight bearing, stance, and gait. He is seen here in full upright weight bearing on the healed foot. This profile view shows the extent of the oblique calcanectomy, which merely followed the contours of skin necrosis. (Figure 24c) For stability, the patient uses a space filling orthotic wrapped around his ankle. (Figure 24d) Using a normal sneaker, his left leg prosthesis, and a walker, he is independent and ambulatory. A complex problem was solved with no donor sites, no risk to foot or patient, excellent biological healing, and preservation of function and lifestyle, all as an outpatient. For many of these challenging problems, Integra is a superior option, working when and where conventional repair, grafts, and flaps cannot.
Figure 24 a (left), b (middle top), c (middle bottom), d (right)
Case Study 25, Radiation ulcer, tissue engineering. An 82 year old woman had a skin cancer of the scalp treated by radiation, 6500 cGy, resulting in a chronically ulcerated parietal cranium. Integra was used as a carrier of mitotically competent cells that were first incubated in a remote subcutaneous wound chamber. The transplanted cells were responsible for the graft healing. Details are presented below in the discussion about radiation ulcers (figure 30).
See figure 30 below.
Key Points. In all of these cases, certain common concepts emerge which define the value and virtues of Integra for chronic and pathological wounds. It is only as good as the general care of the patient, and accurate diagnosis and management of underlying disease is crucial. It is a high quality artificial skin, and while this effect is more dramatic in large acute problems such as burns and fasciitis, it serves to protect wounds and underlying structures, minimizing symptoms and simplifying care. However, it is more than just an effective skin substitute. Its ability to suppress inflammation means that it stabilizes pathological wound behavior and eliminates unexpected exaggerated adverse wound complications after trauma and surgery (pathergy). This permits safe debridement and wound closure in the face of severe immunopathy and ischemia. Because it is not living, it will perform well where skin grafts cannot. Its ability to get good results without donor sites nor any significant “cutting and sewing” other than wound excision makes it extremely safe for high risk limbs, patients, ulcers, and diseases.
Integra closes complex wounds with exposure of visceral and musculoskeletal structures. In this regard, it serves many of the roles that conventional flaps do. This means it is the best solution when flaps are not available or cannot be used. There are times when it is simply superior to flaps, permitting limb salvage and wound closure under circumstances where conventional methods are technically impossible, guaranteed to fail, or apt to create more problems than they solve. It is effective for closure of bone, joint, tendons, visceral organs, and even alloplastic hardware. For select areas and problems, such as heel and achilles, midfoot amputations, and dorsum of the hand and wrist, it is easier, safer, and gives better results than customary methods. It is effective for a broad spectrum of wound and soft tissue pathologies, often being the only successful choice for arteriopathic, hematological, and immunopathic ulcers.
When conventional flaps are more appropriate, Integra can be a useful ally, facilitating or simplifying the overall reconstruction. Integra need not be used only according to its nominal pathway of “one piece – healed”. Multiple sequential pieces for deliberate purposes, and secondary touchup pieces to finish an otherwise largely complete reconstruction should all be considered as part of the ordinary modalities of its use. Integra often succeeds where all else has failed, where no conventional options exist or they have run out, and where patients and physicians have forgone hope. Integra seems to be resistant to recurrent disease. It reconstructs a skin that has superior mechanics and esthetics compared to scar, approaching the properties of normal skin.
It simplifies care. It minimizes pain and nursing. It facilitates recuperation and preservation of function and lifestyle. It allows complex problems to be managed as an outpatient. Even when it is not fully healed, open Integra is always superior to the original wound. As such, patients are accepting of incomplete results, and they are willing to bear the time required to complete the reconstruction. Its effectiveness and safety profile can make it a preferred choice even when conventional methods would work. As a method of in situ tissue engineering, it is not a substitute nor alternative to flaps and grafts, but rather a new paradigm of surgical wound repair with its own distinctive role. This role is especially effective for treating chronic and pathological wounds.
Methods of wound closure, from topical care in support of natural contraction through surgical repair, flaps, and grafts, are usually opted by individual circumstances. These include size, location, acuity or severity of the wound, exposure of visceral or skeletal structures, and patient age, risk, and comorbidities. Most surgery and wound care are done with the implicit faith that wound healing is competent and that the wound or repair will heal. However, these assumptions are invalidated by certain chronic illnesses which cause chronic ulceration and impair the physiological process of wound healing. Arterial insufficiency, venous disease, immunopathies, hematopathologies, and other disorders are the causes of chronic refractory ulcers which defy usual attempts to close them. Integra Dermal Regeneration Template®, can reliably close such ulcers.
The 111 patients in this study all had chronic and pathological ulcers. Most had failed multiple modalities of treatment. One third had prior failed operations. Many were deemed hopeless by other physicians, and some had been offered amputation. For most, disease and pathological anatomy made them ineligible for the repairs or reconstructions that would have been done for comparable defects due to trauma in healthy patients. Part of the good outcomes in most of these patients can be attributed to systematic and comprehensive wound management, including proper diagnosis, treatment of underlying diseases, proper wound preparation, and long term management by a consistent and knowledgeable staff of physicians and allied health professionals. Nevertheless, for most of these patients, Integra was the crucial component of care which solved the problems. Integra closed wounds when pathology could not be fully eliminated, when wound healing was delayed or impaired, and when flaps or other complex repairs ordinarily would have been required but were disallowed by circumstances of disease or anatomy. It did so safely, without donor sites nor significant risk to any patient.
The author’s practice is devoted exclusively to wounds and reconstructive surgery. In the 6 years of this study, the 132 patients having Integra were a small fraction of the entire operative and clinical experience. Integra was not used indiscriminately, neither for its novelty nor any other reason. For example, for each venous patient treated with Integra, there were many more treated by compression, topical modalities, phlebectomy, skin grafts, and other care. All patients were treated according to some disciplined schema for the evaluation and treatment of chronic wounds and their underlying causes, with Integra opted based upon certain consistent criteria. To understand the indications for Integra for chronic and pathological wounds, its unique biological properties must be understood.
Properties of Integra
General Biological Effects
Integra is a non-living semi-biological implant. Both the native and the regenerated material have desirable properties. In its role as an artificial skin, the Integra sponge persuades the wound that there is no injury, suppressing inflammation and its sequelae while the silicone functions as an effective epidermis. In its role as an agent of regeneration, Integra has histoinductive and histoconductive effects on mesenchymal tissues which lead to a regenerated analogue of normal dermis. Integra’s favorable properties, its clinical utility, and its superiority for certain reconstructions all derive from its structure and composition.
Chemical composition. The Integra material is made from type 1 collagen (from bovine achilles tendon) and chondroitin-6-sulfate (chondroitin sulfate C, a glycosaminoglycan, GAG, from shark cartilage). These materials are chemically cross linked then processed into a porous sponge referred to as CGM, collagen-GAG matrix. Unlike many proprietary collagen dressings marketed for wound care, Integra is emphatically not a “collagen product”. Integra depends on both components. Collagen provides mainly structural form. The chondroitin, 8% of weight, is what confers key properties. The glycosaminoglycans, including hyaluronan, dermatan, keratan, and others have vital roles in constituting the extracellular matrix and regulating cell development and differentiation. They predominate in un-proteinized embryonic tissues, and they accumulate in fetal wounds which heal by regeneration without inflammation nor fibrous scar 8. 9, 10. Integra’s chondroitin also masks binding sites on the collagen, thereby preventing platelet adhesion and resulting inflammation 11, 12.
Microarchitecture. The average pore or cell size of the spongy manufactured material is 5 – 150 microns, averaging 80 – 100 microns. This size was deliberately engineered. Too small, and histogenetic cells can not invade nor occupy the matrix. Too capacious, and potential histogenetic cells would “see” a non-stimulatory flat surface. This size, which tends to match the collagen reticulum in normal dermis, is within a target range that engages cells to undergo histogenetic proliferation.
Macroarchitecture. The spongy Integra
matrix is formed into sheets
Acute Physiological Effects
Suppresses inflammation and its effects. Inflammation is the normal response to injury, leading to normal inflammatory fibrous wound repair. When Integra is applied to a wound, inflammation ceases. Not only does it seem to be “invisible” to platelets and inflammatory leukocytes, but it also seems to be recognized as self. At no time are there microscopic inflammatory cell infiltrates nor any clinical signs of inflammation. Pain is often conspicuously absent after Integra, and any pre-operative periwound erythema and edema abate rapidly. Hypotheses explaining this phenomenon include: (1) lack of platelet adhesion prevents the thrombotic cascade to inflammation from being triggered (figure 25); (2) the artificial skin sequesters the wound, eliminating ambient exposure, desiccation, bioburden, and similar secondary injury; (3) the chondroitin matrix looks sufficiently like normal tissue that blood borne leukocytes and lymphoid cells that might find their way into the matrix do not recognize anything abnormal that would trigger a defensive response 13 (figure 26).
Figure 25, a (left), b (right)
(a) Platelets adhere as expected to a collagen-cellulose matrix that has been incubated in platelet rich plasma.
(b) Under the same
circumstances, platelets do not adhere to the Integra collagen-GAG
matrix. The chondroitin has rendered
the collagen invisible to platelets.
(Photographs on file, Ethicon,
Figure 26, a (left), b (middle), c (right)
(a) This biopsy was taken 4 hours after excising skin and placing Integra for an elective reconstruction with no prior inflammation. A blood vessel is present at the wound surface between Integra matrix (top and left) and normal adipose (bottom and right). There is margination and migration of polymorphonuclear leukocytes (neutrophils). This means that post-traumatic thrombosis and platelet effects have recognized the injury. This is the normal response to injury, the start of inflammation.
(b) For whatever leukocytes that do find their way into the matrix, they find nothing exciting. They do not recruit other cells nor incite any other component of inflammation. They subside and disappear, and any incipient inflammation that would accompany a normal injury is completely extinguished. Seen here at 5 days after surgery and Integra, cellularity is sparse, with neither neutrophils, plasma cells, eosinophils, lymphocytes, nor monocyte-macrophages. At no time does a defensive response ever appear in the matrix. Note the cells that are present. These are the early histogenetic cells. The small round cells are the “pioneers”. Some of them have elongated and flattened into “transitional cells”, a sign of recognition and attachment to the matrix, a characteristic interaction of cells with glycosaminoglycans.
(c) This biopsy is 4 days after Integra, from another patient. The situation is the same, no inflammation. Three cells are seen. The small mononuclear lymphoid cell (but not a lymphocyte) at the center is an early pioneer. These seem to be “patrol cells”, either resident in tissues or blood borne, which find the matrix by happenstance. Defensive reactions and cellular recruitment do not occur. The round cell at the bottom is a pioneer which is starting to accumulate cytoplasm, the first sign of matrix recognition. The cell at the top is starting to flatten and elongate, denoting attachment to the matrix. Once this transition happens, histogenesis begins. Histogenesis could not occur if inflammation was active. The effects of Integra re two: it quenches incipient inflammation triggered by injury, and it does not incite any inflammation on its own. It is recognized by the host as an acellular “self”.
Suppression of pathergy. General pathergy (in its more liberal contemporary definition) refers to self-destructive effects of injury and inflammation which cause necrosis, tissue lysis, wound bursitis, dehiscence, and other undesirable wound complications. Paradigms are the injury-induced necrosis of pyoderma gangrenosum and the dermatitis of Behçet’s syndrome. It occurs with any disorder causing severe ischemia or pathological inflammation including athero- and other macro-occlusive diseases, hypercoagulable, microthrombotic, and micro-occlusive disorders, autoimmune vasculitis and angiopathies, and any active immunopathy or connective tissue disorder or similar disease of immunity and inflammation. In these disorders, every surgical procedure from simple debridement and biopsy to amputation and complex repair is at risk. Applied to such wounds or patients, Integra controls or eliminates this risk. By suppressing inflammation, by appearing as normal tissue, and by sequestering mesenchyme, it arrests the progressive auto-amplifying injury which leads to acute wound failure.
Immediate closure of wound and recognition as normal tissue. The biocompatible sponge and the silicone pseudo-epidermis together form an effective artificial skin. When Integra is placed on a wound, all of the events which define the usual response to injury are halted. Physiologically, the wound ceases to be a wound. To the lymphoid patrol cells which do eventually find the matrix, the chondroitin lattice appears to be an acellular but otherwise normal tissue. The only response triggered is a regenerative one.
Sub-Acute Physiological Effects
Suppresses normal inflammatory wound repair. Inflammation begets normal wound repair. Macrophages (transformed monocytes) accumulate in a wound and direct repair via cytokine stimulation of local histoprogenitor cells. This leads to the proliferative wound module of inflammatory repair which produces scar 14. By turning off inflammation, Integra turns off this entire series of events. Integra heals by a different mechanism. Its histogenesis does produce collagen, but it is comparable to normal dermis and distinct from scar. Assuming that the Integra remains uninjured and uncomplicated and that no inflammation is thereby incited, inflammatory fibroplasia (scar) never occurs. This means that contractures, keloids, and other reactive or pathological fibroses and their clinical effects are averted (figures 27, 28-6,7,8).
Figure 27, a (left), b (right)
(a) These two images contrast normal inflammatory wound module repair versus Integra histogenesis. In this image, Integra (on the thigh following necrotizing fasciitis) is regenerated and ready for skin grafts. In an open seam between two pieces of Integra, normal wound healing has occurred, resulting in granulation tissue in the gap.
(b) This is healed Integra at 24 months (on the flank in a 7 year old girl). Looking past the epidermal pigment variegation and the contour depression from lack of subcutaneous adipose, the Integra skin per se looks mostly normal, soft, pliable, free of erythema and fibrosis. In the center though is typical hypertrophic scar, arising where normal wound healing and granulation tissue developed in a seam gap. The differences in these photographs, between granulation tissue and Integra histogenesis, between scar and Integra neodermis, epitomize all of the biological differences between these two processes. Histological examination of the process, as shown in the next series of images, illustrates the biophysics behind these differences.
Induction of embryonic histogenesis. If Integra did nothing other than control inflammation, pathergy, and scar, it would still be a valuable device, but it would then be just another biological dressing ultimately needing replacement by autogenous grafts. What makes Integra unique among all other surgical grafts and implants is that Integra histogenesis is highly analogous to normal embryonic dermatogenesis. The surgeon who uses Integra is incubating a re-engineered tissue devoid of scar and having the characteristics of developmentally normal dermis. The geometry and especially the aminoglycans of the matrix are presumed to be the key triggers for this phenomenon. The similarity of embryonic and Integra dermatogenesis, and their distinction from inflammatory healing and scar can be understood by observing the histology of these events, depicted in the figure 28 sidebar.
Figure 28 sidebar, the process of Integra histogenesis. Integra artificial skin has beneficial physiological effects when applied to acute and pathological wounds. Regenerated Integra neodermis has superior anatomical and functional characteristics that obviate the need for late surgical revision of scars and contractures. There are anatomical and biophysical reasons why Integra has these properties Figures 28-1 through 28-8 document the process of Integra histogenesis. This series of images and legends are a sidebar to the main subject of this report, but they are included so that some of the reasons for Integra’s favorable performance can be seen directly.
Figure 28-1, transformation of syncytial cells and early “first set” histogenesis, a (left), b (middle), c (right)
Figure 26 showed suppression of inflammation. This was followed by early population of the matrix with a low density of small pioneer cells which then attached to the matrix. Matrix attachment is the crucial transition, triggering these cells to perform a latent function that has no parallels in normal post-fetal life. They are about to undergo a process completely analogous to embryonic dermatogenesis. The geometry and gross anatomy of the embryonic and Integra systems are different, an enlarging solid tissue model versus space filling of a fixed void volume, but the dynamics of cells and their interactions are the same. The earliest histogenetic events are shown in this set of images.
(a) At 13 days, the matrix remains only sparsely populated. Small pioneers and transitional cells can be seen, but there are also large cells. Occurring as singlets or in small clusters, these polymorphic cells with abundant basophilic cytoplasm and nucleoplasm are the “syncytial fibroblasts”. They are what the pioneer cells have ultimately transitioned to. From bottom to top, host tissue to silicone, they are distributed evenly throughout the matrix. They will multiply into small independent insular clusters of cells which begin to make fine fibrillar collagen. This is the “first set” of histogenesis.
So far, this developing tissue has no vascular infiltration, so first set histogenesis will be limited by substrate diffusion. The fact that early pioneer cells and syncytial clusters are scattered uniformly through the matrix, at seemingly long distances from the host, is not surprising. Cell-to-vessel distances are vitally important to histogenesis, gas exchange, substrate supply, and vasculogenesis. However, the biophysics of these processes dictate that “cell-to-vessel distance” is a normalized metric measured in unit cell widths along a diffusion gradient, and not in actual physical lengths. As long as there are only about 5 – 10 cells on a diffusion vector, they can be widely scattered. Thus the matrix is uniformly dispersed with early pioneer cells cum syncytial fibroblasts, and they all function normally. However, as they become metabolically active (thereby lowering the system’s threshold cell-to-vessel distance), and as the cells start to divide and form clusters with more cells, new blood vessels are required to restore effective vascular density. Until vascular supply is established, continued growth to confluence and filling of the space will be delayed.
Like all embryonic and other proliferative cells, these burgeoning syncytial fibroblasts are starting to make angiogenic factors which, via their effect on nearby angiocytes, will attract new vessels. In the substrate fascia on which the Integra sits, the blood vessel to the left is normal, with small flattened orderly angiocytes. On the right side, close to the matrix, angiocytes have become large, polymorphic, mitotic (not captured in this image), and migratory. Blood vessels are the normal reservoir of proliferative mesodermal cells which can heal a wound or regenerate tissue. Under the stimulus of the proliferating syncytial cells, the angiocytes are in turn “coming to life”.
(b) This is a closer view of a syncytial cluster. The name is taken from descriptions of embryonic dermatoblasts which appear identical to the Integra cells: large, polymorphic, indistinct, with numerous pseudopods 15. Their boundaries cannot be seen clearly, hence “syncytial”. The cluster is composed of less than a dozen cells, within which faint pink young collagen is starting to form. Note that this cluster lives and functions in physical isolation from any other biological structure. Further growth and proteogenesis will be limited by competition with other clusters until vasculogenesis starts to occur.
(c) In the center is a pair of two indistinguishable cells accompanied by some pale pink material, early fibrillar collagen. Nearby, spindle shaped migratory cells recruited from the substrate are beginning to invade the matrix, and organization of these cells into a new vessel penetrating the matrix is seen at right. This is the inception of a tissue level of histological organization.
Figure 28-2, functions of the syncytial fibroblasts, a (left), b (middle), c (right)
The syncytial fibroblasts are of crucial importance. Their appearance is the keystone event in Integra histogenesis. They are the transition between normal cells and embryonoid processes. They originate and regulate the histogenetic process within the matrix. They are not normal cells in post-fetal life, and they never appear during normal post-inflammatory wound module healing, neither as they appear here nor in any comparable form. Their morphology and function are typical of embryonic cell interactions with glycosaminoglycans. The Integra matrix is explicitly triggering this transformation and histogenesis.
(a) A close-up view a highly proliferated, metabolically active cluster that is not yet vascularized. Cells are large, indistinct, basophilic and granular, and metabolically and proteogenically productive. Young collagen is abundant, within the cluster and to the left. The cluster can get no larger until nearby vascularization occurs.
(b) Once an active domain is vascularized, a “second set” of histogenesis occurs. The clusters can then grow until space is filled and loss of contact is corrected. Cells and collagen accumulate, and the many independent domains of histogenesis grow to confluence, and in so doing they create an organized tissue. In this view, second set histogenesis is well underway. Cell density is increased and pink collagen is more abundant. In some areas, the collagen is turning fibrous, from pale to a denser more saturated pink, and associated cells are getting trapped and flattened in that new collagen. New cells come from two sources. Some are migratory histogenetic cells from underlying blood vessels, and some come from mitosis of the embryonoid syncytial cells, two of which are captured here in prometaphase and metaphase.
(c) In this cluster, large syncytial cells in the center continue making young fibrillar collagen. At the periphery, fibrous collagen is getting dense, taking on an organized lamellar architecture, with entrapped cells now looking like classic fibroblasts. Compared to normal inflammatory healing and scar, this tissue is relatively acellular, and the collagen is wavier with interstitial spaces.
Figure 28-3, vasculogenesis and “second set” histogenesis, a (left), b (middle), c (right), d(bottom)
At 10 – 20 days in normal wounds, fibrous repair is sufficiently mature to permit suture removal. Skin grafts are adhered and vascularized (or else they have died by now). But in Integra, the process of histogenesis is just barely underway. The early period of pioneers, syncytial clusters, and incipient angiogenesis was organized at a cellular level. The system now moves into the second set of development, where true histogenesis occurs, the formation of a confluent structurally integrated tissue.
(a) In this view, scattered syncytial clusters are exerting their effect on subjacent blood vessels which are responding. Vascular invasion of the graft is beginning, and as a circulatory network is established, cell proliferation and connective protein production proceed.
(b) Second set angiogenesis can only occur in the vicinity of new blood vessels. Tissue formation begins around vascular entry points, and the process pushes further into the matrix following the paths of vasculogenesis. In this view, a local domain of vascular ingrowth is associated with dense filling of the matrix. Beyond this consolidated domain, insular syncytial cells in empty matrix are creating the angiogenic cytokines which will attract new vessels to reach them.
(c) In this close-up view, the cellular events of second set histogenesis can all be seen. Some pores are empty, and some are filling and growing to confluence. Syncytial cells are making collagen, and some cells are entrapped in collagen, assuming a common fibroblast appearance. Clusters of migratory spindle cells are angioblasts reorganizing new blood vessels.
(d) A wide view shows that the process occurs concurrently in many locales, and the locales gradually become confluent. A true histological and physical connection of matrix to host is occurring.
Figure 28-4, inflammatory angiogenesis versus embryonic vasculogenesis, a (left), b (second), c (third), d(right)
Angiogenesis is obviously crucial for basic cell survival and tissue growth. However, seen from a systems or physics point of view, vasculogenesis and vascular network topology simply reflect the dynamical growth of the host tissue. In normal embryogenesis, vascular network formation is a tightly controlled closed loop process. The same is true of Integra vasculogenesis, whereas inflammatory repair has unregulated open loop angiogenesis. Vascular density is thus another indication of Integra’s identity to embryonic growth and its distinction from inflammatory repair 16, 17, 18.
(a) Inflammatory angiogenesis is an open loop process. Macrophages which stimulate and attract angioblasts are extrinsic to the developing tissue, and they are not inhibited by the arrival of vessels (the same is true for histioblasts and fibrogenesis). Compared to normal tissues, granulation tissue is hypervascular due to robust open loop overproduction of blood vessels. This is seen grossly as a saturated red color that contrasts sharply with pale surrounding normal skin.
(b) Histology corroborates gross appearance. Blood vessels are excessively dense and enlarged, far in excess of what is needed for basic blood supply and normal metabolic needs. After the wound is closed and can mature, vascular density slowly returns to normal over months or years.
(c) This is a lower power wider view of regenerated Integra, yet there are far fewer vessels than in the picture of granulation tissue. Recognizable as thin cellular chords and small transverse rings, vessel count and blood volume are much less. The tissue is obviously alive, so vascular density is sufficient. It is in fact exactly matched to the needs of the tissue, because Integra vasculogenesis is a closed loop interaction between syncytial cells and angioblasts.
(d) Integra in this picture is fully regenerated and ready for skin grafts. Its white color appears virtually identical to the adjacent normal skin. This is because they have equal vascular density, both densities being just exactly what is needed to supply the tissue. Precise and efficient vascular network formation results because Integra and embryonic vasculogenesis are nearly identical dynamical processes. They are both tightly regulated closed loops controlled by cells (syncytial fibroblasts and embryonic dermatoblasts) that are intrinsic to the developing tissue. Unlike what happens in scar, vascular density in Integra is just what it should be, and it will not change as the tissue matures.
Figure 28-5, confluent histogenesis and matrix filling, a (left), b (right)
(a) Although first set syncytial histogenesis begins with cells scattered evenly throughout the matrix, second set histogenesis is limited by the availability of new blood vessels. Of necessity, these can only enter at the base and progress upward. Therefore, organized confluent tissue formation also begins at the base, rising toward the silicone. This 17 day image shows regeneration half complete, 1-2 weeks away from skin grafting. At the top level, empty pores have scattered pioneer and transitional cells. Just below, syncytial clusters bide their time, awaiting the arrival of nutrient capillaries, making some fibrillar collagen as they wait. At center level, migratory angioblasts are organizing into early erythrocyte-carrying vessels. Cell and collagen density are increasing, but the central layer is still more basophilic than eosinophilic, more cellular and cytoplasmic than proteinized. In lower strata, large conducting vessels carry blood locally and to developing strata above, and bright pink dense fibrous collagen is becoming the bulk of the tissue. At the lowest level, entrapped fibroblasts are flattened between maturing parallel collagen bundles. Matrix and host now have a firm physical connection of collagen and vascular structures. Blood vessels in the substrate fascia are still hypertrophied, but basophilia is more cytoplasmic than nuclear, the proliferative response winding down as active histogenesis and angiogenesis shift to upper levels where mid-zone vessels are now the angiogenic source. This process will continue shifting upward.
(b) As second set histogenesis progresses upward, the result is a uniformly consolidated matrix, seen here at 6 weeks, biopsy taken at the time of skin grafts. Note the large foreign body giant cells at the top. Often appearing within a week of Integra’s placement on the wound, this is a common and normal response to the unnatural silicone. Some people get them, some do not. It is a safe, non-inflammatory process which at worst causes some turbid blistering and premature silicone separation. This has no effect on the matrix, and it does not jeopardize the skin grafts.
Figure 28-6, collagen morphology of Integra versus dermis versus scar, a (left), b (middle), c (right)
The similarities of Integra and normal skin, and their distinction from scar can be seen histologically.
(a) This is young scar, representing normal inflammatory wound repair at peak fibroplasia. Highly cellular at this point, the densely packed fibroblasts are making thick chords of collagen. In ensuing weeks, the scar will become even more heavily collagenized. Increasing connective proteins will make the scar progressively less compliant or distensible. Dense packing of fibers and lack of interstitial spaces and individualized bundles mean no fluidity of the material. There is no folding, coiling, or waviness that would confer elasticity or distensibility. Collagen bundles are multidirectional at this point, but subjected to tensile stresses, they will reorient themselves to resist that load. Compounded further by myofibroblast mediated contraction, the scar becomes ever more non-compliant. These are the mechanisms of scar’s distinctive and detrimental properties, the origins of contractures, stiffness, strictures, stenoses, and disfigurement.
(b) This is normal reticular dermis. Typical fibroblasts are dispersed in typical densities, seeming quite dilute in comparison to scar fibroblasts. Collagen bundles are variable in size, mostly large, with great variability in orientation. They are highly individualized and distinct, separated by interstitial spaces. The bundles are also coiled, wavy, or springy. All of these factors permit elastic compliance of the material, and normal motion of associated body parts
(c) This is fully regenerated Integra. Compared to scar, it has a completely different histology, morphology, and biomechanics.
Cellularity is low. Collagen bundles are thick but organized into individualized bundles or packets. Collagen conforms to the matrix without causing any distortion or contraction of the septae. The matrix itself partitions the collagen, having a similar effect on the structure and mechanics of the material that the interstitial spaces have in normal dermis. These spaces, the interruptions and incoherence between collagen clusters, and the springiness of the septae mean that the material is fluid, elastic, and deformable. The Integra does not look precisely like normal dermis, but the two materials share many structural properties, and Integra can be expected to behave like normal dermis. Both are distinctly different than scar whose collagen density and geometry defy mechanical compliance.
Figure 28-7, composite structure of Integra versus dermis versus scar, a (left), b (second), c (third), d (fourth), e (right)
This is another direct comparison of Integra, dermis, and scar, looking not just at collagen, but at the composite skin structure.
(a) Papillary dermis is a lamina propria that supplies metabolically active epidermis. Its generation and the papillation of the epidermis are epidermal functions that are independent of the substrate. In this image, regenerated Integra has recently been skin grafted. Epidermal strata have reorganized. There is no papillary dermis yet, but increasing subepidermal cellularity indicates the onset of this process.
(b) Integra at one year. Epidermis is normal. The papillary dermis is also completely normal, and it is a clearly defined lamina distinct from the Integra which is the de facto reticular dermis. Even at this late interval, the matrix is present, undistorted by scar contraction, maintaining the architectural features that confer compliance and which make it similar to normal dermis and distinct from scar.
(c) For comparison, this is normal skin, with distinct reticular and papillary layers, and all of the architectural features which characterize normal skin and its physical properties.
(d) This is normal healed scar. A thin papillary dermis and subepidermal plexus have formed. The true scar, substituting for the reticular dermis, continues to be dense, cellular, architecturally antithetical to extensibility and mechanical compliance.
(e) This image is healthy Integra at 4 years. It is included to demonstrate that Integra continues looking like normal dermis, never contracting, never accumulating scar, for prolonged periods. Much of the matrix itself is still present (collagen-chondroitin cross linking is an essential part of Integra’s chemical engineering design and manufacture, and it confers remarkable stability and insolubility). There is no evidence that Integra has any diffusible moieties nor any cytotactic properties. The only mechanism for its disappearance would seem to be slow passive hydrolysis, preserving much of its original architecture for as long as four years. This also explains why Integra does not degenerate, why it can safely wait over pathological wounds or voids or alloplastic materials, surviving conditions that kill skin grafts.
Figure 28-8, the wound module of inflammatory repair versus Integra histogenesis, a (left), b (right)
This final comparison shows regenerating Integra side by side with a proliferating wound module, and regenerated Integra side by side with scar.
(a) Just like normal tissue, if Integra is injured, leaving an open wound, it will trigger inflammatory repair. For this image, a 4 week Integra biopsy was left open, resulting in a bead of granulation tissue, and then 2 weeks later this overlapping biopsy was taken. The boundary shows an active normal wound module arising from the Integra. Both systems are developing side by side, each according to its own set of stimuli and responses. This is the same individual, the same cell biology, the same genome, but cells are behaving according to two vastly different programs. Injury has triggered the inflammatory wound healing response which leads to scar. Integra has triggered the embryonic histogenesis program. This response to injury and surgery does not naturally happen in post-fetal life.
(b) This specimen is one year after Integra. On the right is properly healed Integra, looking very much like normal dermis. Epidermis and the papillary dermis are normal. On the left, Integra skin converges on an area of normal post-inflammatory contracted scar. Scar is not static, and is it matures over long intervals, collagen remodeling allows scar to begin resembling dermal collagen, as is the case here. However, seen juxtaposed against the Integra, one can appreciate why Integra behaves so much more like normal skin.
Related Therapeutic Effects
Semibiological, but not
alive to begin with. “Biological dressings” are used to protect
wounds, control inflammation, prevent pathergy and complications, and promote
wound repair prior to definitive closure.
Cadaver allograft, porcine xenograft, allogeneic amnion, and
non-biological materials (e.g. Biobrane®, Bertek Pharmaceuticals,
Biological superdressing. As a non-living semi-biological material, Integra is an excellent biological dressing, but it has an added advantage. As the Integra covered wound becomes healthy and competent to proliferate new tissue, the Integra then acts as the matrix for new tissue growth. Thus, the Integra does double duty, first as a non-living biological dressing which does not die nor degenerate, and then as the agent of skin regeneration and reconstruction. As such, it is much more than just a simple or passive biological dressing, and the term “biological superdressing” designates its ability to automatically transition into the mode of active histogenesis and skin regeneration.
Histoconduction and bridging. The Integra sponge is a trellis that guides the ingrowth of new tissue. When Integra is placed on a healthy wound, histioblasts migrate into the material from the base of the wound, dragging angioblasts in their wake, and then creating a living tissue. It is customary to think of this ingrowth as an orthogonal function, the direction of growth being vertical, at right angles to the wound surface, the same process taking place concurrently at each infinitesimal area of the wound. But there is nothing which prevents histioblasts from migrating tangentially. If there is a gap or void in the wound which cannot source cells into the overlying Integra, cells will migrate in from surrounding healthy regeneration-competent areas. This property is analogous to other histoconductive matrices such as cancellous bone grafts. Tangential histoconduction means that Integra regeneration can “bridge” over surfaces that cannot heal. Objects which customarily need flaps for closure can instead be healed with Integra. This includes, tendons, open joints, cartilage, and even alloplastic hardware.
Suppression of scar, avoidance of scar sequelae. Scar is the product of inflammatory wound healing. It is a dense disorganized deposition of collagen distinctly different than normal dermis and fascias. An indiscriminate glue that binds injured tissues together, scar ensures the health of subjects after injury and surgery, but it also has a dark side. The cause of deformities, contractures, strictures, stenoses, and similar sequelae, it is one of the most prevalent causes of long term morbidity and dysfunction and the need for corrective surgery and physical therapies. Because Integra stops inflammation and normal repair, it stops scar formation. No scar means none of its complications. It can control fibroplasia where old scars once were, it can prevent new scars, and it can correct the adverse consequences of scar. It even suppresses or prevents pathological scars such as keloids (figure 29).
Figure 29, a (left), b (second), c (third), d(right)
(a) Contraction and non-compliance of scar causes the common clinical problem of contractures across joints. In this case, the scar is on the dorsal ankle after an old burn. Motion of the ankle puts tension on the scar, causing it to undergo tendinous metaplasia, further decreasing compliance. Motion (from normal walking) also fractures the scar, causing ulceration which begets more scar. This image not only illustrates the nature of chronic scar and contracture, it also highlights precisely the kind of case which is reconstructable with Integra.
(b) Integra is soft, pliable, and compliant, comparable to normal dermis. While nearby scars were still red and stiff, this recent Integra on the back was very deformable, wrinkling and folding normally in response to any motion or force.
(c) In another patient, the dorsum of the hand was reconstructed with Integra after granulomatous ulceration. The new skin is soft and pliable and has normal dermal wrinkles.
(d) In the same patient, on the dorsum of the hand, manipulation of the material confirms its normal properties. These properties allow joints, the face, and other mobile parts to be reconstructed without contractures.
Similarity to normal dermis, favorable mechanics. More than just taming scar, regenerated Integra has properties comparable to normal dermis. Already apparent from histology and histogenesis (figure 28 sidebar), these attributes are confirmed by mechanical testing of these materials 19. The real proof though is “in the pudding”. Clinically, its texture and quality, its suppleness and pliability, its compliance and elasticity confirm its distinction from scar and its similarity to normal skin (cases 15, 20). This means that the regenerated skin is not apt to contract nor cause the clinical sequelae of scar. There have been numerous independent observations that, compared to skin grafts: (1) healed Integra is better, comparable to normal skin 20 - 24; (2) Integra mechanics and physical properties avoid contractures and give superior functional results and improved range of motion 20 - 22, 2 5- 32; and (3) cosmetic appearance is also superior 20, 22, 28-30, 33 - 39.
Local soft tissue pathology is controlled. Integra is not a pharmacological substance, and it has no direct therapeutic effect on the diseases that cause chronic ulcers. Nevertheless, Integra has a systems level ability to control the local expression and effects of disease. Like most complex physiologies, injury, disease, inflammation, ulceration, and all of their attendant therapies constitute a complex non-linear dynamical multi-control system. Normal tissue, active stable disease, rampant disease, normal wound healing, retarded wound healing, and active ulceration are all basins of attraction or local stability on the chaotic attractor of this system’s state space. In chronic pathological wounds, sick controllers with impaired degrees of freedom cannot easily regulate a desired healthy state. Perturbations of the system by disease, trauma, or treatment can have variable, unpredictable, and even contrary effects. The body has many systems for fighting, controlling, and eliminating disease, but in the chaotic pathological wound, these systems cannot prevail. Integra does not directly cure any diseases, but its ability to control a wound (inflammation, thrombosis, exposure, bioburden, etc.) is profound enough to permit normal physiological systems to recover, regain the upper hand, and overcome residual pathology. Via complex non-linear interactions, Integra controls soft tissue pathology and ulceration and keeps them controlled. (Cases 2, 3, 7, 8, 9, 11, 18, 20).
Resistance to recurrent disease. Continued management of underlying diseases and risks is mandatory for any wound in any patient, before, during, and after the acute phases of healing and reconstruction. This serves both the general health of the patient and the continued health of the closed wound. However, in spite of good care, some patients will have unexpected injury or illness or flare-ups of disease. Many will lapse in their follow-up and preventive care. Like anything else, Integra can be damaged by trauma such as lacerations or pressure. Integra can also be affected if disease and ischemia are severe enough. However, relative resistance to new disease has been a repeated observation when treating patients with inflammatory and lytic disorders such as venous or rheumatoid ulceration. This resilience may be due to two factors: it might not be the Integra, but rather absence of underlying adipose which is where ulcerative panniculitis typically occurs; or it might be the Integra, because as a more embryonic type of tissue, it might have some inherent resistance to these diseases. (Cases 2, 7).
Integra General Indications
Integra has numerous indications and modes of use. (1) As an effective artificial skin, Integra can provide critical coverage for salvage of life and limb. Placed on a wound, it blocks recognition of injury, quenches inflammation, controls pain, pathergy, edema, and fluid fluxes, stabilizes general metabolism with large injuries 40, 41, significantly reduces nursing requirements, and accelerates recovery and rehabilitation 26, 27, 42 - 44. This is of value for any large wound, and Integra is often life saving for large burns, deglovings, and fasciitis 20, 26, 27, 34, 35, 42 - 50. This property also permits elective resection of large areas of skin for non-acute conditions such as lymphedema 51. (2) As a skin regenerant, Integra is valuable for any soft tissue reconstruction where quality of the skin and avoidance of scars and contractures is desirable. (3 ) Integra also provides essential coverage, closing exposed visceral and skeletal structures. The conventional arts of wound closure require that these be covered with vascularized wound healing competent tissues in the form of flaps or other complex repair. As an artificial skin, Integra provides interim protection for these structures, and as an agent of regeneration, it creates the final coverage, supplanting many flaps. (4) When closing pathological wounds, Integra also acts in both modes (artificial skin and skin regenerant), the concept of a biological superdressing. In these situations, the artificial skin actually has a true therapeutic role, allowing residual inflammation and pathology to subside, controlling the risks which threaten wound healing and surgical repair. Many chronic ulcers also have exposed essential structures, as evident in the patients in this study, a consequence of disease and of the thorough wound excision needed prior to placing Integra. Worldwide, clinicians and investigators have reported favorable experiences with Integra when used in any of these modes 20 - 56, most of it with acute trauma and elective reconstruction in healthy people, but also in chronic wounds 50,56.
Rationale and Indications for Chronic and Pathological Wounds
Chronic and pathological wounds are prolonged and poorly healing because there is underlying disease which either perpetuates the ulcer or inhibits healing. While control of underlying disease is mandatory in principle, in practice it can be impossible to completely eliminate adverse factors such as autoimmune inflammation, arterial insufficiency, and the effects of radiation. The disease itself may cause anatomical complications or caveats, such as rheumatoid synovitis causing exposed ankle tendons or severe atherosclerosis eliminating the usual flaps used to cover open skeletal structures. It is these wounds which are subject to pathergy and wound healing failure, leading to prolonged care, multiple failed procedures, and prolonged frustration and expense. For unwary surgeons, autogenous materials are prone to be wasted, and donor site complications may enlarge the original wound. Integra’s properties allow it to manage or solve these problems. Often superior to conventional methods of wound closure (repair, grafts, flaps), and sometimes the only option, Integra should be used preferentially for the following circumstances. (Case studies which illustrate these points are referenced).
High risk history and susceptible disorders. Use Integra: if the patient has a history of failed surgery for the ulcer or related condition; if the patient has a history of failed surgery for other reasons; if there were wound and soft tissue complications of prior surgery or trauma (pathergy); if prior reconstruction or wound closure has become re-ulcerated; if the patient has arterial disease, immunopathic diseases, longstanding or advanced venous disease, or hypercoagulable and micro-occlusive disorders, especially if severe, difficult to manage, or actively flared up. (Cases 1, 2, 3, 8, 10, 15, 18, 20, 21, 23, 24).
High risk ulcer profile. Use Integra: if the current ulcer has failed or progressed in spite of reasonable prior care; if examination shows persistent inflammation, necrosis, lysis, and progressive ulceration; if there was pathergy and progressive necrosis after debridement and supervised care; if pain is difficult to control; if skeletal or visceral structures are exposed or can be anticipated after debridement; if periwound transcutaneous oxygen levels are seriously diminished; if the ulcer or its location are ordinarily considered to be at high risk for amputation. (Cases 2, 7, 8, 11, 13, 15, 16, 18).
Inflammation and disease persist. If the physician has done everything that current art and science permit to treat the disease and control the wound, but inflammation or active ulceration persist, then conventional repair or grafts with living materials are apt to fail, and Integra should be used. Integra is not only preferred because it is not alive, but it is also therapeutic, and rapid subsidence of pain, inflammation, drainage, and ulceration can be expected. (Cases 1, 2, 3, 7, 8, 9, 12, 13, 14, 15).
Topical care not succeeding. It is necessary with any chronic wound to have a preliminary treatment phase in which diagnosis is made, risk factors are corrected, and basic wound care is initiated. By the time these activities are concluded, a few weeks of observation will have revealed if the wound is wound-healing competent and beginning to proliferate an active wound module. If the wound is incompetent to heal under ordinary circumstances, Integra ought to be used in lieu of conventional surgery. (Cases 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 21).
Control of symptoms. If severe pain is present due to persistent pathological inflammation (i.e. the inappropriate inflammation of immunopathic or similar disorders, as opposed to the reactive inflammation of controllable factors such as trauma and bioburden), wound excision and closure with Integra will cure the pain, and it should be done for humane symptomatic relief. (Cases 2, 11).
Surgical complications or wound failure anticipated. Use Integra: if residual pathology, inflammation, or ischemia threaten complications of conventional flaps, grafts, and repairs; if prior attempts to do surgery for the same condition failed; if the established diagnoses or confirmed ischemia carry a high risk of pathergy and surgical complications. (Cases 1, 2, 3, 7, 8, 10, 11, 15, 16, 18, 19, 20, 21, 22, 23, 24).
Skin grafts ineligible. Skin grafts are technically convenient but biologically complex, being completely dependent on a healthy and wound healing competent host wound. Conditions such as ischemia, devascularized structures, and minor residual inflammation nullify the use of skin grafts because the grafts will die or not adhere. Not being alive, Integra does well in these circumstances. (Cases 1, 2, 7, 8, 10, 11, 15, 16, 18, 19).
Flaps ineligible or at high risk. As normal vascularized tissues which are independently capable of and responsible for healing a wound, flaps usually solve what grafts cannot. However, flaps are not always safe or even technically possible. Integra can be safe and successful when flaps cannot or should not be used: if local anatomy has a limited choice of flaps (such as the distal leg and ankle); if eligible flaps are in the zone of risk and therefore likely to fail; if active inflammatory diseases threaten wound complications along new incisions; if vascular disease and ischemia threaten flap necrosis; if atherosclerosis or hypercoagulability or general patient condition make a free flap unwise. (Cases 3, 10, 11, 15, 16, 18, 19, 23, 24).
Exposed essential structures. One of the preeminent indications for flaps is the closure of visceral, skeletal, and alloplastic structures. If flaps are ineligible for any of the above reasons, Integra is a highly dependable substitute, because of its role as a high quality artificial skin, and because of tangential histoconduction and its ability to bridge a non-living hiatus. There is no limit to the extent of coverage if Integra is placed on living structures, such as abdominal organs or healthy bone. It is unknown how much of a void it can bridge, but case 16 describes the details of closing 2-3 cm of exposed metal hardware. (Cases 1, 3, 4, 6, 8, 9, 10, 14, 15, 16, 19, 21, 22, 24).
Biological coverage desirable. Biological dressings are used for interim wound closure, to control persistent mild inflammation or to provide interim protection of a wound in preparation for later closure. If the needs for wound closure are truly transient, if the wound is going to be subject to further debridement, or if it is going to disappear after later repair or flap inset, then less costly materials such as cadaver allograft or Biobrane are better suited. However, if the involved wound surface will need its own closure, then Integra is preferable. It will eliminate intermediate steps, because it serves both purposes, short term biological coverage and definitive reconstruction or wound closure. (Cases 11, 12, 16, 17, 23)
High risk patient. Integra placement is quick and safe, the only “cut and bleed” risk to the patient being the wound excision. Subsequent skin grafts have no more risk than the graft donor sites. Integra should be used in lieu of conventional repairs for any patient who is sick or a poor anesthesia risk. If disabilities and psychosocial circumstances warrant minimum surgery-induced disruption of daily affairs, Integra can be the simplest yet most dependable approach to wound closure. Integra is the ultimate “play it safe” wound closure option. (Cases 1, 2, 21, 22, 23).
Large surface area. Large wounds need correspondingly large flaps or grafts. These create potential post-operative problems of increased inflammation, physiological stress, pain, drainage, soiled dressings, septic risk, nursing requirements, and functional inhibitions. In a sick or disabled person, simultaneous large donor sites for large wounds can be “too much”. By using Integra, net physiological load on the body is significantly reduced. The primary defect immediately ceases to be a wound (physiologically speaking), donor sites are eliminated, and the later skin grafts done by themselves are easier to manage. Integra should be considered whenever it is desirable to limit collateral injury, minimize wound surfaces, minimize acute physiological stress, and simplify post-operative symptoms and nursing. (Cases 5, 11, 12).
High risk donor sites. Flap and graft donor sites can be at risk because of disease, location, ischemia, inflammation, and any other factor discussed above. Even if a donor site can be harvested without wound complications, there can be functional contraindications. For example, the latissimus dorsi muscle is crucial for competent use of crutches, walkers, and wheelchairs, all necessary orthotics for many chronic wound patients. Yet a latissimus free flap is one of the first choices for many plastic surgeons wanting to cover a complex lower extremity wound. Preservation of health, function, and lifestyle are the real goals, not simply wound closure for its own sake. If it is desirable to avoid donor sites, Integra eliminates this risk while giving equivalent or superior coverage of the target wound. (Cases 2, 10, 15, 18, 22, 23, 24).
High risk for recurrent disease. Patients with chronic wounds have chronic disorders, and recurrent ulceration is a risk, especially for immunopathic, venous, lymphatic, and hematological disorders. Because Integra reconstructed areas seem to be somewhat resistant to recurrent disease, it is superior to scars and conventional skin grafts which are prone to re-ulceration. Integra should be used in areas of unstable skin and scar with a history of either repetitive ulceration or risk for future ulceration. If a wound is still small but is surrounded by wide areas of extensive trophic changes, dermatitis, and liposclerosis, areas at risk for broader ulceration, then strong consideration should be given to pre-emptive dermatofasciectomy of the entire area and skin reconstruction with Integra (usually involving the distal leg and ankle). (Cases 1, 2, 5, 7, 8, 12, 13, 14).
Avoiding scar and improving reconstruction. Regardless of the reason for Integra, it controls scar, and late revisions for scar contracture, such as after burns, are infrequently required. For chronic wounds, if the area involves joints, hands, face, neck, genitalia, or any other mechanically compliant area, then Integra should be given primary consideration unless some suitable flap or direct repair can do an equivalent or quicker job. (Cases 10, 17, 20).
Simplifying care and preserving function. Upon placement of Integra, the wound is immediately closed. Pain, drainage, and other symptoms cease. Nursing requirements are nil, permitting almost all care to be outpatient, requiring only periodic (weekly) dressing changes. For patients with obligations at work or home, who must preserve function and lifestyle, who must travel, who live remotely and cannot come for frequent medical visits, or in whom other illnesses take precedence, Integra can be used because of its ability to simplify care. (Cases 5, 12, 14, 16, 17, 23).
Absent risk factors, a superior reconstruction. Integra can heal problematic wounds. It can succeed where flaps would ordinarily be used, sometimes with superior results. It can succeed where flaps cannot be used. It can avoid sequelae of conventional surgery (scars and contractures after skin grafts, or revisions and “debulking” of flaps). It can do so with neither risks nor donor sites nor inpatient care. These are valuable properties regardless of the circumstances of the primary wound. For benign non-pathological wounds, situations where the ordinary means of repair would be safe, reliable, successful, and customary, Integra might nevertheless be preferred, precisely because of its own advantageous properties. In some of the case studies (1, 10, 12, 15, 16, 17, 19, 20, 21, 22, 23, 24), imagine that the given situations occurred due to trauma or surgery in young healthy people, and then contemplate whether customary grafts and flaps would have been easier, safer, less resource intensive, or would have given better results that those that were actually obtained with Integra.
Use of Integra, Discussion by Diagnosis and Pathology
Macro-arterial Arterial insufficiency, usually due to atherosclerosis, was the most common risk factor in this group of patients. It was also the group with the highest percentage failure and lowest percentage group 1 success (along with the diabetic group, all of whom had arterial insufficiency as one of the secondary diagnoses, Table 3b). Atherosclerotic macroarteriopathy is distinctive in that it is an anatomical condition of blood vessels but not an active disease which causes ulceration nor damages intrinsic wound repair physiology. The relative degree of arterial insufficiency governs how easy or difficult wound repair and surgery will be. Thus, the results with Integra fell across a spectrum of outcomes from total success to total failure. Note that length of treatment is one of the lowest (Table 4), indicating that in the absence of an active ulcerative disease, these patients either got better quickly or they failed altogether, contingent on the severity of the insufficiency. Ideally, arterial insufficiency should be corrected prior to any wound closure surgery, Integra or otherwise. To the extent that revascularization restores wound healing competence, an ulcer might be closed by topical care only or by customary one-stage grafts and flaps. Integra is valuable for two reasons in patients with more severe disease. The first is its ability to control wound conditions, averting the pathergy that ordinarily complicates this condition. As a non-living material it will not fail the way that grafts and flaps might, and it is ideally suited to the retarded or delayed histogenesis that can accompany arterial insufficiency. The second reason is its ability to bridge exposed essential structures, performing well in lieu of conventional flaps which might be unavailable or too risky.
Efficient selection and management of these patients would be facilitated by knowing when arterial insufficiency is so severe as to ensure failure. There was insufficient data to permit precise correlation of outcomes with clinical measures of arterial circulation, but some general guidelines can be stated. For ankle-brachial indices (ABI’s) of 0.7 to 0.8, conventional repair, grafts, and flaps are permissible, although Integra might be preferable for the closure of tendons, bones, and joints in lieu of higher risk flaps. ABI’s below 0.2 to 0.3 are likely to result in failure regardless of method. In these circumstances, if operative closure of any kind is attempted, Integra is not only safe and of marginal risk, it is also probably superior to conventional repair in the likelihood of success, losing nothing but time if it is attempted. Nevertheless, at these low ABI’s, failure is mostly assured. It is in the middle zone where conventional surgery is likely to fail or carry substantial risk that Integra is likely to be successful. In just over half of these patients, hyperbaric oxygen therapy was used to restore missing oxygen, typically started at the time of Integra placement or up to a few weeks in advance, with courses of treatment typically 20 to 40 sessions depending on progress. Adjunct hyperbaric therapy was felt to be worthwhile, although many patients not having this therapy also did well. Salvaging complicated stumps, such as coaxing a below knee amputation wound to heal rather than conversion to an above knee amputation, is a particularly valuable capability (4 patients in this group had successful salvage of an amputation already performed by another surgeon for which higher amputation had been recommended, and 5 patients avoided immediately impending amputations scheduled by other surgeons). (Cases 10, 18, 19, 21, 22, 23, 24).
Hypercoagulable and other micro-occlusive. These are a wide range of metabolic and hematological disorders which cause micro-occlusion, but no other active injurious pathology. They include the prethrombotic and immune mediated hypercoagulable states, hemoglobinopathies and disorders of formed blood elements, dysproteinemias, and metabolic disorders such as calciphylaxis. Pathophysiological issues and discussion are comparable to atherosclerotic ulcers and necrosis, including severe ischemic pain, pathergy, refractoriness and multiple treatment failures, and threatened or prior amputations. But there is an important difference: these conditions are easier to manage. They tend to occur in younger otherwise healthier patients, and the problems or their effects are correctable, such as treating hypercoagulable patients with anticoagulants. The consequence is that patients in this category had a high success and a low failure rate. Because these are ischemic conditions, hyperbaric oxygen is of potential benefit for short periods (therapeutic anticoagulation, natural thrombolysis, vascular recanalization, and regenerative angiogenesis mean that ischemia corrects itself in these conditions, so hyperbaric therapy need not be done for more than a week or two, as was done in 50% of these patients). (Cases 2, 3, 8, 11, 20).
Diabetes. Diabetes does not cause any type of inflammatory or metabolic injury which directly inhibits wound repair. Thus, for the 19 patients having diabetes as a secondary diagnosis, it was simply coincidental and did not influence good or bad outcomes. For the 5 patients having a characteristic “diabetic ulcer”, results were mostly poor. Arterial insufficiency was a contributing factor, but in those patients with adequate circulation, Integra was technically successful, regenerating and accepting skin grafts. For those 5 ulcers on weight bearing plantar surfaces, the real problems were mechanical load and patient compliance. Even though the material performed properly, these patients were categorized as failures (table 3b) because the Integra did not contribute to a good final outcome. The foot itself is not a problem. Integra is extremely dependable on non-weight bearing foot surfaces, and in those patients who are responsible about activities and orthotics. Lessons learned were (1) if a patient cannot be compliant during a plantar reconstruction, it might be best not to begin at all (true for any type of diabetic foot reconstruction), and (2) even when Integra heals properly under the calcaneus or other plantar weight bearing surfaces, it will ulcerate when subjected to ambulation and weight bearing. Comorbidities such as arterial insufficiency and neurological or psychological inadequacies amplify these risks, so an Integra reconstruction on the weight bearing plantar surface is probably best avoided in diabetic foot patients. (Cases 18, 19, 21, 23, 24).
Venous and lymphedema. These disorders are grouped together because (1) they share some common pathophysiological mechanisms, (2) the chronic trophic tissue changes and other anatomical pathology are similar, and (3) treatment principles and frustrations are similar. Many patients with these disorders have never had systematic sustained care, and most will improve without surgery if proper care is initiated. For those who have had comprehensive good care and then need surgery, skin grafts often succeed (along with continued compression and maintenance care). In the 18 study patients who had these as primary diagnoses, the indications for Integra were based on advanced, refractory, complicated disease: (1) long duration with prior failed skin grafts, (2) advanced liposclerosis and scarification of the sural fascias which, after excision, left bare muscle, tendon, and synovium upon which to place grafts, (3) pre-excisional ulceration into skeletal structures such as tibialis and peroneus tendons, the bony malleoli, or the ankle joint. Good preparation is essential, including vigorous wound and skin care, topical or systemic steroids (control of venous vasculitis and dermatitis) and strict compression (control of edema and venous hypertension). If venous interruption was not previously done as an independent form of treatment, it should be done (as anatomically required) at the time of wound excision and Integra. In the compliant patient, these goals are easily achieved, and the success rate was one of the highest. (Cases 4, 5, 6, 14).
Immunopathic. Immunopathies are active diseases. Their designations as connective tissue and collagen-vascular disorders underscore the effects they have on these tissues, and progressive lytic ulceration of skin and fascias and wound healing impairments are common in the leg, ankle, and elsewhere. Panniculitis and ulceration are sometimes the only overt manifestation of disease. Immunopathic ulcers are often misdiagnosed and mistreated, but even when diagnosis and care are properly instituted, resolution of these wounds can be difficult and prolonged (Table 6). While it is true that rheumatoid and similar patients have prosthetic arthroplasties and other elective surgery performed successfully, the presence of chronic ulceration indicates locally advanced pathology and active systemic disease which consistently stymie attempts to treat. Histories of many years or decades duration and failed prior wound surgery are common. The prospects for successful surgery using nearby autogenous tissues are very small. Many of the patients in this study, being older, had concurrent venous or arterial disease of varying degrees. Because the pathology of these disorders causes lytic ulceration, it is common for adipose fascias to be dissolved, leaving muscles, tendons, retinacular ligaments, bones, and joints uncovered. Therefore, most of the study patients with these diagnoses had exposed structures compounding the issue of active refractory pathology. Seven of the patients had extensive or circumferential leg ulceration comparable to the one in case study 12. Effective management begins with control of the underlying disease to the extent that it is possible. It is not always possible though, and residual dermatitis, panniculitis, positive serologies, systemic symptoms, and wound inflammation and active ulceration may prevail. It is in these circumstances, where aggressive treatment has improved but not eliminated pathological inflammation, that the concept of a biological superdressing is particularly applicable. Integra’s ability to subside the residual inflammation, then reconstruct skin and cover exposed essential structures had consistently good results in these patients. When some of these patients had subsequent flare-ups with new wounds, the Integra reconstructed skin was spared from re-ulceration. (Cases 1, 2, 7, 12, 15).
Table 6: Duration of care of immunopathic ulcers
data is taken from one of the hospital based wound clinics where many of the
study patients were cared for. This
shows length of care for all clinic patients, collated for administrative
purposes, compiled for a two year period roughly coinciding with the last two
years of the current study. These data
confirm that immunopathic patients are difficult to heal, lengths of
treatment exceeding other categories by substantial factors.
Mechanical, anatomical, trauma, and surgery. Typical histories in this category included pseudarthrosis, ulcerated contractures, and open shearing tendons. These patients tended to be younger, and ulcerative or inflammatory diseases were not a concern. Essential coverage situations were not only common but they were often part of the actual wound pathology, since it was exposure of these structures which were inhibiting wound repair or closure. In these patients, Integra was opted because of limited options for flaps, risky flaps due to concomitant vascular disease, and anatomic locale such as the dorsum of the hand or across joints where a thin but compliant reconstruction was desirable. (Cases 9, 15, 16, 19, 20).
Granulomatous, infectious, and miscellaneous. There are some incidental chronic ulcers due to infections, metabolic disorders, and other infrequent pathological conditions. These include atypical infections (mycobacteria, fungi, actinomycetes), granulomatous inflammation, osteomyelitis, and localized calcium dystrophies, with or without other risk. These are all comparable to mechanical and traumatic ulcers in that disease is localized, that it can be eliminated by adequate excision and adjuvant therapy, and that general health and wound healing competence are not affected. In all of these situations, excision of disease, good wound preparation, proper adjuvant treatments, and control of motion allow Integra to be used to cover essential structures and to induce stable healing wounds.
Radiation and malignancy. In the few radiation ulcers in this study, time to skin grafts and time to completion were long, but Integra nevertheless healed. Because radiation damages the proliferative potential of local wound module progenitor cells, normal wound healing can fail. Integra has the virtue that, even if it is healing slowly, it provides superb protection to the wound, allowing regeneration to occur at whatever slow rate it will. To the extent that the pioneers and some angioblasts are migratory cells ultimately derived from bone marrow, Integra might theoretically succeed even over highly irradiated tissues (> 6000 cGy). One of Integra’s properties, fulfilling the concept of “tissue engineering”, is that the matrix can be a carrier of seeded cells, allowing the surgeon to supply what the host wound cannot. This concept was used successfully in two patients with bare irradiated calvarium (case 25, figure 30). Integra was also used in two patients in this study for wound closure and essential coverage after wide resection of ulcerated tumors, but it was never used to close gross tumor itself. Its use in that regard can be considered the same as closure of any surgical or anatomical defect.
Figure 30 a (top left), b (top middle), c (top right), d (bottom left), e (bottom middle), f (bottom right)
(a) This 82 year old woman had scalp skin cancer treated by radiation, 6500 cGy. The resulting chronic ulcer of parietal cranium was vascular and viable but not wound healing competent. The situation was compounded by advanced Paget’s disease of bone, causing deformity, atrophy, and immobility of the surrounding scalp making local flaps impossible. Various large remote flaps would have succeeded, but the patient was only willing to consent to minor outpatient and clinic procedures. The solution was to use Integra as a carrier of healthy cells. The reconstruction started by placing a small fenestrated plastic chamber under abdominal skin. Two weeks later, proliferative tissue within the chamber has removed, then mashed, partly trypsinized, and filtered. The resulting paste of mitosis-competent mesenchymal cells was worked into a piece of Integra which was then applied to the debrided scalp wound. This image is the scalp ulcer after debridement, just prior to placing the seeded Integra.
(b) This is the matrix at 2 weeks. Some small unmacerated yellow fat lobules are present from the original seeding. Scattered through the matrix, especially center, right, and top, is a multifocal bloom of opacifying loci distinct from normal Integra regeneration patterns. The matrix may have been populated in part by wound-derived cells, either blood borne or locally resident, but this image suggests that it was mainly the cell transplants which generated the neodermis.
(c) When the first piece of Integra was regenerated, it was opted to place a second piece to build a thicker lamina of new tissue. This image is at 4 weeks, at the time of the exchange.
(d) This is the second piece of Integra, completely regenerated and ready for skin grafts.
(e) The skin grafts appear normal here, 2 weeks after their placement.
(f) The skin grafts healed transiently. Seen here 5 months later, dystrophic pagetoid bone is starting to extrude through the reconstruction, beginning to cause new ulceration. The patient has since adopted a program of chronic maintenance care for the open areas, and she remains healthy. While this was an odd and unlikely set of circumstances, it demonstrates that Integra can be used as an in situ reactor or incubator to engineer a new tissue using cultivated cells not derived from the substrate wound.
Adjunct. Patients in this category had large or long-standing defects needing a complex reconstruction. Integra was not the preferred option to directly close the primary wounds, and large or delayed flaps were used for that purpose. However, Integra was an ideal companion to the flaps. They were used in coordination for these reasons: (1) A flap donor site might have its own needs for closure. (2) For flaps in intermediate stages of transfer, Integra can close and protect an unsatisfied open end, and it can cover a bare undersurface to simplify care and prevent contraction. (3) Integra can close the donor wound under a delayed flap, preventing revascularization where delay incisions have already been made, and simplifying the final transfer. (4) A mosaic reconstruction can be done, using a small, safe, dependable flap where it is most crucially needed, and using Integra to close remaining areas where the flap cannot cover. If Integra is used for these purposes, in lieu of skin grafts, it will protect an open or delayed flap, improve the safety and dependability of the flaps, make the flap donor site easier to manage, avoid extra donor sites, simplify a complex reconstruction, improve quality of the final result, simplify post-operative care, and minimize wound area, pain, drainage, and nursing needs (this was especially useful for the 2 children in this series, case 17).
Use of Integra, Discussion by Anatomy
Head, trunk, upper extremity. As would be expected, wounds and reconstruction on upper parts of the body tended to do well. The indications for Integra were comparable to those already discussed: refractory ulcers by history, failed prior procedures, exposed essential structures, lack of suitable local flaps, and the desire to limit donor sites. Integra was particularly effective for closing the dorsum of the hand. Situations which by convention require groin, abdominal, radial forearm, and similar flaps also require staged transfers, imposed disabilities, risk to the forearm and hand, difficult nursing and daily activities, and staged reductions of fat once the flaps are healed. Integra results in a thin and compliant tissue comparable to normal dorsal hand skin, with neither donor sites, nursing and functional problems, risk of flap necrosis and dehiscence, nor late revisions. Whether for trauma, chronic wounds, or elective reconstruction, Integra should be considered the option of choice for restoring skin on the dorsum of the hand and wrist.
Lower extremity. Most chronic wounds are on the lower extremity, reflected in the distribution of these cases. Special circumstances and caveats apply when doing any reconstruction on the lower extremity, Integra or otherwise. Integra tends to mitigate pathology and inflammation, which is why it is effective when other treatments have failed, but the following issues must always be considered. Never overlook the possibility of concurrent arterial or venous disease, or any other combination of multiple risks, and treat each risk accordingly. Regeneration times may be prolonged, 6 - 7 weeks sometimes. Edema control and graft fixation are essential. Use splints or boots to control motion of joints or major tendons that are covered with Integra. Avoid pressure injury due to tight bandaging around the foot and ankle. Do whatever is required to protect the reconstruction, but do allow ambulation and preserve function as long as mechanical loads and strains on the graft are completely eliminated in responsible patients. Concurrent treatment of the underlying disorder must continue (e.g. steroids for immunopathic disorders, anticoagulants for hypercoagulable disorders) depending on the status of the disease and complications of treatment.
Exposed structures. Conventional plastic surgery principles dictate that open bones, joints and bursas, tendons, viscera, and alloplastic materials all be covered with flaps, i.e. vascularized composite tissues capable of independently healing the recipient wound. Skin grafts and other living or autogenous materials can be, at best, only a temporary biological dressing. As a skin substitute, Integra provides superior acute coverage of these structures. Because of its ability to conduct histogenesis tangentially, it readily bridges these defects. In this study, Integra closed 90% of all such instances (table 3d). It did so when flaps were not possible, without donor sites and donor morbidity, and without late revision. Since exposure of these structures is what prompts many surgeons to suggest amputation, Integra resulted, in principle, in many saved limbs. Notable points are the following.
Integra does well on bone, because healthy bone is healthy tissue, mechanically stable and alive, capable of sourcing cells and circulation into the graft (cases 7, 8, 14, 15, 18, 19, 21, 22, 23, 24, 25). If Integra over bone (or any tissue) turns black, it means that the subjacent bone is dead. Further tangential bone debridement and reapplication of Integra will succeed. Integra performed well over open joints, especially small joints of the hands and feet. Until healed, control of motion by bandages or orthotics is essential. Integra performed well over tendons (cases 1, 2, 3, 5, 7, 10, 12, 16, 20, 23). It does especially well over small extensor tendons. Tendon diameter does not seem to be necessarily important, but a combination of size and excursion is, with peroneus tendons just above the malleolus and tibialis tendons across the ankle being most likely to require secondary coverage by flaps or new Integra. Note that if Integra can control and heal a large wound to the point that only a small accessory flap is needed to close a small peroneus exposure (category 2 incomplete healing), this is a clinical success (case 4). Integra does uniformly well over the achilles tendon, as long as the tendon is properly debrided. Pressure ulcers of achilles tendon and of heel (calcaneus) are common, independently or accompanying each other, and when surgery is indicated, Integra readily solves both problems (cases 1, 21, 23, 24). Visceral organs and alloplastic hardware are best closed by flaps, but when flaps are unavailable or patient risk contradicts their use, Integra does a remarkably good job of closing and restoring skin over them (case 16). One of Integra’s values is that it buys time for the surgeon and patient. It can protect a wound or structure while ancillary matters are stabilized or while a final flap is being delayed. If, while being used as an interim skin substitute, it regenerates and heals the wound, then the parallel plan of closure can be abdicated.
Technique and Management
Good outcomes with Integra are contingent on technique and details of management. The nominal methods of use, which are comparable to ordinary skin grafts, are described in prior literature and in the package insert. This section discusses additional details especially relevant to its use in chronic wounds.
Control disease and prepare the wound. All chronic wound patients must have accurate diagnosis and treatment of underlying disease and risks. There must be thorough pre-operative control of inflammation, ulceration, debris and bioburden, and edema (as best as the disease and available treatments permit). Integra can control some residual pathological inflammation, but to ignore proper wound preparation invites abscess and loss of the material. The most common preparatory treatment profile for patients in this group was twice daily hygiene and silver sulfadiazine dressings, edema control by elastic or multilayer bandaging, and incidental therapies related to individual diagnoses.
Excise the wound. Regardless of how well the wound has been prepared and how healthy it looks, Integra must not be placed on an existing wound surface. Not only does this risk infection, but if Integra is placed on a proliferative wound module of cells already committed to conventional inflammatory fibrous repair, the full late phase benefits of a compliant scarless tissue will not be realized. At the time of surgery, the entire existing wound must be completely excised. If anatomical circumstances preclude safe excision (e.g. the wound is on open internal organs), then thorough curettage should be done to remove all “granulation tissue”. Integra is a surgical implant, not a wound dressing, and it must be accorded due respect.
Forms and availability. The original product, packaged in isopropyl alcohol, is available in three rectangular sizes, 4x5, 4x10, and 8x10 inches. As much as is needed can be opened and applied to cover the prepared wound after first rinsing out the alcohol. A new package using only electrolyte buffer is recently available. If needed, the Integra sponge can be gently scraped from the silicone and used by itself for extra thickness or bulk filling in small bursas or cavities.
Antibiotics. Antibiotics are used by many surgeons, usually as part of the preliminary rinse. All patients in this study had concentrated antibiotics impregnated into the sponge after the rinses were complete (Table 7), supplemented by several days of systemic antibiotics (oral for outpatients, intravenous for inpatients). The low, nearly zero infection rate is attributed predominantly to good pre-operative preparation, complete excision of the wound, and good fixation and compression. Whether antibiotics are useful or not is a matter of faith, but they are a cheap and safe hedge against an undesirable complication.
Table 7: Antibiotic use and concentration
Antibiotics can be impregnated into the Integra matrix. Choice of drugs is arbitrary. The investigator’s practice has been to use 1 gm vancomycin dissolved in 3 vials of gentamicin solution (6 cc’s, 240 mg), one such mix applied to each Integra sheet (4 x 10 or 8 x 10 inches) after rinsing and preparation. This mixture was chosen based on its antimicrobial spectrum and the simple reality that these are the drugs stocked in the operating rooms where the author practices. This practice has been safe, as measured by serum drug levels. Representative patient A had closure of the leg for extensive rheumatoid ulceration (750 sq cm Integra), and patients B and C had dermatofasciectomy of the leg for primary lymphedema (2000 sq cm Integra). The total “dose” is indicated. Serum drug levels were measured at the indicated times after surgery. Serum drug levels remained low, at or below normal therapeutic trough levels. There have been no instances of oto- nor nephrotoxicity, but the practice ought to be amended in the face of renal insufficiency (or alternate drugs used). It seems that the Integra is either binding or sequestering the drugs, presumably maintaining high local concentrations without significant systemic exposure. This discussion does not advocate a specific formula or choice of drugs, but simply demonstrates that the practice is safe.
Application to wound. The Integra must conform to and contact the wound surface. Tension within the material will shear the sponge from the silicone, so the material must not be stretched. The material as is is sufficiently deformable to let it conform to most wound surfaces, but it can be folded, pleated, darted, and mosaicized in any way desired so that unstrained material is everywhere in contact with the wound. It can be affixed with sutures, staples, or any suitable alternative. While not used on any of these patients, others have reported good success using fibrin glues to cement the product on the wound.
Fixation and compression. Fixation and compression are of paramount importance. The principles and art are no different than for affixing any skin graft. Elastic bandages, padded “tie-over” dressings, and vacuum devices, interphalangeal pins and other hardware fixation, and splints, boots, and other orthotics are all used, depending on circumstances, to ensure that the material adheres to the wound without shear, and that hematomas and seromas do not accumulate. In the patients in this study, elastic compression bandages, occasional tie-over dressings, and plaster or prefabricated splints across joints were the common forms of fixation.
Interim management & observation. If disease has been controlled, the wound properly prepared and excised, and the graft properly fixated, then post-operative care and concerns are minimum. Because histogenesis is observable through the silicone, it is necessary to periodically examine the graft. For these patients, examinations were done at one week intervals during normal clinic hours, consisting of unwrapping and then rewrapping new compression bandages. If there are no problems with the graft or the dressings, examination intervals of 2-3 weeks suffice. When the graft is fully opacified with new tissue, skin grafts are ready to be placed. Time until skin grafts is usually 3 - 4 weeks in young healthy people with upper body reconstructions. For chronic wound patients in this study, intervals were mostly 5 – 6 weeks (table 4). Activities and lifestyle are permitted to the extent that splinting and edema control can be maintained.
Separated silicone. As regeneration nears completion, new tissue dislodges the silicone overlayer. The nominal usage of Integra is to place skin grafts when histogenesis is complete, but before the silicone separates. Silicone sometimes separates before grafts can be placed. Blistering of the silicone is irrelevant, but if it opens onto an edge, then some minor inflammation and benign sub-silicone abscess can result. Removing or windowing the silicone and beginning regular hygienic topical care will keep the matrix healthy, regenerating, and ready for the skin grafts. Usually of no consequence, this rarely affects whether the wound heals, but it can risk getting some inflammatory wound module and scar. Another problem is premature silicone ejection due to benign foreign body giant cell reaction. This should not be confused with acute inflammation or infection, and it will not jeopardize the skin grafts (figure 28-5b).
Overgrafts. When dermatogenesis is complete, the silicone is lifted, and thin epidermal autografts are placed on the neodermis. These skin grafts are managed as any other, but thin grafts (3 – 8 thousandths of an inch) are typically used, trying to minimize the amount of mature dermis which is transplanted, and minimizing donor site problems in these at-risk patients. Customary graft care is practiced, and small remaining bare areas will gradually epithelialize. Grafts can heal within 2 – 8 weeks in healthy patients, but in more problematic wounds, complete epidermal healing times can be several months (table 4a). If Integra is open, either because of silicone separation or failed skin grafts, then one has to choose between topical care or new skin grafts. Regenerated Integra is an inherently healthy “naked dermis” which is effectively closing native tissues underneath. With some basic hygienic care, it can remain open like any other wound. Left ungrafted, regenerated matrix either will or will not epithelialize from the margins. In select circumstances in healthy patients with smaller wounds, open care and natural epithelialization can be opted in lieu of operative skin grafts 52. It must be remembered that regenerated Integra is a mesodermal structure, and until epithelialized, some kind of active care will always be required. Delayed epithelialization and extended care seem to be quite acceptable to most patients because the grafts are usually more healed than not, residual open areas tend to be small, and the patients are already much improved.
Ancillary therapies. The nominal
reconstruction of Integra and one simple skin graft (outcome type 1a) is the
norm in young healthy patients with trauma wounds. In these study patients, only 22% had this
outcome. Another 10% required prolonged
topical care until the first skin graft was fully healed. While various non-specific wound dressings were
used, what distinguished this group and others was that some additional
deliberate intervention was done to promote reepithelialization. Used for their pro-proliferative wound
stimulatory effects, platelet-derived growth factor (PDGF, recombinant human
PDGF-BB, becaplermin, Regranex®, Ortho-McNeil,
Secondary procedures. Secondary surgery means using second skin grafts, small flaps, or more Integra to complete a reconstruction where the initial skin grafts did not take and could not be coaxed to epithelialize. Most secondary surgery was supplemental to the original reconstruction in patients doing well rather than a bailout from the original plan in patients doing poorly. There was no consistency about when to do another procedure. Whenever it became clear that the current situation would not improve any further with topical care only, the next procedure was done. The same judgments were applied to the few patients doing poorly who required amputation. (Cases 4, 10).
Planned second Integra. If an Integra reconstruction does mostly well, but there are some unhealed areas, a second piece of Integra can complete closure of those areas. There are also circumstances in which using multiple sequential pieces of Integra is part of the strategic treatment plan. Situations which warrant this include: using Integra as a long duration artificial skin, replacing a fresh piece before silicone separates on the first piece (case 16); maintaining uninterrupted coverage while waiting for tangential histogenesis to bridge a gap (cases 3, 16); needing a thicker multiple layer of regenerated tissue (cases 20, 25).
Long term management. Unlike normal scars, for which maturation and related care can become foremost issues, regenerated Integra is a nearly mature, mechanically compliant, esthetically acceptable tissue by the time that skin grafts are placed and healed. It can be injured by trauma (case 22), but after about 3 months, the new skin seems to be very durable. Simple protective wraps and continued edema control were recommended for several months in most of these patients, but because they were doing well, many did not follow up consistently. While the material might be somewhat resistant to the effects of recurrent inflammatory and ulcerative disorders, this cannot be counted on. Continued management of underlying diseases and risks is mandatory for the general health of the patient and the continued health of the reconstruction.
Complications and problems. With proper wound preparation, excision of the wound, and graft fixation, complication rates should be low. Acute hematomas and loss of adhesion due to motion are avoidable and can be easily managed by evacuation, better fixation, and a new piece of Integra if needed. As regeneration progresses, the silicone can be ejected before skin grafts are placed. If that occurs, the open Integra can be managed by customary daily hygiene and dressings until skin grafts can be placed. This will not jeopardize whether the wound heals, but it does risk getting some inflammation and scar. However, as long as primary disease and inflammation are under control, exposed structures are closed, and the original wound is healed under the Integra, what happens on the superficial surface becomes of lesser concern. Occasionally, silicone separates in limited areas, resulting in blisters with turbid milky exudates. Whether due to foreign body reaction against the silicone or something else, they are not accompanied by pain, erythema, nor destruction of the regenerated matrix. These sterile abscesses have been managed by excising silicone wherever the problem is, and instituting daily care. Skin grafts typically do take in these areas. True infection, manifested as intense inflammation, pain, suppuration, and loss of the material, occurred in only one patient in this series, and it should be avoidable with good wound preparation and excision. The management of lost or delayed skin grafts is discussed above.
Open Integra. Loss of silicone or overgrafts is not the preferred pathway, but it is no catastrophe, and the reconstructed new dermis can be safely managed without a cover, by routine topical hygiene and dressings. A consistent observation is that even when regenerated Integra remains unepithelialized, the wound and periwound tissues remain free of inflammation, pain, active necrosis and ulceration, and any other evidence of the original problem (as long as underlying diseases are also adequately treated). Unepithelialized “naked dermis” Integra is therefore therapeutic, far more tolerable to patients than the original wound was, and sometimes even perfectly acceptable.
Failed Integra. Applied to chronic and pathological wounds, Integra usually succeeds, but active disease and altered wound physiology mean that there is always some potential to fail. While instances of failure were not many, there were several different mechanisms. (1) “Gangrene” of the matrix. When Integra covers non-viable tissues it turns black, a sure sign of residual undebrided eschar or of extreme arterial insufficiency. (2) Failure to regenerate. The matrix can persist as is, without evidence of histogenesis. Usually just patchy, this seems to correlate with general debility or advanced illness. (3) Early lysis or ulceration. Seemingly regenerated matrix can suddenly ulcerate or involute, either before or soon after skin grafting. Accompanied by new ulcers in surrounding native skin, this is a dependable marker of underlying disease flare-up, typically immunopathic or hematological disorders (Integra may be more tolerant of disease recurrence than native tissues, but it is not invulnerable). (4) Failure to accept or support skin grafts. Apparent take and then dissolution of skin grafts has been observed by many practitioners. Second skin grafts usually succeed, but if the Integra remains persistently open, it can be managed as discussed above. This problem seems to have occurred more in younger patients, less than 40 years old, and particular reasons for the problem have not been deduced. (5) Conversion to a conventional wound with inflammatory healing. This is a combination of the above situations. If grafts do not adhere and disease takes over, the open Integra eventually reverts to an ordinary wound. (6) Late ulceration. Integra which has completely healed might reulcerate if disease or maintenance care get out of control. If it already healed once, it should be easy to get an incipient new lesion rehealed with good hygiene, edema control, and anti-inflammatory and disease specific therapies. In all of these situations, the problem is not inherent to the matrix, but reflects problems with disease and patient management. When these events do occur, the following should be done: reestablish good daily wound care; reassess patient and disease status; intensify treatment of underlying disease if needed; check to make sure that arterial vascular status has not changed during the course of treatment; perform further debridement as needed; rethink the overall treatment plan. When wound and disease are back under control, try again for closure, with new Integra or by other means depending on the new plans.
Logistics. Unless a patient’s underlying disease warrants inpatient care, all management is outpatient. Integra and skin grafts are all placed in the operating room, with follow-up care in office or clinic. There is sufficient latitude in the timing of the skin grafts to accommodate the realities of scheduling. Many patients can continue their daily affairs at home, with restrictions on activity, leg elevation, and ambulation based on individual circumstances. When Integra is used for trauma or elective reconstruction in young healthy people, reconstruction is usually complete within 2 – 4 months, but times will be longer for problem wound closure.
It is most important to realize that, when used for chronic and pathological wounds, the cumulative time required to complete an Integra reconstruction is anything but trivial. Using Integra is neither difficult nor arcane, and 4-6 weeks of matrix regeneration is not long, yet until the last square millimeter is epithelialized, active care must continue. For chronic and pathological wounds, treatment averages 5-6 months for most diagnoses, and as much as 10 months for radiation and immunopathic disorders. Physicians who do not regularly treat chronic wounds must appreciate these times and not become anxious nor lose interest. The clinical process is simply mirroring the biological dynamics of its regeneration. Normal inflammatory wound healing works quickly, over days to weeks, and it then leaves a wake of scar related complications that may require months or years of disability and future care. Integra regeneration and related care occupies the middle ground, measured in weeks to months. However, once it is healed, it rarely needs further attention nor late revision. These treatment intervals may seem long to physicians anxious to see good results, but they are accepted by most patients because (1) the ulcer was present for months or years, (2) they are accustomed to needing daily care, (3) once Integra is placed, symptoms and progressive disease resolve, so function, lifestyle, and peace of mind are usually improved, (4) most of the prolonged care is for small unepithelialized but otherwise stable areas, and patients have long since returned to otherwise normal healthy activities, and (5) Integra is succeeding where all else had failed.
Caveats and contraindications. As noted, the number of patients treated with Integra in 6 years was a small fraction of the investigator’s total experience. Many patients with similar problems were treated by topical care or conventional procedures. There are no formal contraindications to using Integra. It is categorically safe, and even if treatment plans change, it is always dependable as a good interim artificial skin in advance of any other reconstruction. Extreme arterial insufficiency was the one single predictable physiological barrier to success, but Integra was also the salvation of many arterial wounds and limbs that could not have been managed by conventional means. Diabetic plantar ulceration was also a poor place to use Integra, but for psychosocial rather than physiological reasons (and for similar reasons, Integra is not well suited to managing pelvic pressure ulcers). The main reason not to use Integra is that a problem can be solved more expeditiously by conventional means. Relative indications for Integra are presented above. The inverse is true, if those conditions do not exist, Integra is not necessary. If underlying structures are not exposed, if disease and risks are easily or fully controlled, if dependable flaps are present, if prior conventional procedures were uncomplicated, if a preliminary period of observation and topical care shows that the wound is wound healing competent, then conventional management and surgery should be done if that is what is best. All decisions should be predicated on the goals of controlling disease and symptoms, healing the wound, doing so as quickly and efficiently as possible with minimized costs and resource utilization, all while preserving function and lifestyle. Whatever treatment can be anticipated to best fulfill these goals should be selected. The great majority of wounds are best managed by ordinary means. Integra is used for those problems, large or small, life or limb threatening, complex, pathological, refractory, and therapeutically challenging, for which customary methods of care have not or will not work
Costs of care were not directly measured, but the inpatient-outpatient rates are an interesting reflection of their times and the success of a new product. The decline of the inpatient rate to zero reflects several factors: (1) increasing familiarity of the investigator with Integra and its capabilities; (2) increasing support for outpatient clinic and home health wound services at the facilities where the investigator practices; (3) concurrent socioeconomic changes in the delivery and payment of medical services in the United States driving care away from the hospital. Integra is clearly a product well suited to taking care of complex problems as an outpatient. Given the prolonged failed care that these patients had prior to Integra or would have had absent Integra, and given the success and outpatient nature of the care, the cost of an Integra reconstruction for a chronic or pathological wound is assumed to be favorable.
Tables 3 show that 71 % of patients (Group 1) had complete success, and 20% (Group 2) had partial success. However, the way that these results were tallied and reported skews the apparent results toward failure, that is, tangible results were actually better. For example, one rheumatoid patient died before the skin grafts were completely healed, so she was assigned to group 2b, but Integra had clearly performed well with dramatic improvements in the patient and all wounds. Case study 10 was likewise classified a partial success (type 2a, group 2x) simply because a small secondary procedure was needed, but the ability of Integra to close a flexor tendon and salvage a finger in an atherosclerotic hand is a remarkable success. In one of the neuropathic diabetic patients, overt non-compliance resulted in re-injury to the foot that necessitated amputation. The Integra was inherently a complete success, but because it did not contribute anything meaningful to the final outcome, it was categorized as a Group 3 failure. In one of the arteriopathic patients, Integra likewise performed perfectly on large leg wounds, but subsequent foot necrosis before the reconstruction was healed necessitated amputation, consigning this case as well to the Group 3 failures.
Integra Dermal Regeneration Template is a unique surgical implant that functions first as a high quality artificial skin, and then becomes the agent of dermal regeneration. Its use is a type of in situ tissue engineering. It has many indications for the closure of traumatic and surgical wounds and for elective reconstructive surgery and the regulation of scar. This study demonstrates its utility or superiority for the management of chronic and pathological wounds. It achieves good results – healed wounds – in situations where conventional wound closure options have failed or amputations are threatened. Unlike topical care alone, Integra can control wound conditions, inflammation, and pathergy, allowing a wound to recover and regenerate at its own rate without further jeopardy. Unlike skin grafts, it is not alive, so it does not risk loss due to necrosis, making it ideal for circumstances in which ischemia and residual pathology threaten a graft. It’s ability to close essential visceral and skeletal structures generally equals conventional flaps, and it is safer and more versatile than many flaps, because it works when and where flaps are unavailable, contraindicated, or uncertain to succeed. In this investigator’s practice, it has supplanted many conventional wound closure procedures. The newly regenerated skin, having certain embryonic characteristics, seems to be resistant to the effects of recurrent disease such as rheumatoid panniculitis and venous vasculitis. Integra has no donor sites, and it incurs no risk to the patient.
There do not seem to be any inherent deficiencies in Integra’s ability to induce regenerative histogenesis in the matrix. Absent surgical faults and inadequate wound preparation, failures and problems can be attributed only to severity and recurrence of disease or injury. Severe arterial insufficiency (ankle-brachial indices approximately 0.3 or less) and non-compliant diabetic patients with plantar wounds were the two consistent causes of failure. Nevertheless, Integra was the means of success for many arteriopathic ulcers. For most other patients in other categories of disease, Integra succeeded where all prior attempts to treat had failed. Even when technical success was only partial, where Integra did not fully epithelialize, clinical success was still good, because wound closure was then completed with only minor further intervention, and because the open Integra was always better than the original wound. Composite results out of 103 patients were 71% complete success and 20% partial success. If those patients now understood to be poorly selected are excluded, results were 92 % substantial or complete success.
Integra is a staged process, and several months are required to complete a reconstruction. However, this is acceptable to patients because ulceration is arrested, symptoms are relieved, care is simplified, and recuperation and preservation of lifestyle are facilitated. Patients with chronic wounds are therefore willing to bear the time required to complete an Integra reconstruction, especially because the necessary care can be strictly outpatient for nearly all subjects. This makes Integra ideally suited to the changing economics and sociology of contemporary medicine.
Integra’s ability to protect a wound, control inflammation, suppress normal wound repair and scar, induce embryonic histogenesis, conduct histogenesis across gaps, withstand future flare-ups of disease, and do so with no risk to the patient is a combination of features unparalleled among surgical and wound products. As a method of in situ tissue engineering, this surgical device is a genuinely new paradigm of wound repair. It is not an alternative to flaps and grafts, but rather an equal option, and all must be selected based on their own merits, indications, and criteria. Integra’s biological properties, its safety profile, and its practicality make it the preferred modality for a variety of problems. This is especially true for chronic and pathological wounds, where conventional repair, grafts, and flaps usually fail or are ineligible, but Integra succeeds. After 30 years of development and 10 years of clinical use, Integra is no longer a novelty product for burn surgery. It is a versatile surgical tool with unique properties and safety, and Integra ought to be adopted as a preferred method of closing chronic and pathological wounds.
1. Yannas IV, Burke JF. Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 14: 65-81, 1980.
IV, Burke JF,
3. Yannas IV. Studies on the biological activity of the dermal regeneration template. Wound Repair Regen 6: 518-23, 1998.
4. Burke JF, Yanna IVs, Quinby, Jr WC, et al. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 194: 413–28, 1981.
5. Heimbach D, Luterman A, Burke J, et al. Artificial dermis for major burns: a multi-center randomized clinical trial. Ann Surg 208: 313–20, 1988.
6. Heimbach DM, Warden GD, Luterman A, et al. Multicenter postapproval clinical trial of Integra® dermal regeneration template for burn treatment. J Burn Care Rehabil 24: 42-48, 2003.
8. Dostal GH, Gamelli RL. Fetal wound healing. Surg Gynecol Obstet 176: 299-306, 1993.
CN. Glycosaminoglycan interactions in
early wound repair, in Hunt TK, Heppenstall RB, Pines E, et al. (eds.). Soft and Hard Tissue Repair: Biological
and Clinical Aspects.
11. Olutoye OO, Barone EJ, Yager DR, et al. Hyaluronic acid inhibits fetal platelet function: implications in scarless healing. J Pediatr Surg 32: 1037-40, 1997.
12. Data on
13. Ronca F, Palmieri L, Panicucci P, et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 6 SupplA: 14-21, 1998.
14. Hunt TK,
Knighton DR, Thakral KK, et al. Cellular
control of repair, in Hunt TK, Heppenstall RB, Pines E, et al. (eds.). Soft and Hard Tissue Repair: Biological and
15. Holbrook KA, Smith LT. Ultrastructural aspects of human skin during the embryonic, fetal, premature, neonatal, and adult periods of life. Birth Defects 17: 9-38, 1981.
16. Gottlieb ME. Modelling blood vessels: a deterministic method with fractal structure based on physiological rules. Proceedings of the 12th International Meeting, IEEE Engineering in Medicine and Biology Society, 1990.
DW, Ben-David K, Perrin KJ, et al.: Comparison of the biomechanical properties
of burns grafted with conventional split thickness skin vs. IntegraTM
artificial skin. Bostwick Burn and
20. Orgill DP, Straus FH 2nd, Lee RC. The use of collagen-GAG membranes in reconstructive surgery. Ann NY Acad Sci 888: 233-48, 1999.
21. Chou TD, Chen SL, Lee TW, et al. Reconstruction of burn scar of the upper extremities with artificial skin. Plast Reconstr Surg 108: 378-84, 2001.
22. Dantzer E, Queruel P, Salinier L, et al. Dermal regeneration template for deep hand burns: clinical utility for both early grafting and reconstructive surgery. Br J Plast Surg 56: 764-74, 2003.
23. Moiemen NS, Staiano JJ, Ojeh NO, et al. Reconstructive surgery with a dermal regeneration template: clinical and histologic study. Plast Reconstr Surg 108: 93-103, 2001.
24. Stern R, McPherson M, Longaker MT. Histologic study of artificial skin used in the treatment of full-thickness thermal injury. J Burn Care Rehabil 11: 7-13, 1990.
A, Voigt D,
26. Wiley DE,
Kowal-Vern A, Latenser BA. Successful
Application of Integra® in a Polytrauma Case.
Presented at John A. Boswick Burn and Wound Care Symposium,
27. Lorenz C, Petracic A, Hohl HP, et al. Early wound closure and early reconstruction. Experience with a dermal substitute in a child with 60 per cent surface area burn. Burns 23: 505-8, 1997.
28. Palao R, Gomez P, Huguet P. Burned breast reconstructive surgery with Integra dermal regeneration template. Br J Plast Surg 56: 252-9, 2003.
29. Kopp J,
30. Berger A, Tanzella U, Machens HG, et al. Administration of Integra on primary burn wounds and unstable secondary scars. Chirurg 71: 558-63, 2000.
AR, Drew P,
32. Soejima K, Nozaki M, Sasaki K, et al. Reconstruction of burn deformity using artificial dermis combined with thin split-skin grafting. Burns 23: 501-4, 1997.
33. Gonyon DL, Zenn MR. Simple approach to the radiated scalp wound using INTEGRA skin substitute. Ann Plast Surg 50: 315-20, 2003.
34. Dantzer E, Braye FM. Reconstructive surgery using an artificial dermis (Integra): results with 39 grafts. Br J Plas Surg 54: 659-64, 2001.
35. Dantzer E, Queruel P, Salinier L, et al. Integra, a new surgical alternative for the treatment of massive burns. Clinical evaluation of acute and reconstructive surgery: 39 cases. Ann Chir Plast Esthet 46: 173-89, 2001.
36. Wang JCY, To EWH. Application of dermal substitute (Integra) to donor site defect of forehead flap. Br J Plast Surg 53: 70-2, 2000.
37. Hunt JA, Moisidis E, Haertsch P. Initial experience of Integra in the treatment of post-burn anterior cervical neck contracture. Br J Plast Surg 53: 652-8, 2000.
38. Giovannini UM, Teot L. Aesthetic complex reconstruction of the lower leg: application of a dermal substitute (Integra) to an adipofascial flap. Br J Plast Surg 55: 171-2, 2002.
40. King P. Artificial skin reduces nutritional requirements in a severely burned child. Burns 26: 501-3, 2000.
SM, Gulati S. Salvage of a Patient with
Abdominal Wall Dehiscence and Necrotized Skin using Integra®. Presented at John A. Boswick Burn and Wound
42. Besner GE, Klamar JE. Integra Artificial Skin as a useful adjunct in the treatment of purpura fulminans. J Burn Care Rehabil 19: 324-9, 1998. .
43. Ryan CM, Schoenfeld DA, Malloy M, et al. Use of Intergra® Artificial Skin is associated with decreased length of stay for severely injured adult burn survivors. J Burn Care Rehabil 23: 311-7, 2002.
45. Loss M, Wedler V, Kunzi W, et al. Artificial skin, split-thickness autograft and cultured autologous keratinocytes combined to treat a severe burn injury of 93% of TBSA Burns 26 :644-52, 2000.
46. Demarest GB, Resurrecion R, Lu S, et al. Experience With Bilaminate Bioartificial Skin Substitute and Ultrathin Skin Grafting in Non-Burn Soft-Tissue Wound Defects. Wounds 15: 250-56, 2003.
47. Suzuki S, Matsuda K, Isshiki N, et al. Clinical evaluation of a new bilayer "artificial skin" composed of collagen sponge and silicone layer. Br J Plast Surg 43: 47-54, 1990.
KW. Treatment of Necrotizing Fasciitis
Wounds with Integra® Dermal Regeneration Template. Presented at John A. Boswick Burn and Wound
49. Vazquez Rueda F, Ayala Montoro J, Blanco Lopez F, et al. First results with Integra artificial skin in the management of severe tissue defects in children. Cir Pediatr 14: 91-4, 2001.
JE, Falabella AF,
ME. Lower Extremity Lymphedema -
Management by Total Dermatofasciectomy and Skin Reconstruction with
Integra®. Presented at John A. Boswick
Burn and Wound Care Symposium,
52. Prystowsky JH, Siegel DM, Ascherman JA. Artificial skin for closure and healing of wounds created by skin cancer excisions. Dermatol Surg 27: 648-53, 2001.
53. Soejima K, Nozaki M, Sasaki K, et al. Treatment of giant pigmented nevus using artificial dermis and a secondary skin graft from the scalp. Ann Plast Surg 39: 489-94, 1997.
54. Thomas WO, Rayburn S, Leblanc RT, et al. Artificial skin in the treatment of a large congenital nevus. South Med J 94: 325-28, 2001.
55. Shermak MA, Wong L, Inoue N, et al. Reconstruction of complex cranial wounds with demineralized bone matrix and bilayer artificial skin. J Craniofac Surg 11: 224-31, 2000.
56. Yeong EK, Yang CC. Chronic leg ulcers in Werner's syndrome. Br J Plast Surg 57: 86-88, 2004.
Data compilation and manuscript preparation supported by a
grant from Ethicon,