Use of a collagen-elastin matrix with split-thickness skin graft for defect coverage in complex wounds.

OBJECTIVE: Severe soft tissue damage with destruction of the dermis requires plastic reconstructive treatment. For multimorbid patients or patients unable to undergo major reconstructive surgery, use of dermal substitutes, such as a collagen-elastin matrix (CEM) with a split-thickness skin graft (STSG), instead of local or free flap surgery, may be a valid and easy treatment option. We aimed to investigate and compare the outcomes and rate of successful defect reconstruction using CEM plus STSG, using either a one-step approach (simultaneous CEM and STSG) or a two-step approach (CEM and negative wound pressure therapy (NPWT), with secondary STSG transplantation). METHOD: A single-centre, retrospective follow-up study of patients who had received CEM was conducted. Wounds had been treated with an STSG transplantation covering a CEM (MatriDerm, MedSkin Solutions Dr. Suwelack AG, Germany). Previous attempts at wound closure with conventional methods had failed in the selected patient population, which would usually have resulted in flap surgery. RESULTS: Overall, 46 patients were included (mean age 60.9±20.0 years), with a total of 49 wound sites. We analysed 38 patients with wounds that did not require flap coverage; 18 patients received the one-step approach and 20 patients received the two-step approach. The mean follow-up in these patients was 22±11.5 months, and one patient was lost to follow-up. Overall, 29 (78.4%) wounds remained closed. Wounds which did not successfully heal were related to comorbidities, such as diabetes, alcohol misuse and smoking. Using the one-step approach, long-term defect coverage was achieved in 13 (76.5%) wounds and 16 (80.0%) wounds were closed using the two-step approach. However, there was no statistically significant differences between the one- or two-step approaches regarding the rate of development of a wound healing disorder. CONCLUSION: Wound closure was achieved in 38 complex wounds using CEM plus STSG, while 11 wounds needed secondary flap coverage. In the flap-free wounds, there were no statistically significant differences between the one-step versus two-step approach. Using a simple defect reconstruction algorithm, we successfully used CEM plus STSG to treat complex wounds.

Regression of calcinosis cutis after inkless tattoo in a patient with dermatomyositis: therapeutic potential of microneedling.

Calcinosis cutis is defined as abnormal deposition of calcium salts in the skin and subcutaneous tissues. Dystrophic calcification, the most common form of calcinosis cutis, is associated with autoimmune connective tissue diseases. This condition is associated with severe pain and can affect the patient's quality of life and lead to long-term disability. Treatment is often challenging, and there is a very limited evidence base for potential treatments of calcinosis cutis associated with systemic sclerosis and dermatomyositis. Inkless tattoo is very similar to microneedling, a minimally invasive procedure stimulating the wound-healing cascade contributing to elastin and collagen formation as well as neovascularization. This technique has not been reported as a potential therapeutic option for calcinosis cutis. Here, we present a patient with calcinosis cutis in the setting of dermatomyositis that responded dramatically to inkless tattoo application. Our results support the need for future studies of microneedling in patients with this disorder.

Nanotoxicology of an Elastin-like Polypeptide Rapamycin Formulation for Breast Cancer.

The clinical utility of rapamycin (Rapa) is limited by solubility, bioavailability, and side effects. To overcome this, our team recently reported an elastin-like polypeptide (ELP) nanoparticle with high affinity, noncovalent drug binding, and integrin-mediated cellular uptake. Given the scarcity of pharmacology/toxicology studies of ELP-based drug carriers, this article explores safety and efficacy of ELP-Rapa. ELP-Rapa nanoparticles tested negative for hemolysis, did not interfere in plasma coagulation nor in platelet function, and did not activate the complement. Upon incubation with HepG2 cells, ELP-Rapa revealed significant cellular uptake and trafficking to acidic organelles, consistent with lysosomes. Internalized ELP-Rapa nanoparticles increased oxidative stress 4-fold compared to free drug or free ELP controls. However, mice bearing orthotopic hormone receptor positive BT-474 breast tumors, given a high dose (∼10-fold above therapeutic dose) of 1 month administration of ELP-Rapa, did not induce hepatotoxicity. On the other hand, tumor growth and mTOR signaling were suppressed without affecting body weight. Nanoparticles assembled using ELP technology appear to be a safe and efficient strategy for delivering Rapa.

DERMAL REPLACEMENT WITH MATRIDERM - FIRST EXPERIENCE AT THE PRAGUE BURN CENTRE.

INTRODUCTION: The quality of resulting scar tissue plays an important role in patients return to normal life and full functioning in society. The use of artificial skin substitutes in clinical practice improves functional and cosmetic outcomes. This is true for any patient, and not only those suffering from burns. MATERIAL AND METHODS: The collagen elastin dermal substitute Matriderm® allows for immediate application of a dermal substitute together with a skin graft. The authors present a group of 10 patients representing their first experience in utilizing Matriderm® as a dermal substitute in the treatment of skin losses due to various etiologies. RESULTS: The average healing time in the group was 19.6 days. Healing took place without serious infectious complications and with good functional results. CONCLUSION: Matriderm® can be utilized as an alternative to the most commonly used dermal substitute so far, Integra®, in the treatment of acute skin loss due to various etiologies and in reconstructive surgery.

Reconstruction of Nasal Defects With Dermal Skin Substitutes-A Retrospective Study of 36 Defects.

OBJECTIVES: It is uncertain whether dermal regeneration templates (DRTs) are helpful to reconstruct nasal defects. The aim of this study was to assess whether the aesthetic subunits determine the outcome. METHODS: In this unicentric, retrospective study, the surgical procedures and outcomes of patients who received DRTs to reconstruct nasal defects were assessed and compared with the involved aesthetic subunits. RESULTS: DRTs were used for reconstruction of 36 nasal defects in 35 patients with involvement of 76 aesthetic subunits: nasal sidewall (n = 21), nasal ala (n = 13), nasal tip/columella (n = 12, n = 1, respectively), nasal dorsum (n = 12), and extranasal aesthetic areas (n = 17). Fifty-eight nasal and 8 extranasal aesthetic subunits were reconstructed with DRTs, 10 subunits with a flap. Twenty-nine of 36 defects healed without any complications (80.5%). All reconstructed nasal tips/columella and the nasal dorsa healed without any complications. Region-specific complications were retraction of the ala rim (4/12; 33.3% of the patients with involvement of the nasal ala) and the formation of a fistula in the nasal sidewall (1/21; 4.8%). Region-specific complications of extranasal subunits were the development of an ectropium (2/3; 66.7% of the patients with involvement of the lower lid). CONCLUSIONS: DRTs can be helpful to reconstruct nasal defects. However, if the defect involves the aesthetic subunits nasal ala or the infraorbital region, different techniques should be preferred.

Development of Tissue-Engineered Ligaments: Elastin Promotes Regeneration of the Rabbit Medial Collateral Ligament.

When ligaments are injured, reconstructive surgery is sometimes required to restore function. Methods of reconstructive surgery include transplantation of an artificial ligament and autotransplantation of a tendon. However, these methods have limitations related to the strength of the bone-ligament insertion and biocompatibility of the transplanted tissue after surgery. Therefore, it is necessary to develop new reconstruction methods and pursue the development of artificial ligaments. Elastin is a major component of elastic fibers and ligaments. However, the role of elastin in ligament regeneration has not been described. Here, we developed a rabbit model of a medial collateral ligament (MCL) rupture and treated animal knees with exogenous elastin [100 µg/(0.5 mL·week)] for 6 or 12 weeks. Elastin treatment increased gene expression and protein content of collagen and elastin (gene expression, 6-fold and 42-fold, respectively; protein content, 1.6-fold and 1.9-fold, respectively), and also increased the elastic modulus of MCL increased with elastin treatment (2-fold) compared with the controls. Our data suggest that elastin is involved in the regeneration of damaged ligaments.

Semi-IPN- and IPN-Based Hydrogels.

Semi-interpenetrating polymer networks (semi-IPNs) and interpenetrating polymeric networks (IPNs) have emerged as innovative materials for biomedical and pharmaceutical applications. The interest in these structures is due to the possibility of combining the favorable properties of each polymeric component of the IPNs or semi-IPNs leading to a new system with properties that often differ from those of the two single components. In this respect, polysaccharides represent an opportunity in this field, combining a general biocompatibility and a good availability. Moreover, the functional groups along the polymer chains allow chemical derivatization, widening the possibilities in semi-IPNs and IPNs building up. At the same time, materials based on proteins are often used in this field, due to their similarity to the materials present in the human body. All these overall properties allow tailoring new materials, thus designing desired properties and preparing new hydrogels useful in the biomedical field. In the present chapter, we chose to describe systems prepared starting from the most important and studied hydrogel-forming polysaccharides: alginate, hyaluronic acid, chitosan, dextran, gellan, and scleroglucan. Besides, systems based on proteins, such as gelatin, collagen, and elastin, are also described. With this chapter, we aim describing the routes already traveled in this field, depicting the state of the art and hoping to raise interest in designing new promising strategies useful in biomedical and pharmaceutical applications.

MatriDerm Decreases Donor Site Morbidity After Radial Forearm Free Flap Harvest in Transgender Surgery.

BACKGROUND: Phalloplasty with the radial forearm free flap is associated with a large donor site defect. AIM: To compare two methods of donor site closure for functional and cosmetic long-term results: full-thickness skin grafting vs split-thickness skin grafting with MatriDerm. METHODS: Thirty-seven transgender patients had a neophallus created from a radial forearm free flap, and all were operated on by the same senior surgeon. Eight patients had their donor site defect closed by total skin grafting and 29 patients, operated on after 2009, received a split-thickness skin graft with MatriDerm closure. All 37 patients were evaluated by questionnaire and by careful clinical examination. Pressure perception was assessed with the Semmes-Weinstein monofilament test. Sensory recovery, skin quality, and cosmetic result also were compared. The contralateral arm was used as the control. OUTCOMES: Pressure perception values showed better sensory return in the MatriDerm group. Split-thickness skin grafting with MatriDerm achieved superior results in skin sensibility, superficial radial nerve recovery, and cosmetic aspect. RESULTS: Our findings support the hypothesis that MatriDerm can be used to preserve sensory function and decrease morbidity of the donor site. CLINICAL IMPLICATIONS: The use of a dermal substitute decreases the morbidity of the forearm free flap donor site. STRENGTHS AND LIMITATIONS: The strength of this study is its retrospective nature conducted of a prospectively maintained database of 37 consecutive radial forearm free flaps with superimposable dimensions and location performed by the same surgeon, thus limiting biases. A limitation is its small sample (particularly for the control group). CONCLUSION: Our experience showed that the combination of a split-thickness skin graft with MatriDerm substantially decreases postoperative complications at the donor site defect on the forearm of transgender patients. Watfa W, di Summa PG, Meuli J, et al. MatriDerm Decreases Donor Site Morbidity After Radial Forearm Free Flap Harvest in Transgender Surgery. J Sex Med 2017;14:1277-1284.

Rationally Designed Redox-Sensitive Protein Hydrogels with Tunable Mechanical Properties.

Protein hydrogels are an important class of materials for applications in biotechnology and medicine. The fine-tuning of their sequence, molecular weight, and stereochemistry offers unique opportunities to engineer biofunctionality, biocompatibility, and biodegradability into these materials. Here we report a new family of redox-sensitive protein hydrogels with controllable mechanical properties composed of recombinant silk-elastin-like protein polymers (SELPs). The SELPs were designed and synthesized with different ratios of silk-to-elastin blocks that incorporated periodic cysteine residues. The cysteine-containing SELPs were thermally responsive in solution and rapidly formed hydrogels at body temperature under physiologically relevant, mild oxidative conditions. Upon addition of a low concentration of hydrogen peroxide at 0.05% (w/v), gelation occurred within minutes for the SELPs with a protein concentration of approximately 4% (w/v). The gelation time and mechanical properties of the hydrogels were dependent on the ratio of silk to elastin. These polymer designs also significantly affected redox-sensitive release of a highly polar model drug from the hydrogels in vitro. Furthermore, oxidative gelation was performed at other physiologically relevant temperatures, and this resulted in hydrogels with tunable mechanical properties, thus, providing a secondary level of control over hydrogel stiffness. These newly developed injectable SELP hydrogels with redox-sensitive features and tunable mechanical properties may be potentially useful as biomaterials with broad applications in controlled drug delivery and tissue engineering.

A novel approach to reconstruct a large full thickness abdominal wall defect: successful treatment with MatriDerm® and Split.

OBJECTIVE: Reconstruction of large abdominal wall defects is a challenging procedure, often contraindicated in critically ill patients, with high incidences of complications. We present a case of a patient with a large abdominal wall defect who had reconstruction with MatriDerm® (an engineered dermal template) and split thickness skin grafting (SSG) as an alternative to reconstruction with myo- or fascio-cutaneous flaps. Successful wound closure was achieved with a single technique, while providing a robust reconstruction and an interface between skin and underlying viscera, should further surgery be necessary.

Dermal equivalents in oncology: benefit of one-stage procedure.

BACKGROUND: In oncology, dermal equivalent may be indicated to cover losses of substance related to skin tumors or after the removal of skin flaps. OBJECTIVE: To report our experience of two dermal equivalents, Matriderm 1 mm with a one-stage graft (DE1) and Integra DL with a two-stage graft (DE2) in oncology. PATIENTS AND METHOD: Retrospective, single-center study involving 16 patients. RESULTS: Sixteen patients received dermal equivalents as an alternative to flaps (7 cases), over tendinous areas (7 cases), and for cosmetic purposes (2 cases). Twelve patients received DE1 and four DE2. Wound healing times with DE1 were 4 weeks less than those with DE2. Three cases of infection were noted with DE2. The use of dermal equivalents as an alternative to skin flaps was effective, and no adhesions were found over the tendinous areas. CONCLUSION: The learning curve, the two-stage graft required with DE2, and not using a vacuum-assisted closure system can explain the high infection rate. The use of dermal equivalents is particularly indicated in the treatment of skin defect in oncology. The possibility of a one-stage graft with DE1 and combination with negative pressure therapy is beneficial.

A novel surgical approach to calcinosis cutis using a collagen-elastin matrix.

Calcinosis cutis is a cutaneous disorder characterised by abnormal deposition of calcium in the dermis. Treatment of this condition has variable success rates and includes medical, topical and surgical management. Here we describe a case of a woman with a painful calcinosis lesion on the buttocks, treated with excision and application of a bovine collagen-elastin dermal regeneration template, a thin, porous membrane consisting of a native bovine type I, II and V collagen-fibre template coated with elastin hydrolysate. The patient's wound healed without complication and without the use of a skin graft. She remains recurrence free at 10-month follow up, with satisfactory outcome.

A new model for preclinical testing of dermal substitutes for human skin reconstruction.

BACKGROUND: Currently, acellular dermal substitutes used for skin reconstruction are usually covered with split-thickness skin grafts. The goal of this study was to develop an animal model in which such dermal substitutes can be tested under standardized conditions using a bioengineered dermo-epidermal skin graft for coverage. METHODS: Bioengineered grafts consisting of collagen type I hydrogels with incorporated human fibroblasts and human keratinocytes seeded on these gels were produced. Two different dermal substitutes, namely Matriderm(®), and an acellular collagen type I hydrogel, were applied onto full-thickness skin wounds created on the back of immuno-incompetent rats. As control, no dermal substitute was used. As coverage for the dermal substitutes either the bioengineered grafts were used, or, as controls, human split-thickness skin or neonatal rat epidermis were used. Grafts were excised 21 days post-transplantation. Histology and immunofluorescence was performed to investigate survival, epidermis formation, and vascularization of the grafts. RESULTS: The bioengineered grafts survived on all tested dermal substitutes. Epidermis formation and vascularization were comparable to the controls. CONCLUSION: We could successfully use human bioengineered grafts to test different dermal substitutes. This novel model can be used to investigate newly designed dermal substitutes in detail and in a standardized way.

Engineered elastin-like polypeptide-based hydrogel delivering chemotherapeutics and PD-L1 antibodies for potentiated cancer immunotherapy.

Immune checkpoint inhibitors (ICIs) have effectively eradicated advanced tumors by inducing durable and systematic antitumor immune responses. However, when used as a standalone treatment, ICIs typically exhibit a low response rate in many cancers. In this study, we engineered an in situ-formed gel depot using elastin-like polypeptides (ELPs) to efficiently deliver PD-L1 antibodies (aPD-L1) and gemcitabine (GEM) for enhanced immunotherapy in melanoma. Sustainably released chemotherapeutics from gel depots could kill melanoma cells and promote PD-L1 upregulation in tumor cells. Moreover, aPD-L1/GEM-encapsulated ELP hydrogel promoted a 3.0-fold increase of tumor-infiltrated CD8+ T cells and 60% Tregs depletion compared with PBS group, eliciting a robust antitumor immune response for immunotherapy in melanoma mouse models. This research highlights the promising potential of ELP-based hydrogels in delivering ICIs and chemotherapeutic agents for potentiated cancer immunotherapy.

A Histological and Clinical Study of MatriDerm® Use in Burn Reconstruction.

Dermal substitutes are well established in the reconstructive ladder. MatriDerm® (Dr. Otto Suwelack Skin & Health Care AG, Billerbeck, Germany) is a single-layer dermal substitute composed of a bovine collagen (type I, III, and V) and elastin hydrolysate, that allows for immediate split-thickness skin grafting (SSG). The aim of this study was to histologically characterize the integration of MatriDerm® when used during burns surgery reconstruction. Eight subjects with nine burn scars and one acute burn wound underwent reconstruction with MatriDerm® and an immediate SSG. MatriDerm® integration and skin graft take were assessed with serial biopsies performed at weeks 1, 2, 3, and 4 and months 2, 3, 6, 9, and 12. Biopsies were assessed with standard special stains and immunohistochemistry, and representative slides were imaged with a transmission electron microscope. Patient satisfaction and clinical scar outcome were assessed with the Vancouver Scar Scale and a patient questionnaire. Histological analysis showed similar stages of wound healing as shown in other dermal templates but on a different timescale. There is early evidence of vascularization and an inflammatory infiltrate in the first 2 weeks. MatriDerm® is resorbed earlier than other dermal substitutes, with evidence of resorption at week 3, to be completely replaced by a neodermis at 2 months. The use of MatriDerm® in reconstruction with immediate skin grafting is supported histologically with early evidence of vascularization to support an epidermal autograft. Future histological studies may help further characterize the ideal dermal substitute.

[One-stage defect closure of deperiosted bone and exposed tendons with MATRIDERM® and skin transplantation. Possibilities and limitations]. / Einzeitige Defektdeckung von denudiertem Knochen und freiliegenden Sehnen mittels MATRIDERM® und Spalthaut. Möglichkeiten und Grenzen.

BACKGROUND: Full-thickness skin defects over functional structures (tendons, vessels) or deperiosted bones of the extremities usually require extensive soft tissue reconstruction to cover the defect. A new option for coverage of the defect is the application of MATRIDERM®, a bovine matrix consisting of collagen and elastin, as a neodermis underneath skin transplants. Can this combined one-stage surgical intervention successfully cover deperiosted bone or tendon? PATIENTS AND METHODS: We performed this one-stage procedure in ten patients instead of soft tissue reconstruction. The success of wound coverage with the one-stage method and in combination with skin transplantation for defects generally associated with considerable loss of transplants (deperiosted bones and tendons without paratenons) was determined. RESULTS: In nine of ten patients, complete defect coverage could be achieved. A one-stage wound closure in extensive defects with exposed tendons in four of five locations could be achieved. In deperiosted bone defects the one-stage coverage was only successful in two of six patients. However, complete wound closure could be achieved with a second skin transplantation in a patient with exposed tendon and bone in three of the four locations. CONCLUSION: As a one- or two-stage procedure, MATRIDERM® application with skin transplantation resulted in an effective defect closure without the need for a complex plastic reconstructive procedure. With regard to its functionality it cannot be considered as a substitute for skin flaps. In selected cases MATRIDERM® is an interesting and successful method in plastic reconstructive surgery.

[Role of skin substitutes in surgical repair of the sequelae of burn injuries]. / Place des dermes équivalents en chirurgie réparatrice des séquelles de brûlures.

The therapeutic management of the sequelae of deep burns always relies in principle on dermal-epidermal grafts. The latter, the price of which to pay is heavy scarring, cannot always be performed because the surface of skin available may not be sufficient. Research pathways have turned towards the creation of skin substitutes to minimise the scarring and improve the cosmetic quality of the grafts. We review the technical characteristics of collagen matrixes (Intégra(®) - Matriderm(®)) and their method of use.

Machine learning to determine optimal conditions for controlling the size of elastin-based particles.

This paper evaluates the aggregation behavior of a potential drug and gene delivery system that combines branched polyethyleneimine (PEI), a positively-charged polyelectrolyte, and elastin-like polypeptide (ELP), a recombinant polymer that exhibits lower critical solution temperature (LCST). The LCST behavior of ELP has been extensively studied, but there are no quantitative ways to control the size of aggregates formed after the phase transition. The aggregate size cannot be maintained when the temperature is lowered below the LCST, unless the system exhibits hysteresis and forms irreversible aggregates. This study shows that conjugation of ELP with PEI preserves the aggregation behavior that occurs above the LCST and achieves precise aggregate radii when the solution conditions of pH (3, 7, 10), polymer concentration (0.1, 0.15, 0.3 mg/mL), and salt concentration (none, 0.2, 1 M) are carefully controlled. K-means cluster analyses showed that salt concentration was the most critical factor controlling the hydrodynamic radius and LCST. Conjugating ELP to PEI allowed crosslinking the aggregates and achieved stable particles that maintained their size below LCST, even after removal of the harsh (high salt or pH) conditions used to create them. Taken together, the ability to control aggregate sizes and use of crosslinking to maintain stability holds excellent potential for use in biological delivery systems.

Single-stage Matriderm® and skin grafting as an alternative reconstruction in high-voltage injuries.

This article presents a retrospective analysis of a series of nine patients requiring reconstruction of exposed bone, tendons or joint capsules as a result of acute high-voltage injuries in a single burn centre. As an alternative to free tissue transfer, the dermal substitute Matriderm(®) was used in a one-stage procedure in combination with split-thickness skin grafts (STSG) for reconstruction. Nine patients, in the period between 2005 and 2009 with extensive high-voltage injuries to one or more extremities which required coverage of exposed functional structures as bone, tendons or joint capsule, were included. A total of 11 skin graftings and 2 local flaps were performed. Data including regrafting rate, complications, hospital stays, length of rehabilitation and time until return to work were collected. Eleven STSG in combination with Matriderm(®) were performed on nine patients (success rate 89%). One patient died. One patient needed a free-flap coverage as a secondary procedure. The median follow-up was 30 months (range 6-48 months). The clinical results of these nine treated patients concerning skin-quality and coverage of exposed tendons or joint capsule were very good. In high-voltage injuries free-flap failure occurs between 10% and 30% if performed within the first 4-6 weeks after trauma. The use of single-stage Matriderm(®) and skin grafting for immediate coverage described in this article is a reliable alternative to selected cases within this period.

The use of Matriderm and autologous skin grafting in the treatment of diabetic ulcers: a case report.

The aim of our case report was to analyse the results obtained with the Matriderm system and autologous skin grafting for the surgical treatment of diabetic ulcers. We recruited one patient with diabetic ulcers admitted at the Department of Plastic and Reconstructive Surgery, University of Rome 'Tor Vergata'. The patient underwent Matriderm system and autologous skin grafting for diabetic ulcer treatment. After just a single treatment, we obtained reduction in ulcer after 15 days from the surgical treatment. We achieved a reduction in pain and exudate secretion of the ulcer. We noticed an almost complete restoration of the missing volume and good quality of skin. Matriderm system and autologous skin grafting is a simple, safe and feasible technique. This method, when compared with other methods of treatment, is simple, cheap, less time consuming and does not require sophisticated laboratory facilities.