Skin Replacement Research Articles

Alternative protein from Pereskia aculeata Miller leaf mucilage: technological potential as an emulsifier and fat replacement in processed mortadella meat

Considering that bio-based ingredients have attracted the attention of food industries and the great demand for emulsifiers, the present work studied the mucilage of Pereskia aculeata Miller (OPN) as an alternative emulsifier in meat product. Aqueous extraction by physical process was used to obtain mucilage from the leaves of the plant with high emulsifying activity. The OPN mucilage was characterized by its proximal composition, emulsifying potential and amino acid profile and was evaluated as an emulsifier and fat replacement in processed meat. Different formulations of mortadella-type meat product were developed and studied in terms of nutritional composition, color, texture profile, product-emulsion stability, firmness and sensory acceptance. OPN mucilage had a high emulsifying potential, is rich in minerals, and contains all the essential amino acids in its composition, which characterizes it as a nutritionally attractive food ingredient. The use of this mucilage allowed the replacement of chicken skin, which is an emulsifier traditionally used in mortadella-type meat product, contributing to the reduction of the overall fat content of the product. The selected formulation showed high sensory acceptance demonstrating the great potential for using OPN mucilage in meat products and as food ingredient.

Made in Germany: A Quality Indicator Not Only in the Automobile Industry But Also When It Comes to Skin Replacement: How an Automobile Textile Research Institute Developed a New Skin Substitute.

Successful research and development cooperation between a textile research institute, the German Federal Ministry of Education and Research via the Center for Biomaterials and Organ Substitutes, the University of Tübingen, and the Burn Center of Marienhospital, Stuttgart, Germany, led to the development of a fully synthetic resorbable temporary epidermal skin substitute for the treatment of burns, burn-like syndromes, donor areas, and chronic wounds. This article describes the demands of the product and the steps that were taken to meet these requirements. The material choice was based on the degradation and full resorption of polylactides to lactic acid and its salts. The structure and morphology of the physical, biological, and degradation properties were selected to increase the angiogenetic abilities, fibroblasts, and extracellular matrix generation. Water vapor permeability and plasticity were adapted for clinical use. The available scientific literature was screened for the use of this product. A clinical application demonstrated pain relief paired with a reduced workload, fast wound healing with a low infection rate, and good cosmetic results. A better understanding of the product’s degradation process explained the reduction in systemic oxidative stress shown in clinical investigations compared to other dressings, positively affecting wound healing time and reducing the total area requiring skin grafts. Today, the product is in clinical use in 37 countries. This article describes its development, the indications for product growth over time, and the scientific foundation of treatments.

Extremely stretchable and tough hybrid hydrogels based on gelatin, κ-carrageenan and polyacrylamide.

Nowadays, several approaches are being suggested to endow hydrogels with improved mechanical properties for practical applications as cartilage and skin replacements, soft electronics, and actuators. However, it remains a challenge to develop DN gels with both high fracture toughness and fracture stretch. Here, we introduce (bio)polyelectrolyte complexes (PECs) consisting of gelatin and κ-carrageenan as the first brittle network and covalently crosslinked polyacrylamide (PAAm) as the second stretchable network to fabricate a highly stretchable and notch-insensitive gelatin/κ-carrageenan/PAAm hydrogel. The unprecedented high stretchability (∼51.7) is ascribed to the reduction of stress concentration and defects in the network structure through the fracture of the PEC gel. In addition, a high fracture toughness (∼16053.34 J m-2) is achieved by effective energy transfer between the PECs and PAAm gel due to their covalent crosslinking, and efficient energy dissipation through destroying inter- and intramolecular interactions in the PEC gel.

Three-way pectoralis major osteo-myo-cutaneous flap in oral cancer: An option revisited

While free flap is the standard of care for bony reconstruction of the mandible, complex oro-mandibular defects after oral cancer ablation require adequate skin and soft-tissue replacement for optimum functional results. We report a case of multifaceted oral cavity resection effectively reconstructed in single stage by the three-way pectoralis major osteomyocutaneous flap. The technical aspects, benefits, deficiencies, and literature review are discussed. In the background of multiple recurrences and comorbidities, this flap is a viable alternative and should be given due reconsideration in oral cancer surgery. This gains more relevance in the context of developing countries.

Quality Improvement of the Chicken Sausage with Pepper Seed (Capsicum Annuum L.)

The chicken sausages were manufactured replacing part (8%) of chicken skin with powder (1%) and oil (7%) of pepper seed (Capsicum annuum L.). The replacement of chicken skin with pepper seed lowered the content of total fat, saturated fatty acids, cholesterol, and sodium in chicken sausages than that of the control by reducing 13.4%, 75.0%, 42.2%, 22.6%, respectively (p<0.05). In addition, the pepper seed retarded lipid oxidation in chicken sausages represented by lower TBARS value than that of the control in 14 days of storage at 4 °C (p < 0.05). Even though pepper seed hardly changed textural properties of chicken sausages except decreasing hardness, it favorably affected sensory attributes such as appearance, flavor, and overall acceptability. In conclusion, the application of pepper seed in manufacturing chicken sausages improved nutritional value and sensory properties of the products, which could be a good alternative for the people in favor of low fat and healthy products.

Evaluation of a cross-linked versus non-cross-linked collagen matrix in full-thickness skin defects

Autologous skin transplantation is the gold standard for treatment of full-thickness skin defects such as deep burn injuries, but has the disadvantages of limited donor sites and donor site morbidities. Alternative skin replacement products, such as xenografts and allografts, are not a permanent solution. Numerous manufactured skin substitutes already show promising approaches, but have limited efficacy. Therefore, wound dressings adaptable to the physiology of wound healing are still needed.In a randomized controlled in vivo study, a newly designed biocompatible collagen nonwoven matrix was compared to the Integra® bilayer dermal substitute and untreated controls in 48 full-thickness skin defects in a swine model.The take of all templates was complete, and all the tissue-engineered products accelerated dermal wound healing compared to the untreated controls, as identified by planimetric measurements. The higher collagen dose treatments and Integra®-covered wounds developed the thickest, cell-rich neoepidermal tissue in histological examination.The innovative biocompatible collagen matrix is flexibly applicable and modifiable, and offers potential as a carrier membrane for therapeutic supplemental products such as growth factors to further develop effective wound dressings.

Total nasal reconstruction using three layered forehead paramedian pedicle flap, rib grafts and skin graft

Introduction: Nose is a complex three dimensional structure and the aesthetic focus of the face. Total nasal reconstruction following a total rhinectomy is a complex surgical challenge for a reconstructive surgeon. The aim of the reconstruction is to maintain function and aesthetics. Replacement of the lost structures skin, cartilage bone and relining the internal lining poses a unique challenge. Various options are described in the literature including prosthesis, free flaps and reconstruction with forehead flaps with cartilage grafts.

Poly(dimethylsiloxane): A Sustainable Human Skin Alternative for Transdermal Drug Delivery Prediction

Despite the advantages of transdermal drug delivery (TDD), which makes it a fast-growing area of research in pharmaceutics, numerous challenges affect their development, which limits exploring the full potential of this alternate drug delivery route. In trying to address one of these problems, it is strongly believed that the need for a sustainable skin alternative is paramount. Efforts made in an attempt to provide a sustainable alternative to employing skin in pharmaceutical analysis, by better utilising a polymer membrane, namely poly(dimethylsiloxane), also known as PDMS are discussed. Several combined properties of this polymer, which includes its relative stability in comparison with human skin, make it a good candidate for the replacement of skin. Modifications undertaken to this polymer membrane (to create an enhanced skin mimic for permeation analysis) are discussed and reviewed in this paper, including the improved ability to predict permeability for both hydrophobic and hydrophilic drugs. Optimisations related to studying TDD including limitations encountered are also documented and reviewed. It is hoped that such developments in this field will ultimately lead to researchers replacing skin with optimised polymer-based alternatives to predict transdermal drug delivery.

Full-thickness Skin Microcolumns Implanted into a Dermal Regeneration Template: A Novel Method for “Donor-free” Skin Replacement Therapy

BACKGROUND: Split-thickness skin graft is the current standard in the treatment of large full-thickness skin defects. The donor site resulting from tangential skin harvest is well recognized as painful and unsightly, even after it has healed. Several efforts have been made in the past to address this problem by limiting the amount of skin harvested while significantly expanding the skin elements (ReCell, Meek). These efforts suffer from short comings such as graft fragility and failure to achieve adequate closure in a reasonable period of time. Full-thickness skin columns are a novel concept in skin harvest with little to no donor site when the diameter of the columns falls below a certain threshold. There is also a theoretical advantage that the columns harvested contain elements of full-thickness skin including sweat glands and hair follicles. Here, we present 2 cases where full-thickness skin columns were harvested and implanted into a bilayer dermal regenerative template (Integra) to achieve durable single-stage skin replacement. METHODS: Wounds in 2 elderly patients were treated using standard excisional preparation techniques. Both patients refused a standard split-thickness skin graft with concerns of difficulty healing the donor site. Informed consent using full-thickness skin columns and Integra combination were obtained. Full-thickness skin columns were harvested from a small area of the upper thigh using skin biopsy punches (1.5–2 mm). The columns were implanted orthotopically into a sheet of Integra dermal matrix with the epidermis placed immediately deep to the silicone layer. The Integra-skin column composites were applied onto the wounds similar to a traditional skin graft. The punch biopsy donor sites were allowed to heal secondarily. RESULTS: Patient 1 was 90 years old and had a small lower extremity wound treated with 2 mm skin columns (n = 9) and a 3 × 1.5 cm2 Integra. Patient 2 was 88 years old had a larger volar forearm wound treated with 1.5 mm skin columns (n = 51) and an 8 × 5 cm2 Integra. Visual evaluation showed centripetal healing with epithelial cells radiating from the columns as well as from the periphery. Complete healing was achieved in 3–4 weeks; donor sites healed in less than a week with minimal evidence of skin harvest at 1 month. CONCLUSIONS: Full-thickness skin columns implanted into a dermal regeneration template represent a novel technique for skin replacement that allows single-stage healing of full-thickness skin wounds with little to no donor site, and without any biochemical processing of the tissue.

An administration on artificial skin for burning patient skin recovery through tissue engineering

Background: Artificial skin has been tried to implement on subject which is damaged by burn effect.In this research i tried with Silk fibroin as a block biopolymer and which is very high biodegradability and more flexible for cell culture as being a part of human body.With this artificial skin of SF/Chitosan will help to produce more pores of tissue engineering which will create a good implantation system.Skin is the longest and most important organ of human body.Artificial skin is a collagen scaffold that causes skin regeneration in animals such as humans. The innovative biomaterial silk consists of this collagen.I also tried to introduce collagen consisting of silk nanofibers for human body linked to burning patients impacted areas via tissue engineering administration.Body comprises of three layers.They are sometimes called the hypodermis, epidermis, dermis and the fat layer. Purpose: An exploration to implement human compatible artificial skin for burned body. Materials and methods: At first turned silk fibroin through degumming process as a block biopolymer and then check oxygen permeability with silk fibroin and chitosan combination.Check mechanical properties and this total experiment done through tissue engineering and cell culture. Tissue-built skin substitutes may offer a viable helpful choice for the treatment of patients with skin harms. Results: Implementable long term sustainability and high biodegradability artificial skin through cell culture. Conclusion: In this research, artificial skin has been developed with chitosan/SF layer based with complete block biopolymer and i got a significant result which will be compatible for human original skin with high oxygen and water permeability with cell culture and it is effective and result oriented for burning patient skin recovery and accidental case in the replacement of skin. Discussion: Artificial skin is a collagen scaffold that induces regeneration of skin in mammals such as humans.The novel biomaterial silk consists of this collagen.In this research work,we tried to implement collagen consisting silk nanofibers for artificial skin for human body related to burning patients affected areas through tissue engineering administration.

Coverage of skin defect due to losses of substance in the elbow

Skin defects of the elbow follow severe trauma or bone exposure after skin necrosis, osteitis, or management of infected pseudarthrosis. The orthopedic and plastic management of these lesions is fundamental. The authors describe the different clinical frameworks that can lead to bone and/or joint exposure. Before, during or at a distance from bone management (external fixation, internal fixation, temporary cementoplasty, bone graft…), they detail the surgical techniques aimed at covering skin defects of the elbow. The authors review simple skin replacement techniques such as Z-plasties, emphasizing the interest of pedicled flaps of the arm and forearm, as well as muscle or fascio-cutaneous flaps, which are able to cover almost all the elbow skin defects.

Advanced Hydrogels as Wound Dressings.

Skin is the largest organ of the human body, protecting it against the external environment. Despite high self-regeneration potential, severe skin defects will not heal spontaneously and need to be covered by skin substitutes. Tremendous progress has been made in the field of skin tissue engineering, in recent years, to develop new skin substitutes. Among them, hydrogels are one of the candidates with most potential to mimic the native skin microenvironment, due to their porous and hydrated molecular structure. They can be applied as a permanent or temporary dressing for different wounds to support the regeneration and healing of the injured epidermis, dermis, or both. Based on the material used for their fabrication, hydrogels can be subdivided into two main groups—natural and synthetic. Moreover, hydrogels can be reinforced by incorporating nanoparticles to obtain “in situ” hybrid hydrogels, showing superior properties and tailored functionality. In addition, different sensors can be embedded in hydrogel wound dressings to provide real-time information about the wound environment. This review focuses on the most recent developments in the field of hydrogel-based skin substitutes for skin replacement. In particular, we discuss the synthesis, fabrication, and biomedical application of novel “smart” hydrogels.

Suitability of biological acellular dermal matrices as a skin replacement

Tissue defects are associated with loss of epidermal and dermal components of the skin. For full-thickness tissue defects, dermal equivalents are useful to enable rapid wound closure. Split-thickness skin grafts are associated with loss of tissue elasticity resulting in scar contractures that can impair joint mobility. Synthetic collagen matrices and allogeneic acellular dermal matrices (ADM) are commercially available and could serve as skin tissue replacement. The aim of this study was to investigate whether ADM of different dermal layers or bioartificial matrices can serve as cutaneous replacement. For this purpose, cellular migration, differentiation and the inflammatory reaction were studied in an established ex vivo skin organ model. Human split-thickness skin grafts were transplanted onto ADM (Epiflex, DIZG, Berlin, Germany), de-epidermized dermis (DED) or an artificial collagen-elastin matrix (Matriderm, Dr. Suwelack, Billerbeck, Germany). Epithelial migration was studied using an established skin culture model at the air-liquid interface. In addition, the effect of tissue from different dermal compartments, e. g. papillar and reticular dermis, on epithelial migration was compared. Epithelial resurfacing and differentiation of matrices as well as the inflammatory reaction were studied using histological, immunohistochemical and biochemical analyses. Significantly more epithelial outgrowth area was found on DED (2.54 mm ± 0.43 mm, mean ± SEM) compared to papillary ADM (1.32 mm ± 0.44 mm, p = 0.039), to reticular ADM (no horizontal growth, p < 0.0001) and collagen-elastin matrix (0.78 mm ± 0.11 mm, p = 0.0056) measured by fluorescence microscopy over 10 days presumably due to the presence of pro-migratory basement membrane residues on DED. Reepithelialization was significantly higher (p < 0.002) on papillary dermis compared to ADM of reticular origin. In contrast to the biological matrices, a complete horizontal penetration was found in the macroporous collagen-elastin matrix. Pro-inflammatory mediators varied depending on the human skin donor and matrix. In summary, the biochemical structure of the matrix' surface and its origin influenced the epithelial behaviour with regard to migration, differentiation and inflammatory response.

806 Bioprinted skin integrates and forms epidermal rete ridges in full-thickness wounds

Current tissue engineered skin fails to meet the need for skin replacement in full-thickness wounds. Bioprinting technology allows for fabrication of full-thickness skin with multiple cell types organized into biomimetic layers in vitro. The purpose of this study is to determine if bioprinted skin will integrate, form an epidermal barrier, and vascularize when implanted into full-thickness wounds on mice. Cells were isolated from human skin, expanded in vitro, suspended in a fibrinogen bioink, bioprinted to form a biomimetic tri-layer skin construct, and implanted onto 2.5 x 2.5cm full-thickness excisional wounds on mice. A significant difference in total wound closure was found between bioprinted skin and non-treated wounds, as well as an accelerated time to wound closure (14.8 vs. 24.5 days, p<0.001). By day 90, H&E and Masson’s trichrome staining revealed rete ridge formation in the bioprinted skin comparable to native human epidermis, compared with a flat epidermis in controls. Picrosirius red stained samples demonstrated a normal basket weave collagen orientation in bioprinted skin-treated wounds, and hypertrophic scar-like, parallel collagen alignment in controls (41.3% vs. 80.0% alignment, p<0.001). Immunohistochemical staining confirmed the presence of human cells in the regenerated skin, the formation of epidermal rete ridges, and incorporation of human endothelial cells in infiltrating host blood vessels. Measurement of blood vessels demonstrated an increase in small diameter blood vessels in bioprinted skin treated wounds compared to control (8.4 vs. 4.3 blood vessels, p<0.01). In conclusion, bioprinted skin accelerates full-thickness wound closure, with implanted cells laying down a healthy, basket-weave collagen matrix. The remodeled skin forms epidermal rete ridges and a vascular network composed of both graft and infiltrating host vessels. Ultimately, this technology could translate into a new treatment for full-thickness wounds in human patients.

Autologous Homologous Skin Constructs Allow Safe Closure of Wounds: A Retrospective, Noncontrolled, Multicentered Case Series.

An autologous homologous skin construct (AHSC) has been developed for the repair and replacement of skin. It is created from a small, full-thickness harvest of healthy skin, which contains endogenous regenerative populations involved in native skin repair. A multicenter retrospective review of 15 wounds in 15 patients treated with AHSC was performed to evaluate the hypothesis that a single application could result in wound closure in a variety of wound types and that the resulting tissue would resemble native skin. Patients and wounds were selected and managed per provider's discretion with no predefined inclusion, exclusion, or follow-up criteria. Dressings were changed weekly. Graft take and wound closure were documented during follow-up visits and imaged with a digital camera. Wound etiologies included 5 acute and chronic burn, 4 acute traumatic, and 6 chronic wounds. All wounds were closed with a single application of AHSC manufactured from a single tissue harvest. Median wound, harvest, and defect-to-harvest size ratio were 120 cm2 (range, 27-4800 cm2), 14 cm2 (range, 3-20 cm2), and 11:1 (range, 2:1-343:1), respectively. No adverse reactions with the full-thickness harvest site or the AHSC treatment site were reported. Average follow-up was 4 ± 3 months. An AHSC-treated area was biopsied, and a micrograph of the area was developed using immunofluorescent confocal microscopy, which demonstrated mature, full-thickness skin with nascent hair follicles and glands. This early clinical experience with ASHC suggests that it can close different wound types; however, additional studies are needed to verify this statement.

Severe and massive necrosis following high definition power-assisted liposuction: a case report

Although liposuction is one of the most sought-after surgical procedures in the world, there are plenty of acknowledged complications associated with it. There are, however, no case reports such as this one regarding severe complications deriving from the high-definition technique. We describe the management of a patient with massive necrosis following a high definition power-assisted liposuction. A 37-year-old woman, who presented an overweight body mass index and no other comorbidities, had a liposuction with abdominoplasty done in 2012. In early 2019, she underwent a high definition liposuction, being transferred 8 days after the procedure into a tertiary and university-related hospital with necrotizing fasciitis and sepsis. The patient received treatment for a life-threatening condition at the ICU and several interventions for debridement and skin replacement. She was discharged 2 months after admission. High definition liposuction is a new technique that has recently become widespread. However, it is not fail-safe, as the present case shows. It should be restricted to selected cases and its technique should be reviewed and trained extensively to reduce its possible risks. Level of evidence: Level V, risk/prognostic study.

The role of labeled cell therapy with and without scaffold in early excision burn wounds in a rat animal model.

Objective(s):One of the essential problems in burn therapy is performing the permanent replacement of skin in full and deep thickness injuries. Human Wharton’s Jelly mesenchymal stem cells (HWJMSCs) have a unique combination of prenatal and postnatal properties. Decellularized human amniotic membrane (DHAM) can be used as a scaffold for HWJMSCs-therapy. We aimed to evaluate the quantity and quality of healing in the early excision burn wound dressing with 3-dimensional and 2- dimensional cell cultures.Materials and Methods:Amniotic and umbilical cords were isolated from the mothers who were candidates for cesarean section. HAM was decellularized using the mechanical and enzymatic method. HWJMSCs were isolated and cultured; cell surface markers were examined for authentication of MSCs and labeled using a viral vector containing the cGFP gene. Burns were created using brass bar in 32 adult male Albino rats and randomly divided into four groups (DHAM+HWJMSCs, injection of HWJMSCs, HWJMSCs was spread on the wound, and DHAM alone). Rats were sacrificed on the 7th and 14th days for pathological examination of the wound. Comparisons between the study groups were made by one-way analysis of variance.Results:Wound healing process in DHAM+HWJMSCs was much more progressed during the first week in comparison to other groups, and exhibited significant differences in re-epithelialization, formation of granulation tissue, and hemorrhage (P<0.05).Conclusion:The utility of the amniotic scaffold seeded by the human mesenchymal stem cells is recommended for accelerating the healing process.

Identification of a fibrin concentration that promotes skin cell outgrowth from skin explants onto a synthetic dermal substitute

SummaryBackgroundOur overall objective is to develop a single-stage in-theatre skin replacement by combining small explants of skin with a synthetic biodegradable dermal scaffold. The aim of the current study is to determine the concentration of fibrin constituents and their handling properties for both adhering skin explants to the scaffold and encouraging cellular outgrowth to achieve reepithelialization.MethodsSmall skin explants were combined with several concentrations of thrombin (2.5,4.5,and 6.5 I.U) and fibrinogen (18.75,67, and 86.5 mg/ml), cultured in Green's media for 14 days and cellular outgrowth was measured using Rose Bengal staining. They were also cultured on electrospun scaffolds for 14 and 21 days. Hematoxylin and eosin (H&E) staining was undertaken to visualize the interface between skin explants and scaffolds and metabolic activity and collagen production were assessed.ResultsA thrombin/fibrinogen combination of 2.5 I. U/ml /18.75 mg/ml showed significantly greater cell viability as assessed by Rose Bengal stained areas at days 7 and 14. This was also seen in DAPI images and H&E stains skin explant/scaffold constructs. Fibrin with a concentration of thrombin 2.5 I.U./ml took 5–6 min to set, which is convenient for distributing skin explants on the scaffold.ConclusionThe study identified concentrations of thrombin (2.5 I.U/ml) and fibrinogen (18.75 mg/ml), which were easy to handle and aided the retention of skin explants and permitted cell outgrowth from explants.

Quality Properties of Chicken Emulsion-Type Sausages Formulated with Chicken Fatty Byproducts.

During poultry slaughtering, fatty byproducts are generated, mainly comprising abdominal and gizzard fat, which are mostly discarded and result in consequent environmental problems. The objective of this work was to use these fatty byproducts as fatty raw material in the production of chicken sausages (emulsion-type). They were applied for the partial replacement (40% and 50%) of chicken skin (fatty source usually used in chicken sausages). The effect of these partial replacements on the quality properties (proximate composition, lipid profile, color, texture, and microbiological and sensory properties) of chicken sausages were assessed. Sausages with fatty byproducts added (40% and 50%) showed lower moisture but higher fat content than control. Nevertheless, all of them meet the nutritional requirements of the Colombian regulation for this type of meat product. Sausages with 40% and 50% substitution level showed similar texture properties and microbiological quality as control. When these fatty byproducts were used at 50% substitution level, differences in several color properties and sensorial attributes (color, flavor, and meat taste) were noticed with respect to control. When the substitution level was reduced to 40%, no sensorial differences were detected. Chicken fatty byproducts can be successfully applied as partial replacement of chicken skin in emulsion-type sausages.

Nanostructured Materials for Artificial Tissue Replacements.

This paper review current trends in applications of nanomaterials in tissue engineering. Nanomaterials applicable in this area can be divided into two groups: organic and inorganic. Organic nanomaterials are especially used for the preparation of highly porous scaffolds for cell cultivation and are represented by polymeric nanofibers. Inorganic nanomaterials are implemented as they stand or dispersed in matrices promoting their functional properties while preserving high level of biocompatibility. They are used in various forms (e.g., nano- particles, -tubes and -fibers)—and when forming the composites with organic matrices—are able to enhance many resulting properties (biologic, mechanical, electrical and/or antibacterial). For this reason, this contribution points especially to such type of composite nanomaterials. Basic information on classification, properties and application potential of single nanostructures, as well as complex scaffolds suitable for 3D tissues reconstruction is provided. Examples of practical usage of these structures are demonstrated on cartilage, bone, neural, cardiac and skin tissue regeneration and replacements. Nanomaterials open up new ways of treatments in almost all areas of current tissue regeneration, especially in tissue support or cell proliferation and growth. They significantly promote tissue rebuilding by direct replacement of damaged tissues.