File Name: skin tissue engineering and regenerative medicine .zip
- Skin Tissue Engineering and Regenerative Medicine: From skin repair to regeneration
- On Tissue Engineering and Regenerative Medicine of Skin and Its Appendages
- Skin Tissue Engineering: Application of Adipose-Derived Stem Cells
- Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies
Metrics details. Normal wound healing is a dynamic and complex multiple phase process involving coordinated interactions between growth factors, cytokines, chemokines, and various cells.
Agnes S. Perception of the adipose tissue has changed dramatically over the last few decades. Identification of adipose-derived stem cells ASCs ultimately transformed paradigm of this tissue from a passive energy depot into a promising stem cell source with properties of self-renewal and multipotential differentiation. As compared to bone marrow-derived stem cells BMSCs , ASCs are more easily accessible and their isolation yields higher amount of stem cells. Therefore, the ASCs are of high interest for stem cell-based therapies and skin tissue engineering.
Skin Tissue Engineering and Regenerative Medicine: From skin repair to regeneration
Metrics details. Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds.
Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells. These advances have contributed to reduced morbidity and mortality from both acute and chronic wounds but, to date, have failed to replace all of the structures and functions of the skin. Among the remaining deficiencies in cellular or biologic skin substitutes are hypopigmentation, absence of stable vascular and lymphatic networks, absence of hair follicles, sebaceous and sweat glands, and incomplete innervation.
Correction of these deficiencies depends on regulation of biologic pathways of embryonic and fetal development to restore the full anatomy and physiology of uninjured skin. Elucidation and integration of developmental biology into future models of biologic skin substitutes promises to restore complete anatomy and physiology, and further reduce morbidity from skin wounds and scar.
Advances in burn care during the recent past have included improvements in fluid resuscitation, early wound excision, respiratory support and management of inhalation injury, improved nutrition and modulation of the hypermetabolic response, infection control and enhanced immune function, incorporation of aerobic exercise during recovery, and development of anti-scarring strategies [ 1 ].
These advances have led to significant reductions in mortality, hospital stay, and long-term morbidity. In addition to these comprehensive innovations, skin cell therapies have become part of the treatment plan for extensive burns. This review will summarize several of the most significant advances since and discuss prospects for further progress in cutaneous regeneration in the future.
Cutaneous burns can generate a continuum of injuries with increasing depth into the skin. Partial-thickness burns often do not require grafting and, if debrided and treated with antimicrobial dressings, will heal spontaneously from regrowth of epithelial appendages hair follicles, sebaceous and sweat glands to cover the wounds.
Transplantation can be accomplished by either conventional split-thickness skin grafts STSG , applications of keratinocyte suspensions or sheets, or dermal-epidermal skin substitutes [ 2 , 3 , 4 , 5 ].
Autologous keratinocytes may persist indefinitely and provide permanent wound closure, whereas allogeneic keratinocytes will remain on the wound for a few days to weeks [ 6 , 7 , 8 ], delivering growth factors and extracellular matrix components to wounds that promote more rapid wound closure by autologous cells [ 9 ]. Combinations of widely meshed and expanded i. Conversely, unmeshed sheet grafts applied as early as possible to critical areas i.
Wound closure after full-thickness burns requires reestablishment of stable epidermis as a minimum requirement. Stability of the epidermis depends on reformation of the basement membrane and vascularized connective tissues to anchor the outer skin to the body. Split-thickness skin satisfies these requirements but does not replace the epidermal adnexa hair follicles, sebaceous glands, sweat glands or regenerate a full complement of sensory or motor nerves.
It is important to note that split-thickness skin at the first harvest does not regenerate hair follicles, sebaceous glands, or sweat glands but does contain pigmented melanocytes and vascular and neural networks which the engineered skin does not. At the second and subsequent harvests of autografts, pigmentation becomes irregular and scar is more pronounced.
Each of these materials protects open wounds, promotes ingrowth of fibrovascular tissue, and may suppress granulation tissue and scar. However, the biologic materials i. In comparison, synthetic polymers i. Similar results have been described recently using the BTM material which currently remains in clinical trial [ 22 ].
Transplantation of cellular skin substitutes has had wide-ranging results for temporary or permanent wound coverage. Temporary cellular dressings include direct harvest of split-thickness skin, available as either fresh or cryopreserved human cadaver skin [ 28 , 29 ], or porcine skin with storage by chemical fixation or lyophilization [ 30 , 31 , 32 ]. Limitations of keratinocyte sheets have included poor durability and ulceration [ 40 , 41 ] and with sprayed keratinocyte suspensions a requirement for co-application with widely meshed skin autograft [ 42 ] which reduces the conservation of donor skin and increases scarring after wound closure.
Clinical application of autologous engineered skin substitutes ESS. Scales in centimeters. Preclinical investigations have reported more complex models that also include melanocytes [ 43 , 44 , 45 ], microvascular endothelial cells [ 46 , 47 , 48 ], mesenchymal stem cells [ 49 , 50 , 51 ], adipocyte stem cells [ 52 ], sensory nerve cells [ 53 ], hair follicle progenitor cells [ 54 , 55 , 56 ], or induced pluripotent stem cells iPSCs [ 57 , 58 ]. These kinds of models promote activation of biological signaling pathways which may stimulate more rapid and complete healing, or drive expression of additional phenotypes to correct anatomic deficiencies.
The prospective benefits of progenitor cells may include generation of additional populations of differentiated parenchymal cells e. As biologic complexity increases and phenotypes are restored, engineered tissues gain structures and functions that do not result from mechanisms of wound healing. These added properties may derive from embryonic or fetal mechanisms that regulate tissue morphogenesis, in addition to the mechanisms of wound healing.
Together, the combination of developmental biology, wound healing, and biomedical engineering constitute the emerging field of regenerative medicine. Correction of pigmentation with cultured autologous melanocytes in preclinical studies. Induction of hair follicles in vivo from neonatal dermal cells grafted to immunodeficient mice.
Scales in cm. Although great progress has been made in reductions of morbidity and mortality in management of burn wounds, some of the most exciting advances remain ahead. These prospective advances include, but are not limited to, a complete restoration of skin anatomy and physiology, b gene therapies for specific applications, c automated and robotic fabrication of engineered tissues to increase efficiencies and reduce costs, and d quantification of wounds with non-invasive biophysical instruments.
Among these phenotypes are epidermal barrier, dermal-epidermal junction, hair folliculogenesis and cycling, sebaceous glands, pigmentation, sensory and motor innervation, cardiovascular systems, and subcutaneous fat.
Each of these phenotypes results from specific gene expression pathways that regulate its formation. Examples of these pathways are listed and referenced in the table. Similarly, there are members of the Sry-regulated HMG box Sox family of transcription factors that are expressed in formation of hair Sox-2, , sebaceous glands Sox-9 , pigmentation Sox , innervation Sox-2, , and cardiovascular development Sox-7, , Despite these similarities, each pathway is expressed in a context of its microenvironment e.
Undoubtedly, as continuing studies in developmental biology elucidate these pathways, greater capabilities to guide the anatomy and physiology of biologic skin substitutes will be gained. Gene therapies for the skin have been studied extensively over the years and have met with limited success [ 62 , 63 , 64 ]. Risks from use of retrovirus-based expression systems suggest that lentiviral-mediated genetic modifications may have greater safety and efficacy in prospective studies [ 65 , 66 ]. However, at least two examples of gene therapy in skin substitutes are currently active in the areas of innate antimicrobial peptides e.
These approaches to gene therapies require careful considerations for safety and efficacy in clinical applications. Constitutive overexpression of human beta defensin-3 with a non-viral plasmid DNA in an allogeneic model of a skin substitute has been evaluated for microbial management of contaminated wounds and was not tumorigenic [ 71 ]. These kinds of approaches provide novel examples for wound management and correction of congenital skin diseases and open countless opportunities for future reductions of morbidity and mortality from skin wounds.
In addition to unique compositions of cells, gene expression, and scaffolds to construct analogs of skin, a critical and limiting factor to greater availability of skin substitutes is manual fabrication of these complex materials. To address this limitation, numerous methods for robotic fabrication of skin and other tissue substitutes have been described [ 75 ].
Many of these approaches are highly precise and involve extrusion of cell-populated matrices into specific shapes for transplantation. Although these robotic systems accomplish physical transfers with relatively high efficiency, they may injure cells by transient exposures to high pressure, temperature, or chemical toxicities. Importantly, cells suspended in viscous scaffolds may be deprived of cellular attachments to cell surface receptors e. Avoidance of these kinds of growth inhibitions will be essential to the eventual success of robotic systems.
It is important to recognize that these kinds of attachment and signaling deprivations do not occur during fetal morphogenesis or wound healing. Therefore, providing tissue-specific ligands for cell surface receptors, or maintaining signaling pathways that regulate proliferation, will likely be required to optimize the mitotic rates of cells in engineered tissues.
One approach to satisfying this requirement is formation of cellular organoids [ 75 ] which provide cell-cell attachments to preserve cell cycle signaling without attachment of cells to scaffolds or plastic vessels.
Assessments of skin wounds have progressed from subjective examinations by clinicians to more objective measures with non-invasive instruments for both diagnostic and prognostic evaluations. For diagnostic purposes, scanning laser Doppler flowmetry has been shown to provide accurate assessments of burn depth and color with simultaneous image capture [ 80 , 81 , 82 ].
Accuracy in determining the TBSA of burns has also been improved with computer software for digital mapping of skin injuries to better calculate critical interventions such as fluid resuscitation. Three-dimensional photography and laser surface scanning [ 83 , 84 ] provide topographic data that may be coupled with body mapping to generate virtual representations of patients that can be revised during the hospital course to construct a timeline of clinical progress.
Non-invasive instruments for assessments of color, shape, surface texture, visco-elastic properties, blood flow, temperature, pH, surface hydration, and water vapor transmission have been adapted from applications in dermatology for more objective determinations of scars [ 85 ]. Although these kinds of instruments have high accuracy, they often provide assessments of individual points within fields of wounds or scars which must be considered in sampling plans for data interpretation.
Because point measures typically do not represent heterogeneous wounds, data collection at multiple sites is needed to compensate for the subjective selection of individual points to measure within the treatment field. With these kinds of considerations, application of non-invasive instruments for wound assessments has been shown to correct for inter-rater variability in ordinal or observational evaluations of wounds and scars.
Biologic skin substitutes have increased in complexity from models that replace either dermis or epidermis, to dermal-epidermal models, to those that deliver combinations of biopolymer scaffolds, multiple cell types, or multiple cell sources, to those that express gene products for prospective improvements in wound healing. This spectrum of unprecedented materials presented questions regarding the regulatory framework within which each model would be evaluated for consideration of permission to market.
Availability of cadaveric allograft has been provided under regulations for tissue banking, which are administered by CBER. As the spectrum of research models of skin substitutes broadened during the s and s, several investigative therapies had components that required consideration by multiple centers at FDA. The agency responded proactively with two initiatives that have contributed to greater clarity of the regulatory process and with Guidance for Industry [ 86 , 87 ] on how to propose a path to market.
Beginning in , this organization has had members from academics, government, and industry participating in a consensus process for composing definitions of materials and provision of methods for calibration and testing of the materials. With regard to skin substitutes, the ASTM process has resulted in a Standard Guide for Classification of Therapeutic Skin Substitutes [ 89 ], providing consensus definitions and nomenclature.
This office confers with the Centers for Human Therapeutics to designate new therapies at a lead center at FDA with participation from other centers as appropriate. Together, these initiatives have added clarity to the assignment of novel therapeutics to a designated regulatory path [ 91 ].
As the name implies, this law is intended to facilitate and expedite the availability of novel therapies to patients with serious, or potentially life-threatening, conditions. The Cures Act provides for expedited therapeutic development programs including the Regenerative Medicine Advanced Therapy RMAT designation for eligible biologics products, and the Breakthrough Devices program which is designed to facilitate the review of certain innovative medical devices [ 94 ].
These new designations by FDA are in addition to previous expedited regulatory pathways of Fast Track development [ 95 ], Breakthrough Therapy designation [ 96 ], Accelerated Approval [ 97 ], and Priority Review designation for drugs [ 98 ].
Together, these alternative pathways to provisional or full marketing are likely to increase access to the most advanced therapies by patient populations with the greatest medical needs. Future prospects for biologic skin substitutes are extensive and diverse. Advances in use and regulation of stem cells in the skin are highly likely to lead to autologous skin substitutes with greater homology to uninjured skin by providing restoration of skin pigmentation, epidermal appendages hair, sebaceous and sweat glands , a vascular plexus, and subcutaneous tissues.
Genetic modification of autologous cells opens tremendous opportunities for regulation of wound closure, reductions in scar formation, and correction of congenital diseases. As these advances in biologic skin substitutes translate into clinical care, it can be predicted with confidence that reductions in morbidity from acquired and congenital skin diseases will also be realized.
The P50 research center in perioperative sciences: how the investment by the National Institute of General Medical Sciences in Team Science has reduced post-burn mortality. J Trauma Acute Care Surg. A two-stage technique for excision and grafting of burn wounds. J Trauma. Characterisation of the cell suspension harvested from the dermal epidermal junction using a ReCell R kit.
Growth of human epidermal cells into multiple epithelia suitable for grafting. Biologic attachment, growth, and differentiation of cultured human epidermal keratinocytes on a graftable collagen and chondroitinsulfate substrate.
Falanga V, Sabolinski M. Wound Repair Regen. Survival of Apligraf in acute human wounds. Tissue Eng.
On Tissue Engineering and Regenerative Medicine of Skin and Its Appendages
The skin is the largest human organ system. Loss of skin integrity due to injury or illness results in a substantial physiologic imbalance and ultimately in severe disability or death. From burn victims to surgical scars and plastic surgery, the therapies resulting from skin tissue engineering and regenerative medicine are important to a broad spectrum of patients. This work expands on the primary literature on the state of the art of cell therapies and biomaterials to review the most widely used surgical therapies for the specific clinical scenarios. Biomedical researchers in the fields of tissue engineering and regenerative medicine; stem cell researchers. Albanna expedited the transition of multiple skin bioprinting projects from bench-top into clinics through development of preclinical models for wound healing and skin regeneration, protocols for large scale expansion of skin and stem cells for clinical use. Albanna has several years of expertise in product development of tissue-engineered products including skin wound healing products.
Request PDF | Skin Tissue Engineering and Regenerative Medicine | The skin is the largest human organ system. Loss of skin integrity due to injury or illness.
Skin Tissue Engineering: Application of Adipose-Derived Stem Cells
Skin is the largest organ of the body and is necessary for survival, since it performs many functions such as providing a physical barrier to the external environment, sensation, retention of normal hydration and thermal regulation. Significant skin loss is associated with high mortality and morbidity in the Significant skin loss is associated with high mortality and morbidity in the acute phase, and with physically and cosmetically drastic scarring in the long term.
It seems that you're in Germany. We have a dedicated site for Germany. This new series, based on a bi-annual conference and its topics, represents a major contribution to the emerging science of cancer research and regenerative medicine. Each volume brings together some of the most pre-eminent scientists working on cancer biology, cancer treatment, cancer diagnosis, cancer prevention and regenerative medicine to share information on currently ongoing work which will help shape future therapies.
Data and materials in this manuscript are referenced from previous publications and may be available from commercial suppliers or upon request from the reference laboratories. Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds. Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells. These advances have contributed to reduced morbidity and mortality from both acute and chronic wounds but, to date, have failed to replace all of the structures and functions of the skin.
Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies
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complete full-thickness tissue-engineered skin is likely to be generated. Key words: Regenerative medicine, wound healing, biomaterials, seed cells.