Regenerating Bodies: Tissue and Cell Therapies in the Twenty-First Century (Genetics and Society)

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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.


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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.

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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 ].

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Tissue engineering of skin and regenerative medicine for wound care | Burns & Trauma | Full Text

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.

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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.

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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 ].

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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.

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