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Design of an elastin-layered dermal regeneration template.

ABSTRACT: We demonstrate a novel approach for the production of tunable quantities of elastic fibers. We also show that exogenous tropoelastin is rate-limiting for elastin synthesis regardless of the age of the dermal fibroblast donor. Additionally, we provide a strategy to further enhance synthesis by older cells through the application of conditioned media. We show that this approach delivers an elastin layer on one side of the leading dermal repair template for contact with the deep dermis in order to deliver prefabricated elastic fibers to a physiologically appropriate site during subsequent surgery. This system is attractive because it provides for the first time a viable path for sufficient, histologically detectable levels of patient elastin into full-thickness wound sites that have until now lacked this elastic underlayer.The scars of full thickness wounds typically lack elasticity. Elastin is essential for skin elasticity and is enriched in the deep dermis. This paper is significant because it shows that: (1) we can generate elastic fibers in tunable quantities, (2) tropoelastin is the rate-limiting component in elastin synthesis in vitro, (3) we can generate elastin fibers regardless of donor age, (4) we describe a novel approach to further increase the numbers and thickness of elastic fibers for older donors, (5) we improve on Integra Dermal Regeneration Template and generate a new hybrid biomaterial intended to subsequently surgically deliver these elastic fibers, (6) the elastic fiber layer is presented on the side of Integra that is intended for delivery into its physiologically appropriate site i.e. the deep dermis.

SUBMITTER: Mithieux SM

PROVIDER: S-EPMC5402719 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Design of an elastin-layered dermal regeneration template.

Mithieux Suzanne M SM Weiss Anthony S AS

Acta biomaterialia 20161127

We demonstrate a novel approach for the production of tunable quantities of elastic fibers. We also show that exogenous tropoelastin is rate-limiting for elastin synthesis regardless of the age of the dermal fibroblast donor. Additionally, we provide a strategy to further enhance synthesis by older cells through the application of conditioned media. We show that this approach delivers an elastin layer on one side of the leading dermal repair template for contact with the deep dermis in order to ...[more]

PMID: 27903444

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Project description:Following penetrating injury of the skin, a highly orchestrated and overlapping sequence of events helps to facilitate wound resolution. Inflammation is a hallmark that is initiated early, but the reciprocal relationship between cells and matrix molecules that triggers and maintains inflammation is poorly appreciated. Elastin is enriched in the deep dermis of skin. We propose that deep tissue injury encompasses elastin damage, yielding solubilized elastin that triggers inflammation. As dermal fibroblasts dominate the deep dermis, this means that a direct interaction between elastin sequences and fibroblasts would reveal a proinflammatory signature. Tropoelastin was used as a surrogate for elastin sequences. Tropoelastin triggered fibroblast expression of the metalloelastase MMP-12, which is normally expressed by macrophages. MMP-12 expression increased 1056 ± 286-fold by 6 h and persisted for 24 h. Chemokine expression was more transient, as chemokine C-X-C motif ligand 8 (CXCL8), CXCL1, and CXCL5 transcripts increased 11.8 ± 2.6-, 10.2 ± 0.4-, and 8593 ± 996-fold, respectively, by 6-12 h and then decreased. Through the use of specific inhibitors and protein truncation, we found that transduction of the tropoelastin signal was mediated by the fibroblast elastin binding protein (EBP). In silico modeling using a predictive computational fibroblast model confirmed the up-regulation, and simulations revealed PKA as a key part of the signaling circuit. We tested this prediction with 1 ?M PKA inhibitor H-89 and found that 2 h of exposure correspondingly reduced expression of MMP-12 (63.9±12.3%) and all chemokine markers, consistent with the levels seen with EBP inhibition, and validated PKA as a novel node and druggable target to ameliorate the proinflammatory state. A separate trigger that utilized C-terminal RKRK of tropoelastin reduced marker expression to 65.0-76.5% and suggests the parallel involvement of integrin ?V?3. We propose that the solubilization of elastin as a result of dermal damage leads to rapid chemokine up-regulation by fibroblasts that is quenched when exposed elastin is removed by MMP-12.

Project description:Articular cartilage has limited capacity for regeneration and when damaged cannot be repaired with currently available metallic or synthetic implants. We aim to bioengineer a microfibre-reinforced hydrogel that can capture the zonal depth-dependent mechanical properties of native cartilage, and simultaneously support neo-cartilage formation. With this goal, a sophisticated bi-layered microfibre architecture, combining a densely distributed crossed fibre mat (superficial tangential zone, STZ) and a uniform box structure (middle and deep zone, MDZ), was successfully manufactured via melt electrospinning and combined with a gelatin-methacrylamide hydrogel. The inclusion of a thin STZ layer greatly increased the composite construct's peak modulus under both incongruent (3.2-fold) and congruent (2.1-fold) loading, as compared to hydrogels reinforced with only a uniform MDZ structure. Notably, the stress relaxation response of the bi-layered composite construct was comparable to the tested native cartilage tissue. Furthermore, similar production of sulphated glycosaminoglycans and collagen II was observed for the novel composite constructs cultured under mechanical conditioning w/o TGF-ß1 supplementation and in static conditions w/TGF-ß1 supplementation, which confirmed the capability of the novel composite construct to support neo-cartilage formation upon mechanical stimulation. To conclude, these results are an important step towards the design and manufacture of biomechanically competent implants for cartilage regeneration. STATEMENT OF SIGNIFICANCE: Damage to articular cartilage results in severe pain and joint disfunction that cannot be treated with currently available implants. This study presents a sophisticated bioengineered bi-layered fibre reinforced cell-laden hydrogel that can approximate the functional mechanical properties of native cartilage. For the first time, the importance of incorporating a viable superficial tangential zone (STZ) - like structure to improve the load-bearing properties of bioengineered constructs, particularly when in-congruent surfaces are compressed, is demonstrated. The present work also provides new insights for the development of implants that are able to promote and guide new cartilaginous tissue formation upon physiologically relevant mechanical stimulation.

Dataset Information

Design of an elastin-layered dermal regeneration template.

Publications

Design of an elastin-layered dermal regeneration template.

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