Engineered human vascularized constructs accelerate diabetic wound healing

Shen, Yun-Dun; Cho, Hongkwan; Papa, Arianne; Burke, Jacqueline A.; Chan, Xin Yi; Duh, Elia J.; Gerecht, Sharon

doi:10.1016/j.biomaterials.2016.06.009

Cited by 110 publications

(80 citation statements)

References 45 publications

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“…The inability of these animals to regenerate nerves fully has also been recognized (29)(30)(31). This failure is in contrast to woundhealing studies in healthy animals, such as burn injury models, that reported hair regrowth (72) and signs of reinnervation as judged by the presence of PgP9.5 in the wound (78).…”

Section: Discussioncontrasting

confidence: 48%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

124

156

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There is a clinical need for new, more effective treatments for chronic wounds in diabetic patients. Lack of epithelial cell migration is a hallmark of nonhealing wounds, and diabetes often involves endothelial dysfunction. Therefore, targeting re-epithelialization, which mainly involves keratinocytes, may improve therapeutic outcomes of current treatments. In this study, we present an integrin-binding prosurvival peptide derived from angiopoietin-1, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), as a therapeutic candidate for diabetic wound treatments by demonstrating its efficacy in promoting the attachment, survival, and collective migration of human primary keratinocytes and the activation of protein kinase B Akt and MAPK p42/44 . The QHREDGS peptide, both as a soluble supplement and when immobilized in a substrate, protected keratinocytes against hydrogen peroxide stress in a dose-dependent manner. Collective migration of both normal and diabetic human keratinocytes was promoted on chitosan-collagen films with the immobilized QHREDGS peptide. The clinical relevance was demonstrated further by assessing the chitosan-collagen hydrogel with immobilized QHREDGS in full-thickness excisional wounds in a db/db diabetic mouse model; QHREDGS showed significantly accelerated and enhanced wound closure compared with a clinically approved collagen wound dressing, peptide-free hydrogel, or blank wound controls. The accelerated wound closure resulted primarily from faster re-epithelialization and increased formation of granulation tissue. There were no observable differences in blood vessel density or size within the wound; however, the total number of blood vessels was greater in the peptide-hydrogeltreated wounds. Together, these findings indicate that QHREDGS is a promising candidate for wound-healing interventions that enhance reepithelialization and the formation of granulation tissue.

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Section: Discussioncontrasting

confidence: 48%

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Xiao

Reis

Feric

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

124

156

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“…Blood Flow Measurements. Blood flow profiles of the native abdominal aorta and implanted sdVG were monitored using moorFLPI speckle contrast imager as previously described (84)(85)(86). Measurements were taken immediately postimplantation and before harvest while the mice were anesthetized and normalized to preimplant measurements.…”

Section: Methodsmentioning

confidence: 99%

“…Hematoxylin and eosin, Masson's Trichrome, Verhoeff van Gieson, and von Kossa staining was performed by the Johns Hopkins University Oncology Tissue Services and Reference Histology Cores. Immunohistochemistry staining was performed as previously described (84) and imaged with an upright light microscope (Nikon Accuscope 3000, DS-F12). For analysis, three to eight different sections per condition and per time point were sampled.…”

Section: Methodsmentioning

confidence: 99%

Regenerative and durable small-diameter graft as an arterial conduit

Elliott

Ginn

Fukunishi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(e-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and formation of a confluent endothelium within 3-4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(e-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure formation, reduced calcification, and accelerated tunica media formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates neotissue formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.small-diameter vascular graft | infrarenal abdominal aorta mouse model | electrospinning | hydrogel | endothelial colony-forming cells

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“…Soft and biocompatible hydrogel, possessing three-dimensional (3D) polymer networks and physicochemical properties similar to the extracellular matrices of tissues891011, can provide the 3D microenvironment for the differentiation and engraftment of transplanted NSCs. Injectable hydrogel, delivering cells into localized lesion site within any defect shape via minimally invasive manner, has been extensively applied in the delivery of NSCs121314.…”

mentioning

confidence: 99%

Self-healing polysaccharide-based hydrogels as injectable carriers for neural stem cells

Zhao¹,

Zhao²,

Chen³

et al. 2016

Sci Rep

134

103

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Self-healing injectable hydrogels can be formulated as three-dimensional carriers for the treatment of neurological diseases with desirable advantages, such as avoiding the potential risks of cell loss during injection, protecting cells from the shearing force of injection. However, the demands for biocompatible self-healing injectable hydrogels to meet above requirements and to promote the differentiation of neural stem cells (NSCs) into neurons remain a challenge. Herein, we developed a biocompatible self-healing polysaccharide-based hydrogel system as a novel injectable carrier for the delivery of NSCs. N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) are the main backbones of the hydrogel networks, denoted as CEC-l-OSA hydrogel (“l” means “linked-by”). Owing to the dynamic imine cross-links formed by a Schiff reaction between amino groups on CEC and aldehyde groups on OSA, the hydrogel possesses the ability to self-heal into a integrity after being injected from needles under physiological conditions. The CEC-l-OSA hydrogel in which the stiffness mimicking nature brain tissues (100~1000 Pa) can be finely tuned to support the proliferation and neuronal differentiation of NSCs. The multi-functional, injectable, and self-healing CEC-l-OSA hydrogels hold great promises for NSC transplantation and further treatment of neurological diseases.

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Engineered human vascularized constructs accelerate diabetic wound healing

Cited by 110 publications

References 45 publications

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Regenerative and durable small-diameter graft as an arterial conduit

Self-healing polysaccharide-based hydrogels as injectable carriers for neural stem cells

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