Wound Closure and Metabolic Parameter Variability in a db/db Mouse Model for Diabetic Ulcers

Trousdale, Rhonda K.; Jacobs, S.; Simhaee, David A.; Wu, June K.; Lustbader, Joyce W.

doi:10.1016/j.jss.2008.01.023

Cited by 45 publications

(45 citation statements)

References 45 publications

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“…Furthermore, the db/db mouse is a frequently used model of delayed and diabetic wound healing due to its wellcharacterized microvascular disease phenotype, 34,[38][39][40][41][42][43] which includes delayed cellular wound infiltration, reduced angiogenesis, and altered immune function. 44 The aggregate effect of these diabetes-associated impairments includes delayed wound contraction, [41][42][43][44] and the average time to complete wound closure in an unsplinted wound is *50-70% longer in the db/db mice compared to wild-type controls. [41][42][43][44] The wounds (n = 10) were treated with vehicle control (1% w/v dehydrated methylcellulose [MC]), unconjugated Shh (4.9 mg per wound), or mvShh (4.9 mg Shh per wound and presented with 16:1 valency).…”

Section: Multivalent Conjugate Characterizationmentioning

confidence: 99%

“…44 The aggregate effect of these diabetes-associated impairments includes delayed wound contraction, [41][42][43][44] and the average time to complete wound closure in an unsplinted wound is *50-70% longer in the db/db mice compared to wild-type controls. [41][42][43][44] The wounds (n = 10) were treated with vehicle control (1% w/v dehydrated methylcellulose [MC]), unconjugated Shh (4.9 mg per wound), or mvShh (4.9 mg Shh per wound and presented with 16:1 valency).…”

Section: Multivalent Conjugate Characterizationmentioning

confidence: 99%

See 1 more Smart Citation

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Han

Layman

Rode

et al. 2015

Tissue Engineering Part A

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Despite their preclinical promise, few recombinant growth factors have been fully developed into effective therapies, in part, due to the short interval of therapeutic activity after administration. To address this problem, we developed nanoscale polymer conjugates for multivalent presentation of therapeutic proteins that enhance the activation of targeted cellular responses. As an example of this technology, we conjugated multiple Sonic hedgehog (Shh) proteins onto individual hyaluronic acid biopolymers to generate multivalent protein clusters at defined ratios (i.e., valencies) that yield enhanced Shh pathway activation at equivalent concentrations relative to unconjugated Shh. In this study, we investigated whether these multivalent conjugates (mvShh) could be used to improve the therapeutic function of Shh. We found that a single treatment with mvShh significantly accelerated the closure of full-thickness wounds in diabetic (db/db) mice compared to either an equivalent dose of unconjugated Shh or the vehicle control. Furthermore, we identified specific indicators of wound healing in fibroblasts and endothelial cells (i.e., transcriptional activation and cell migration) that were activated by mvShh in vitro and at concentrations approximately an order of magnitude lower than the unconjugated Shh. Taken together, our findings suggest that mvShh conjugates exhibit greater potency to activate the Shh pathway, and this multivalency advantage improves its therapeutic effect to accelerate wound closure in a diabetic animal model. Our strategy of multivalent protein presentation using nanoscale polymer conjugates has the potential to make a significant impact on the development of protein-based therapies by improving their in vivo performance.

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Section: Multivalent Conjugate Characterizationmentioning

confidence: 99%

Section: Multivalent Conjugate Characterizationmentioning

confidence: 99%

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Han

Layman

Rode

et al. 2015

Tissue Engineering Part A

View full text Add to dashboard Cite

show abstract

“…Lack of VEGF is also responsible for insufficient neovascularization during diabetic wound healing and deranged arteriogenesis [13,18]. Impaired neovascularization in diabetic mice is associated with decreased concentration of fibroblast growth factor (FGF) [51].…”

Section: Discussionmentioning

confidence: 99%

“…Wound healing is delayed, metabolic efficiency is increased [18,19], a hypertrophy of the left ventricle is described [16], and the number of blood leukocytes is decreased [20].…”

Section: Animalsmentioning

confidence: 99%

Decelerated vascularization in tissue-engineered constructs in association with diabetes mellitus in vivo

Schumann¹,

Lindhorst²,

Kampmann³

et al. 2015

Journal of Diabetes and its Complications

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“…30 In a model of diabetic foot ulcers, genetically obese db/db mice had greatly delayed healing compared to both + / + and db/ + controls, with both nondiabetic strains having 100% wound closure at day 21 compared to 50% closure at the same time point in db/db mice. 31 Similarly, genetically obese Zucker rats had larger wound size and reduced wound strength in a model of laparotomy wound healing at 28 days postoperation. 32 Mechanisms.…”

Section: Obesity and Wound Healingmentioning

confidence: 98%