Accelerated Healing of Diabetic Wounds Treated with L-Glutamic acid Loaded Hydrogels Through Enhanced Collagen Deposition and Angiogenesis: An In Vivo Study

Abstract

We have developed L-glutamic acid (LG) loaded chitosan (CS) hydrogels to treat diabetic wounds. Although literature reports wound healing effects of poly(glutamic acid)-based materials, there are no studies on the potential of L-glutamic acid in treating diabetic wounds. As LG is a direct precursor for proline synthesis, which is crucial for collagen synthesis, we have prepared CS + LG hydrogels to accelerate diabetic wound healing. Physiochemical properties of the CS + LG hydrogels showed good swelling, thermal stability, smooth surface morphology, and controlled biodegradation. The addition of LG to CS hydrogels did not alter their biocompatibility significantly. CS + LG hydrogel treatment showed rapid wound contraction compared to control and chitosan hydrogel. Period of epithelialization is significantly reduced in CS + LG hydrogel treated wounds (16 days) compared to CS hydrogel (20 days), and control (26 days). Collagen synthesis and crosslinking are also significantly improved in CS + LG hydrogel treated diabetic rats. Histopathology and immunohistochemistry results revealed that the CS + LG hydrogel dressing accelerated vascularization and macrophage recruitment to enhance diabetic wound healing. These results demonstrate that incorporation of LG can improve collagen deposition, and vascularization, and aid in faster tissue regeneration. Therefore, CS + LG hydrogels could be an effective wound dressing used to treat diabetic wounds.

Effect of ethanolic extract of Melia dubia leaves on full‐thickness cutaneous wounds in Wistar rats

“…Total collagen content was estimated based on hydroxyproline index and (Woessner, ) hexosamine was determined according to the previous method (Elson & Morgan, ). The total collagen was calculated as given below (Thangavel et al, ). …”

“…The percentage of wound contraction was calculated (Thangavel et al, ) using the following formula: where, n = Days 4, 8, 12, and 16.…”

Macrophage metabolism: a wound‐healing perspective

“…Glutamine enters the TCA through α‐ketoglutarate, and glutamine‐derived α‐ketogluarate is required for alternative activation gene networks, maintenance of mitochondrial SRC and FAO in M(IL‐4) macrophages, and can limit inflammatory polarization by facilitating epigenetic demethylation of histones at key M(IL‐4) genes (Figure .). Hydrogels loaded with glutamine were able to increase the speed of wound closure and epithelialization in diabetic mice, with treated wounds showing increased collagen deposition, a hallmark of alternatively activated macrophage activity . Conversely, inhibiting alternative macrophage activation may have benefit in situations of excessive scarring and fibrosis, as excessive arg‐1 activity in macrophages may lead to increased collagen deposition and ultimately scarring.…”

“…Hydrogels loaded with glutamine were able to increase the speed of wound closure and epithelialization in diabetic mice, with treated wounds showing increased collagen deposition, a hallmark of alternatively activated macrophage activity. 78 Conversely, inhibiting alternative macrophage activation may have benefit in situations of excessive scarring and fibrosis, as excessive arg-1 activity in macrophages may lead to increased collagen deposition and ultimately scarring. Targeting arg-1 directly may have therapeutic benefit, and other metabolic pathways central to alternative activation such as FAO, glutaminolysis or Nglycosylation and proline and polyamine synthesis may represent potential therapeutic targets (Figure 3).…”

Review: Multimodal bioactive material approaches for wound healing

“…Disruption of this process can impede tissue formation and is commonly observed in diabetic wounds. 50 VEGF plays a major role in promoting angiogenesis and is common in wound dressings aimed at increasing vascularization. A phase 1 trial was aimed at assessing the safety and efficacy of recombinant human VEGF which was topically applied to chronic diabetic ulcers.…”