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Exploiting Synergistic Effect of Controlled Co-Delivery Medicine for Soft Tissue Transplantation using Double System of Bio-Multifunctional Hydrogel

ABSTRACT: Autologous skin flap transplantation is a common method to repair complex soft tissue defects caused by cancer, trauma, and congenital malformations, among other conditions; however, limited blood supply range and post-transplantation ischemia-reperfusion injury (IRI) can cause distal necrosis of the flap and loss of long-term function, severely limiting the indications for this type of surgery. Here, development of a bio-multifunctional hydrogel for programmatic co-delivery medicine, DCDM, that meets the blood supply requirements of skin flap transplantation and can deliver two types of gas molecules, CO and NO, in a timely manner and with a concentration gradient during surgery, is described. DCDM maintains the immediate opening of blood flow channels in transplanted tissue and effective blood perfusion throughout the perioperative period, activating perfusion of the hemodynamic donor site. These results demonstrate that DCDM promotes distal vascularization and long-term functional reconstruction of transplanted tissues by inhibiting inflammatory damage and accelerating blood vessel formation. The findings presented here are applicable to the extended fields of large soft tissue defect repair and transplant of various organs.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE205580 | GEO | 2022/06/09

REPOSITORIES: GEO

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Project description:Objective/Hypothesis: To assess the efficacy and mechanism of action of a novel approach to mitigate acute and chronic radiation toxicity in a validated animal model. We propose that synthetic triterpenoid RTA-408, an Nrf2 activator, activates additional protective pathways which stabilize soft tissue during radiation, thereby reducing necrosis and improves surgical outcomes in a subsequently created axial rotational flap. Methods: Experimental animal study utilizing Sprague-Dawley rats were divided into 3 cohorts: (i) radiation + DMSO (inert vehicle), (ii) radiation + RTA-408 (therapeutic drug), and (iii) no radiation + DMSO. Two main groups of rats were utilized in these experiments: (i) rotational flap experiment (n=40) and (ii) transcriptome analysis (n=9). In the first experiment all animals in the radiation cohorts underwent 40 Gy of radiation to the soft tissue of the abdomen. Then all three cohorts underwent surgery with construction of an inferior epigastric axial rotational flap, which was performed 30 days after resolution of acute injury from radiation in the radiation groups. Percentage of flap necrosis, the primary endpoint, was calculated by standardized measurement of tissue necrosis by blinded observers and vascular density measured by CD31 staining. In a second experiment, an additional three cohorts, with identical treatment as described above underwent serial punch biopsies of the abdominal skin before, during, and after radiation and drug/vehicle control treatment. Transcriptome analysis utilizing gene set enrichment analysis and digital PCR were performed at the various timepoints. Results: In the first experiment, 40 rats were divided into the three groups and underwent treatment accordingly. The average flap necrosis was 20% (95% CI, 16-45%) in the radiation control group, 3% (95% CI, 0-11%) in the non-irradiated control, and 3% (95% CI, 0.2-10%) in the radiation group treated with RTA-408. Vascular density was preserved in the treatment group as compared to the radiated control. Nine rats were included in the second experiment, and transcriptome analyses in the treatment group revealed robust activation of antioxidant pathways with induced expression of genes associated with hypoxia and adipogenesis/angiogenesis. Conclusions: Administration of RTA-408 during radiation treatment in a rat model resulted in transcriptome changes which appear to mitigate the toxic effects of radiation, preserving capillary networks and improving flap survival and tissue healing after subsequent surgery. Such reductions in toxicity may have broad implications for functional outcomes and salvage surgery following therapeutic irradiation.

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Exploiting Synergistic Effect of Controlled Co-Delivery Medicine for Soft Tissue Transplantation using Double System of Bio-Multifunctional Hydrogel

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