Anti α-Gal Nanoparticles Ameliorate Radiation-Induced Wound Healing Impairment
Arash Samadi1, Justin buro1, Daniel O. Lara1, Matthew A. Wright1, Uri Galili2, Jason A. Spector1.
1Weill Cornell Medicine, New York City, NY, USA, 2Rush Medical College, Chicago, IL, USA.
PURPOSE: Radiation is a common primary, adjuvant and neoadjuvant therapy in oncological patients, resulting in damage to the local tissues and permanently compromised wound healing. As a result, surgery in radiated tissue is known to have significantly higher rates of complications. It is thought that one cause of impaired wound healing is the aberrant inflammatory response that occurs in radiated tissues. Humans are continually and safely exposed to the natural antigen α-gal (Galalpha1-3Galbeta1-(3)4GlcNAc-R), and 1% of their antibodies are directed against the antigen. We have previously demonstrated that the topical application of α-gal nanoparticles can significantly accelerate wound healing in both normal and diabetic wounds likely due to accelerated macrophage recruitment. We hypothesized that application of α-gal nanoparticles would similarly enhance wound healing in irradiated wounds.
METHODS: Since mice normally produce the antigen α-gal, α-1,3galactosyltrasferase knockout mice (which do not produce the antigen and therefore can be stimulated to produce antibodies against it) were used in all experiments. Mice were immunized to produce anti α-gal antibodies at titers comparable to those seen in humans. Dorsal skin was isolated using a low-pressure clamp as previously described and was treated with one session of 40Gy. Ten days after radiation two 6-mm bilateral dorsal splinted wounds were created, and these were then treated with α-gal nanoparticles in a 2% carboxymethyl cellulose (CMC) carrier, immediately after wounding and again on postoperative day 1. Control wild type and knockout mice underwent similar irradiation and wounding protocols but were treated with phosphate buffered saline (PBS) in 2% CMC. Wounds were harvested from all animals on days 3, 6, 9, 12 and 15, fixed, sectioned, and H&E and IHC performed to determine the extent of keratinocyte migration, granulation tissue deposition, neovascularization and macrophage invasion.
RESULTS: Full closure of all wounds by day 9 in the non-radiated control compared to no completely closed wounds in the radiated group confirmed the known inhibitory effects of irradiation on wound healing. In addition, histological changes such as increased epidermal thickness in the tissue surrounding the wound further confirmed the effects of irradiation on the skin. Histologic analysis demonstrated significantly enhanced keratinocyte migration in the α-gal nano-particle treated group by day 15 in comparison to saline treated group (2.37mm versus 0.58mm, p<0.001). Fifteen days after wounding 25% of all α-gal treated wounds were completely healed as oppose to only 10% in the saline treated group. Analysis of later time points is currently underway.
CONCLUSION: Topical application of α-gal nanoparticles onto radiated wounds significantly accelerates the rate and degree of wound closure. We believe this naturally occurring agent has great promise for translation in plastic surgery as it has demonstrated efficacy in not only normal wounds but pathologic (diabetic, radiated) ones as well. Further work continues towards a better understanding of the mechanisms underlying the salutary effects of alpha gal.
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