A bioenergetically-active ploy (glycerol sebacate)-based multiblock hydrogel improved diabetic wound healing through revitalizing mitochondrial metabolism

Abstract

Diabetic wounds impose significant burdens on patients' quality of life and healthcare resources due to impaired healing potential. Factors like hyperglycemia, oxidative stress, impaired angiogenesis and excessive inflammation contribute to the delayed healing trajectory. Mounting evidence indicates a close association between impaired mitochondrial function and diabetic complications, including chronic wounds. Mitochondria are critical for providing energy essential to wound healing processes. However, mitochondrial dysfunction exacerbates other pathological factors, creating detrimental cycles that hinder healing. This study conducted correlation analysis using clinical specimens, revealing a positive correlation between mitochondrial dysfunction and oxidative stress, inflammatory response and impaired angiogenesis in diabetic wounds. Restoring mitochondrial function becomes imperative for developing targeted therapies. Herein, we synthesized a biodegradable poly (glycerol sebacate)-based multiblock hydrogel, named poly (glycerol sebacate)-co-poly (ethylene glycol)-co-poly (propylene glycol) (PEPGS), which can be degraded in vivo to release glycerol, a crucial component in cellular metabolism, including mitochondrial respiration. We demonstrate the potential of PEPGS-based hydrogels to improve outcomes in diabetic wound healing by revitalizing mitochondrial metabolism. Furthermore, we investigate the underlying mechanism through proteomics analysis, unravelling the regulation of ATP and nicotinamide adenine dinucleotide metabolic processes, biosynthetic process and generation during mitochondrial metabolism. These findings highlight the therapeutic potential of PEPGS-based hydrogels as advanced wound dressings for diabetic wound healing.

References

1 Matoori S, Veves A, Mooney DJ. Advanced bandages for diabetic wound healing. Sci Transl Med. 2021;13(585):eabe4839.

2 Wang Z, Lu H, Tang T, et al. Tetrahedral framework nucleic acids promote diabetic wound healing via the Wnt signalling pathway. Cell Prolif. 2022;55(11):e13316.

3 Jiang GY, Jiang T, Chen J, et al. Mitochondrial dysfunction and oxidative stress in diabetic wound. J Biochem Mol Toxicol. 2023;37(7):e23407.

4 Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders - a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1066-1077.

5 Okonkwo UA, DiPietro LA. Diabetes and Wound Angiogenesis. Int J Mol Sci. 2017;18(7):1419.

6 Wu XQ, He WJ, Mu XR, et al. Macrophage polarization in diabetic wound healing. Burns Trauma. 2022;10:tkac051.

7 Lin S, Zhang Q, Li S, et al. Antioxidative and angiogenesis-promoting effects of tetrahedral framework nucleic acids in diabetic wound healing with activation of the Akt/Nrf2/HO-1 pathway. ACS Appl Mater Interfaces. 2020;12(10):11397-11408.

8 Peppa M, Stavroulakis P, Raptis SA. Advanced glycoxidation products and impaired diabetic wound healing. Wound Repair Regen. 2009;17(4):461-472.

9 Boniakowski AE, Kimball AS, Jacobs BN, Kunkel SL, Gallagher KA. Macrophage-mediated inflammation in Normal and diabetic wound healing. J Immunol. 2017;199(1):17-24.

10 Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19(32):5695-5703.

11 Park D, Dilda PJ. Mitochondria as targets in angiogenesis inhibition. Mol Aspects Med. 2010;31(1):113-131.

12 Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537-577.

13 Sharma K, Karl B, Mathew AV, et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013;24(11):1901-1912.

14 Sharma K. Mitochondrial hormesis and diabetic complications. Diabetes. 2015;64(3):663-672.

15 Xu Z, Liu YJ, Ma R, et al. Thermosensitive hydrogel incorporating Prussian blue nanoparticles promotes diabetic wound healing via ROS scavenging and mitochondrial function restoration. ACS Appl Mater Interfaces. 2022;14(12):14059-14071.

16 Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(2):92-103.

17 Blake R, Trounce IA. Mitochondrial dysfunction and complications associated with diabetes. BBA-Gen Subjects. 2014;1840(4):1404-1412.

18 Demling RH. Nutrition, anabolism, and the wound healing process: an overview. Eplasty. 2009;9:e9.

19 Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T. Basics in nutrition and wound healing. Nutrition. 2010;26(9):862-866.

20 Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018;20(7):745-754.

21 Diebold LP, Gil HJ, Gao P, Martinez CA, Weinberg SE, Chandel NS. Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis. Nat Metab. 2019;1(1):158-171.

22 Deng QS, Gao Y, Rui BY, et al. Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles: symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus. Bioact Mater. 2023;27:409-428.

23 Nidadavolu LS, Stern D, Lin R, et al. Valsartan nano-filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds. Wound Repair Regen. 2021;29(6):927-937.

24 Li W, Xie H, Gou L, et al. DNA-based hydrogels with multidrug sequential release for promoting diabetic wound regeneration. JACS Au. 2023;3(9):2597-2608.

25 Zhong R, Xiao M, Zhu C, et al. Logic catalytic interconversion of G-molecular hydrogel. ACS Appl Mater Interfaces. 2018;10(5):4512-4518.

26 Tang Q, Plank TN, Zhu T, et al. Self-assembly of Metallo-nucleoside hydrogels for injectable materials that promote wound closure. ACS Appl Mater Interfaces. 2019;11(22):19743-19750.

27 Liang YP, He JH, Guo BL. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano. 2021;15(8):12687-12722.

28 Dimatteo R, Darling NJ, Segura T. In situ forming injectable hydrogels for drug delivery and wound repair. Adv Drug Deliv Rev. 2018;127:167-184.

29 Zhang SM, Ge GR, Qin Y, et al. Recent advances in responsive hydrogels for diabetic wound healing. Mater Today Bio. 2022;18:100508.

30 Yu L, Zeng GJ, Xu J, et al. Development of poly(glycerol sebacate) and its derivatives: a review of the progress over the past two decades. Polym Rev. 2023;63(3):613-678.

31 Patel A, Gaharwar AK, Iviglia G, et al. Highly elastomeric poly(glycerol sebacate)-co-poly(ethylene glycol) amphiphilic block copolymers. Biomaterials. 2013;34(16):3970-3983.

32 Lin D, Cai BL, Wang L, et al. A viscoelastic PEGylated poly(glycerol sebacate)-based bilayer scaffold for cartilage regeneration in full-thickness osteochondral defect. Biomaterials. 2020;253:120095.

33 Ma YF, Zhang WJ, Wang ZH, et al. PEGylated poly(glycerol sebacate)-modified calcium phosphate scaffolds with desirable mechanical behavior and enhanced osteogenic capacity. Acta Biomater. 2016;44:110-124.

34 Vogt L, Ruther F, Salehi S, Boccaccini AR. Poly(glycerol Sebacate) in biomedical applications-a review of the recent literature. Adv Healthc Mater. 2021;10(9):e2002026.

35 Wang YD, Kim YM, Langer R. In vivo degradation characteristics of poly(glycerol sebacate). J Biomed Mater Res A. 2003;66A(1):192-197.

36 Wang YD, Ameer GA, Sheppard BJ, Langer R. A tough biodegradable elastomer. Nat Biotechnol. 2002;20(6):602-606.

37 Xue LL, Chen HH, Jiang JG. Implications of glycerol metabolism for lipid production. Prog Lipid Res. 2017;68:12-25.

38 Mrácek T, Drahota Z, Houstek J. The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. BBA-Bioenergetics. 2013;1827(3):401-410.

39 Liu SS, Fu S, Wang GD, et al. Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD⁺ to alleviate mitochondrial disease. Cell Metab. 2021;33(10):1974-1987.

40 Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-580.

41 Rambold AS, Pearce EL. Mitochondrial dynamics at the Interface of immune cell metabolism and function. Trends Immunol. 2018;39(1):6-18.

42 Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017;18(7):1545.

43 Sun AR, Sun Q, Wang Y, et al. Surface modifications of titanium dental implants with strontium eucommia ulmoides to enhance osseointegration and suppress inflammation. Biomater Res. 2023;27(1):21.

44 Nassiri S, Zakeri I, Weingarten MS, Spiller KL. Relative expression of proinflammatory and Antiinflammatory genes reveals differences between healing and nonhealing human chronic diabetic foot ulcers. J Invest Dermatol. 2015;135(6):1700-1703.

45 Liang L, Song D, Wu K, et al. Sequential activation of M1 and M2 phenotypes in macrophages by Mg degradation from Ti-Mg alloy for enhanced osteogenesis. Biomater Res. 2022;26(1):17.

46 Lou D, Luo Y, Pang Q, Tan WQ, Ma L. Gene-activated dermal equivalents to accelerate healing of diabetic chronic wounds by regulating inflammation and promoting angiogenesis. Bioact Mater. 2020;5(3):667-679.

47 Wang S, Yao Z, Zhang X, et al. Energy-supporting enzyme-mimic nanoscaffold facilitates tendon regeneration based on a mitochondrial protection and microenvironment remodeling strategy. Adv Sci. 2022;9(31):e2202542.

48 Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal. 2011;15(6):1583-1606.

49 He X, Xue J, Shi L, et al. Recent antioxidative nanomaterials toward wound dressing and disease treatment via ROS scavenging. Mater Today Nano. 2022;17:100149.

50 Russell OM, Gorman GS, Lightowlers RN, Turnbull DM. Mitochondrial diseases: Hope for the future. Cell. 2020;181(1):168-188.

51 Thompson K, Collier JJ, Glasgow RIC, et al. Recent advances in understanding the molecular genetic basis of mitochondrial disease. J Inherit Metab Dis. 2020;43(1):36-50.

52 Hu Y, Chen W, Yin H, et al. Super-aligned carbon nanotubes and GelMA hydrogel composite scaffolds promote spiral ganglion neuron growth and orientation. Mater Today Nano. 2022;18:100181.

53 Na X, Chen X, Xu X, et al. Fabrication of biofunctionalized surfaces for osteo-regeneration by directional seeding of lactoferrin at the solid-liquid interface. Mater Today Nano. 2022;20:100250.

54 Willenborg S, Sanin DE, Jais A, et al. Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. Cell Metab. 2021;33(12):2398-2414.e2399.

55 Zhao F, Lei B, Li X, et al. Promoting in vivo early angiogenesis with sub-micrometer strontium-contained bioactive microspheres through modulating macrophage phenotypes. Biomaterials. 2018;178:36-47.

56 Wu Y, Quan Y, Liu Y, et al. Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes. Nat Commun. 2016;7:13393.

57 Van den Bossche J, Baardman J, Otto NA, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016;17(3):684-696.

58 Igoudjil A, Magrane J, Fischer LR, et al. In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. J Neurosci. 2011;31(44):15826-15837.

59 Singh N, NaveenKumar SK, Geethika M, Mugesh G. A cerium vanadate nanozyme with specific superoxide dismutase activity regulates mitochondrial function and ATP synthesis in neuronal cells. Angew Chem Int ed Engl. 2021;60(6):3121-3130.

60 Doi Y. Glycerol metabolism and its regulation in lactic acid bacteria. Appl Microbiol Biotechnol. 2019;103(13):5079-5093.

61 Langston PK, Nambu A, Jung J, et al. Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nat Immunol. 2019;20(9):1186-1195.

62 Nanditha CK, Kumar GSV. Bioactive peptides laden nano and micro-sized particles enriched ECM inspired dressing for skin regeneration in diabetic wounds. Mater Today Bio. 2022;14:100235.

63 Feng Z, Su Q, Zhang C, et al. Bioinspired nanofibrous glycopeptide hydrogel dressing for accelerating wound healing: a cytokine-free, M2-type macrophage polarization approach. Adv Funct Mater. 2020;30(52):2006454.

64 den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Transl Res. 2019;204:39-50.

65 Zhang H, Nie X, Shi X, et al. Regulatory mechanisms of the Wnt/beta-catenin pathway in diabetic cutaneous ulcers. Front Pharmacol. 2018;9:1114.

66 Yang C, Eleftheriadou M, Kelaini S, et al. Targeting QKI-7 in vivo restores endothelial cell function in diabetes. Nat Commun. 2020;11(1):3812.

67 Lu B, Han X, Zou D, et al. Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation. Mater Today Bio. 2022;16:100392.