1932

Abstract

Although sex differences have been noted in cellular function and behavior, therapy efficacy, and disease incidence and outcomes, the adoption of sex as a biological variable in tissue engineering and regenerative medicine remains limited. Furthering the development of personalized, precision medicine requires considering biological sex at the bench and in the clinic. This review provides the basis for considering biological sex when designing tissue-engineered constructs and regenerative therapies by contextualizing sex as a biological variable within the tissue engineering triad of cells, matrices, and signals. To achieve equity in biological sex within medicine requires a cultural shift in science and engineering research, with active engagement by researchers, clinicians, companies, policymakers, and funding agencies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-bioeng-092222-030857
2023-06-08
2024-04-28
Loading full text...

Full text loading...

/deliver/fulltext/bioeng/25/1/annurev-bioeng-092222-030857.html?itemId=/content/journals/10.1146/annurev-bioeng-092222-030857&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Lee SK. 2018. Sex as an important biological variable in biomedical research. BMB Rep. 51:167–73
    [Google Scholar]
  2. 2.
    Miller VM, Rice M, Schiebinger L, Jenkins MR, Werbinski J et al. 2013. Embedding concepts of sex and gender health differences into medical curricula. J. Womens Health 22:194–202
    [Google Scholar]
  3. 3.
    Klein SL, Schiebinger L, Stefanick ML, Cahill L, Danska J et al. 2015. Sex inclusion in basic research drives discovery. PNAS 112:5257–58
    [Google Scholar]
  4. 4.
    Can. Inst. Health Res 2010. Gender, sex and health research guide: a tool for CIHR applicants Guide, Can. Inst. Health Res. Ottawa, ON, Canada: https://cihr-irsc.gc.ca/e/50836.html
  5. 5.
    Schiebinger L, Klinge I. 2020. Gendered innovations 2: how inclusive analysis contributes to research and innovation: policy review Rep. Publications Office of the European Union Luxembourg:
  6. 6.
    Nielsen MW, Stefanick ML, Peragine D, Neilands TB, Ioannidis JPA et al. 2021. Gender-related variables for health research. Biol. Sex Differ. 12:23
    [Google Scholar]
  7. 7.
    White J, Tannenbaum C, Klinge I, Schiebinger L, Clayton J. 2021. The integration of sex and gender considerations into biomedical research: lessons from international funding agencies. J. Clin. Endocrinol. Metab. 106:3034–48
    [Google Scholar]
  8. 8.
    Schiebinger L. 2022. Integrating sex, gender, and intersectional analysis into bioengineering. Curr. Opin. Biomed. Eng. 22:100388
    [Google Scholar]
  9. 9.
    Tannenbaum C, Ellis RP, Eyssel F, Zou J, Schiebinger L. 2019. Sex and gender analysis improves science and engineering. Nature 575:137–46
    [Google Scholar]
  10. 10.
    Pepine CJ, Ferdinand KC, Shaw LJ, Light-McGroary KA, Shah RU et al. 2015. Emergence of nonobstructive coronary artery disease: a woman's problem and need for change in definition on angiography. J. Am. Coll. Cardiol. 66:1918–33
    [Google Scholar]
  11. 11.
    Volgman AS, Bairey Merz CN, Aggarwal NT, Bittner V, Bunch TJ et al. 2019. Sex differences in cardiovascular disease and cognitive impairment: another health disparity for women?. J. Am. Heart Assoc. 8:e013154
    [Google Scholar]
  12. 12.
    Clocchiatti A, Cora E, Zhang Y, Dotto GP 2016. Sexual dimorphism in cancer. Nat. Rev. Cancer 16:330–39
    [Google Scholar]
  13. 13.
    Zhu Y, Shao X, Wang X, Liu L, Liang H. 2019. Sex disparities in cancer. Cancer Lett. 466:35–38
    [Google Scholar]
  14. 14.
    Shansky RM, Murphy AZ. 2021. Considering sex as a biological variable will require a global shift in science culture. Nat. Neurosci. 24:457–64
    [Google Scholar]
  15. 15.
    Stanhewicz AE, Wenner MM, Stachenfeld NS. 2018. Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am. J. Physiol. Heart Circ. Physiol. 315:H1569–88
    [Google Scholar]
  16. 16.
    Zucker I, Prendergast BJ. 2020. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11:32
    [Google Scholar]
  17. 17.
    Aguado BA, Grim JC, Rosales AM, Watson-Capps JJ, Anseth KS. 2018. Engineering precision biomaterials for personalized medicine. Sci. Transl. Med. 10:eaam8645
    [Google Scholar]
  18. 18.
    James BD, Allen JB. 2021. Sex-specific response to combinations of shear stress and substrate stiffness by endothelial cells in vitro. Adv. Healthc. Mater. 10:e2100735
    [Google Scholar]
  19. 19.
    Wizemann TM, Pardue ML 2001. Exploring the Biological Contributions to Human Health: Does Sex Matter? Washington, DC: National Academies Press
    [Google Scholar]
  20. 20.
    Clayton JA, Collins FS. 2014. Policy: NIH to balance sex in cell and animal studies. Nature 509:282–83
    [Google Scholar]
  21. 21.
    Waltz M, Saylor KW, Fisher JA, Walker RL. 2021. Biomedical researchers' perceptions of the NIH's sex as a biological variable policy for animal research: results from a U.S. national survey. J. Womens Health 30:1395–405
    [Google Scholar]
  22. 22.
    Arnegard ME, Whitten LA, Hunter C, Clayton JA. 2020. Sex as a biological variable: a 5-year progress report and call to action. J. Womens Health 29:858–64
    [Google Scholar]
  23. 23.
    James BD, Guerin P, Allen JB. 2021. Let's talk about sex—biological sex is underreported in biomaterial studies. Adv. Healthc. Mater. 10:e2001034
    [Google Scholar]
  24. 24.
    Kouthouridis S, Robson E, Hartung A, Raha S, Zhang B. 2022. Se(XY) matters: the importance of incorporating sex in microphysiological models. Trends Biotechnol. 40:1284–98
    [Google Scholar]
  25. 25.
    Nawroth J, Rogal J, Weiss M, Brucker SY, Loskill P. 2018. Organ-on-a-chip systems for women's health applications. Adv. Healthc. Mater. 7:1700550
    [Google Scholar]
  26. 26.
    Vallabhajosyula S, Ponamgi SP, Shrivastava S, Sundaragiri PR, Miller VM. 2020. Reporting of sex as a variable in cardiovascular studies using cultured cells: a systematic review. FASEB J. 34:8778–86
    [Google Scholar]
  27. 27.
    Samango-Sprouse C, Kirkizlar E, Hall MP, Lawson P, Demko Z et al. 2016. Incidence of X and Y chromosomal aneuploidy in a large child bearing population. PLOS ONE 11:e0161045
    [Google Scholar]
  28. 28.
    Garieri M, Stamoulis G, Blanc X, Falconnet E, Ribaux P et al. 2018. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. PNAS 115:13015–20
    [Google Scholar]
  29. 29.
    Berletch JB, Yang F, Xu J, Carrel L, Disteche CM. 2011. Genes that escape from X inactivation. Hum. Genet. 130:237–45
    [Google Scholar]
  30. 30.
    Aguado BA, Walker CJ, Grim JC, Schroeder ME, Batan D et al. 2022. Genes that escape X chromosome inactivation modulate sex differences in valve myofibroblasts. Circulation 145:513–30
    [Google Scholar]
  31. 31.
    Felix Velez NE, Gorashi RM, Aguado BA 2022. Chemical and molecular tools to probe biological sex differences at multiple length scales. J. Mater. Chem. B 10:7089–98
    [Google Scholar]
  32. 32.
    Migeon BR. 2008. X inactivation, female mosaicism, and sex differences in renal diseases. J. Am. Soc. Nephrol. 19:2052–59
    [Google Scholar]
  33. 33.
    Klein SL, Flanagan KL. 2016. Sex differences in immune responses. Nat. Rev. Immunol. 16:626–38
    [Google Scholar]
  34. 34.
    Fish EN. 2008. The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 8:737–44
    [Google Scholar]
  35. 35.
    Dumanski JP, Rasi C, Lonn M, Davies H, Ingelsson M et al. 2015. Mutagenesis. Smoking is associated with mosaic loss of chromosome Y. Science 347:81–83
    [Google Scholar]
  36. 36.
    Forsberg LA. 2017. Loss of chromosome Y (LOY) in blood cells is associated with increased risk for disease and mortality in aging men. Hum. Genet. 136:657–63
    [Google Scholar]
  37. 37.
    Forsberg LA, Gisselsson D, Dumanski JP. 2017. Mosaicism in health and disease—clones picking up speed. Nat. Rev. Genet. 18:128–42
    [Google Scholar]
  38. 38.
    Sano S, Horitani K, Ogawa H, Halvardson J, Chavkin NW et al. 2022. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science 377:292–97
    [Google Scholar]
  39. 39.
    Liang G, Zhang Y. 2013. Genetic and epigenetic variations in iPSCs: potential causes and implications for application. Cell Stem Cell 13:149–59
    [Google Scholar]
  40. 40.
    Xu J, Peng X, Chen Y, Zhang Y, Ma Q et al. 2017. Free-living human cells reconfigure their chromosomes in the evolution back to uni-cellularity. eLife 6:e28070
    [Google Scholar]
  41. 41.
    Litvinukova M, Talavera-Lopez C, Maatz H, Reichart D, Worth CL et al. 2020. Cells of the adult human heart. Nature 588:466–72
    [Google Scholar]
  42. 42.
    Tabula Sapiens C, Jones RC, Karkanias J, Krasnow MA, Pisco AO et al. 2022. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376:eabl4896
    [Google Scholar]
  43. 43.
    Walker CJ, Schroeder ME, Aguado BA, Anseth KS, Leinwand LA. 2021. Matters of the heart: cellular sex differences. J. Mol. Cell. Cardiol. 160:42–55
    [Google Scholar]
  44. 44.
    Kassam I, Wu Y, Yang J, Visscher PM, McRae AF. 2019. Tissue-specific sex differences in human gene expression. Hum. Mol. Genet. 28:2976–86
    [Google Scholar]
  45. 45.
    Lopes-Ramos CM, Chen CY, Kuijjer ML, Paulson JN, Sonawane AR et al. 2020. Sex differences in gene expression and regulatory networks across 29 human tissues. Cell Rep. 31:107795
    [Google Scholar]
  46. 46.
    Oliva M, Munoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH et al. 2020. The impact of sex on gene expression across human tissues. Science 369:eaba3066
    [Google Scholar]
  47. 47.
    Hartman RJG, Kapteijn DMC, Haitjema S, Bekker MN, Mokry M et al. 2020. Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets. Sci. Rep. 10:12367
    [Google Scholar]
  48. 48.
    Khramtsova EA, Davis LK, Stranger BE. 2019. The role of sex in the genomics of human complex traits. Nat. Rev. Genet. 20:173–90
    [Google Scholar]
  49. 49.
    D'Antonio-Chronowska A, Donovan MKR, Young Greenwald WW, Nguyen JP, Fujita K et al. 2019. Association of human iPSC gene signatures and X chromosome dosage with two distinct cardiac differentiation trajectories. Stem Cell Rep. 13:924–38
    [Google Scholar]
  50. 50.
    Randolph LN, Bao X, Oddo M, Lian XL. 2019. Sex-dependent VEGF expression underlies variations in human pluripotent stem cell to endothelial progenitor differentiation. Sci. Rep. 9:16696
    [Google Scholar]
  51. 51.
    Serpooshan V, Sheibani S, Pushparaj P, Wojcik M, Jang AY et al. 2018. Effect of cell sex on uptake of nanoparticles: the overlooked factor at the nanobio interface. ACS Nano 12:2253–66
    [Google Scholar]
  52. 52.
    Ogawa R, Mizuno H, Watanabe A, Migita M, Hyakusoku H, Shimada T. 2004. Adipogenic differentiation by adipose-derived stem cells harvested from GFP transgenic mice—including relationship of sex differences. Biochem. Biophys. Res. Commun. 319:511–17
    [Google Scholar]
  53. 53.
    Anguera MC, Sadreyev R, Zhang Z, Szanto A, Payer B et al. 2012. Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 11:75–90
    [Google Scholar]
  54. 54.
    Lobo J, See EY, Biggs M, Pandit A. 2016. An insight into morphometric descriptors of cell shape that pertain to regenerative medicine. J. Tissue Eng. Regen. Med. 10:539–53
    [Google Scholar]
  55. 55.
    Huxley VH, Kemp SS, Schramm C, Sieveking S, Bingaman S et al. 2018. Sex differences influencing micro- and macrovascular endothelial phenotype in vitro. J. Physiol. 596:3929–49
    [Google Scholar]
  56. 56.
    Bonnevie ED, Ashinsky BG, Dekky B, Volk SW, Smith HE, Mauck RL. 2021. Cell morphology and mechanosensing can be decoupled in fibrous microenvironments and identified using artificial neural networks. Sci. Rep. 11:5950
    [Google Scholar]
  57. 57.
    Addis R, Campesi I, Fois M, Capobianco G, Dessole S et al. 2014. Human umbilical endothelial cells (HUVECs) have a sex: characterisation of the phenotype of male and female cells. Biol. Sex Differ. 5:18
    [Google Scholar]
  58. 58.
    McCoy CM, Nicholas DQ, Masters KS. 2012. Sex-related differences in gene expression by porcine aortic valvular interstitial cells. PLOS ONE 7:e39980
    [Google Scholar]
  59. 59.
    Yasuda K, Maki T, Kinoshita H, Kaji S, Toyokawa M et al. 2020. Sex-specific differences in transcriptomic profiles and cellular characteristics of oligodendrocyte precursor cells. Stem Cell Res. 46:101866
    [Google Scholar]
  60. 60.
    Campesi I, Franconi F, Montella A, Dessole S, Capobianco G. 2021. Human umbilical cord: information mine in sex-specific medicine. Life 11:52
    [Google Scholar]
  61. 61.
    Cattaneo MG, Banfi C, Brioschi M, Lattuada D, Vicentini LM. 2021. Sex-dependent differences in the secretome of human endothelial cells. Biol. Sex Differ. 12:7
    [Google Scholar]
  62. 62.
    Cattaneo MG, Vanetti C, Decimo I, Di Chio M, Martano G et al. 2017. Sex-specific eNOS activity and function in human endothelial cells. Sci. Rep. 7:9612
    [Google Scholar]
  63. 63.
    Nelson V, Patil V, Simon LR, Schmidt K, McCoy CM, Masters KS. 2021. Angiogenic secretion profile of valvular interstitial cells varies with cellular sex and phenotype. Front. Cardiovasc. Med. 8:736303
    [Google Scholar]
  64. 64.
    Rietjens I, Vervoort J, Maslowska-Gornicz A, Van den Brink N, Beekmann K. 2018. Use of proteomics to detect sex-related differences in effects of toxicants: implications for using proteomics in toxicology. Crit. Rev. Toxicol. 48:666–81
    [Google Scholar]
  65. 65.
    Aguado BA, Schuetze KB, Grim JC, Walker CJ, Cox AC et al. 2019. Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation. Sci. Transl. Med. 11:eaav3233
    [Google Scholar]
  66. 66.
    Ueno M, Zhang N, Hirata H, Barati D, Utsunomiya T et al. 2021. Sex differences in mesenchymal stem cell therapy with gelatin-based microribbon hydrogels in a murine long bone critical-size defect model. Front. Bioeng. Biotechnol. 9:755964
    [Google Scholar]
  67. 67.
    Batzdorf CS, Morr AS, Bertalan G, Sack I, Silva RV, Infante-Duarte C. 2022. Sexual dimorphism in extracellular matrix composition and viscoelasticity of the healthy and inflamed mouse brain. Biology 11:230
    [Google Scholar]
  68. 68.
    Dworatzek E, Baczko I, Kararigas G. 2016. Effects of aging on cardiac extracellular matrix in men and women. Proteom. Clin. Appl. 10:84–91
    [Google Scholar]
  69. 69.
    Gourgas O, Khan K, Schwertani A, Cerruti M. 2020. Differences in mineral composition and morphology between men and women in aortic valve calcification. Acta Biomater. 106:342–50
    [Google Scholar]
  70. 70.
    Porras AM, McCoy CM, Masters KS. 2017. Calcific aortic valve disease: a battle of the sexes. Circ. Res. 120:604–6
    [Google Scholar]
  71. 71.
    Simard L, Cote N, Dagenais F, Mathieu P, Couture C et al. 2017. Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis: Is valvular fibrosis the explanation?. Circ. Res. 120:681–91
    [Google Scholar]
  72. 72.
    Voisine M, Hervault M, Shen M, Boilard AJ, Filion B et al. 2020. Age, sex, and valve phenotype differences in fibro-calcific remodeling of calcified aortic valve. J. Am. Heart Assoc. 9:e015610
    [Google Scholar]
  73. 73.
    Schroeder ME, Batan D, Gonzalez Rodriguez A, Speckl KF, Peters DK et al. 2023. Osteopontin activity modulates sex-specific calcification in engineered valve tissue mimics. Bioeng. Transl. Med. 8:1e10358
    [Google Scholar]
  74. 74.
    Masjedi S, Lei Y, Patel J, Ferdous Z. 2017. Sex-related differences in matrix remodeling and early osteogenic markers in aortic valvular interstitial cells. Heart Vessels 32:217–28
    [Google Scholar]
  75. 75.
    Scott AJ, Simon LR, Hutson HN, Porras AM, Masters KS. 2021. Engineering the aortic valve extracellular matrix through stages of development, aging, and disease. J. Mol. Cell. Cardiol. 161:1–8
    [Google Scholar]
  76. 76.
    Ariyasinghe NR, Escopete S, De Souza Santos R, Gross A, Sareen D, Parker SJ. 2022. Identification of disease-relevant, sex-based proteomic differences in iPSC-derived vascular smooth muscle. FASEB J. 36:S1R2677
    [Google Scholar]
  77. 77.
    Berger MB, Cohen DJ, Olivares-Navarrete R, Williams JK, Cochran DL et al. 2018. Human osteoblasts exhibit sexual dimorphism in their response to estrogen on microstructured titanium surfaces. Biol. Sex Differ. 9:30
    [Google Scholar]
  78. 78.
    Olivares-Navarrete R, Hyzy SL, Chaudhri RA, Zhao G, Boyan BD, Schwartz Z. 2010. Sex dependent regulation of osteoblast response to implant surface properties by systemic hormones. Biol. Sex Differ. 1:4
    [Google Scholar]
  79. 79.
    Blum KM, Roby LC, Zbinden JC, Chang YC, Mirhaidari GJM et al. 2021. Sex and tamoxifen confound murine experimental studies in cardiovascular tissue engineering. Sci. Rep. 11:8037
    [Google Scholar]
  80. 80.
    Yang JLJ, Narayanamurthy R, Yager JY, Unsworth LD. 2021. How does biological sex affect the physiological response to nanomaterials?. Nano Today 41:101292
    [Google Scholar]
  81. 81.
    Bharadwaj VN, Copeland C, Mathew E, Newbern J, Anderson TR et al. 2020. Sex-dependent macromolecule and nanoparticle delivery in experimental brain injury. Tissue Eng. Part A 26:688–701
    [Google Scholar]
  82. 82.
    Chaudhuri O, Gu L, Klumpers D, Darnell M, Bencherif SA et al. 2016. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15:326–34
    [Google Scholar]
  83. 83.
    Engler AJ, Sen S, Sweeney HL, Discher DE. 2006. Matrix elasticity directs stem cell lineage specification. Cell 126:677–89
    [Google Scholar]
  84. 84.
    Yang C, Tibbitt MW, Basta L, Anseth KS. 2014. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13:645–52
    [Google Scholar]
  85. 85.
    James BD, Allen JB. 2018. Vascular endothelial cell behavior in complex mechanical microenvironments. ACS Biomater. Sci. Eng. 4:3818–42
    [Google Scholar]
  86. 86.
    Lorenz M, Koschate J, Kaufmann K, Kreye C, Mertens M et al. 2015. Does cellular sex matter? Dimorphic transcriptional differences between female and male endothelial cells. Atherosclerosis 240:61–72
    [Google Scholar]
  87. 87.
    Ma Z, Li DX, Kunze M, Mulet-Sierra A, Westover L, Adesida AB. 2022. Engineered human meniscus in modeling sex differences of knee osteoarthritis in vitro. Front. Bioeng. Biotechnol. 10:823679
    [Google Scholar]
  88. 88.
    Dikici S, Mangir N, Claeyssens F, Yar M, MacNeil S. 2019. Exploration of 2-deoxy-D-ribose and 17β-Estradiol as alternatives to exogenous VEGF to promote angiogenesis in tissue-engineered constructs. Regen. Med. 14:179–97
    [Google Scholar]
  89. 89.
    Knewtson KE, Ohl NR, Robinson JL. 2022. Estrogen signaling dictates musculoskeletal stem cell behavior: sex differences in tissue repair. Tissue Eng. Part B Rev. 28:789–812
    [Google Scholar]
  90. 90.
    Barros RP, Gustafsson JA. 2011. Estrogen receptors and the metabolic network. Cell Metab. 14:289–99
    [Google Scholar]
  91. 91.
    Bereshchenko O, Bruscoli S, Riccardi C. 2018. Glucocorticoids, sex hormones, and immunity. Front. Immunol. 9:1332
    [Google Scholar]
  92. 92.
    Annibalini G, Agostini D, Calcabrini C, Martinelli C, Colombo E et al. 2014. Effects of sex hormones on inflammatory response in male and female vascular endothelial cells. J. Endocrinol. Investig. 37:861–69
    [Google Scholar]
  93. 93.
    Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D et al. 1995. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91:755–63
    [Google Scholar]
  94. 94.
    Buckley JP, Kuiper JR, Bennett DH, Barrett ES, Bastain T et al. 2022. Exposure to contemporary and emerging chemicals in commerce among pregnant women in the United States: the environmental influences on Child Health Outcome (ECHO) program. Environ. Sci. Technol. 56:6560–73
    [Google Scholar]
  95. 95.
    Schildroth S, Wise LA, Wesselink AK, De La Cruz P, Bethea TN et al. 2021. Correlates of persistent endocrine-disrupting chemical mixtures among reproductive-aged Black women. Environ. Sci. Technol. 55:14000–14
    [Google Scholar]
  96. 96.
    Guo Y, Kannan K. 2013. A survey of phthalates and parabens in personal care products from the United States and its implications for human exposure. Environ. Sci. Technol. 47:14442–49
    [Google Scholar]
  97. 97.
    Nevzati E, Shafighi M, Bakhtian KD, Treiber H, Fandino J, Fathi AR. 2015. Estrogen induces nitric oxide production via nitric oxide synthase activation in endothelial cells. Acta Neurochir. Suppl. 120:141–45
    [Google Scholar]
  98. 98.
    McIntyre M, Hamilton CA, Rees DD, Reid JL, Dominiczak AF. 1997. Sex differences in the abundance of endothelial nitric oxide in a model of genetic hypertension. Hypertension 30:1517–24
    [Google Scholar]
  99. 99.
    O'Connor C, Brady E, Zheng Y, Moore E, Stevens KR. 2022. Engineering the multiscale complexity of vascular networks. Nat. Rev. Mater. 7:702–16
    [Google Scholar]
  100. 100.
    Lorenz M, Blaschke B, Benn A, Hammer E, Witt E et al. 2019. Sex-specific metabolic and functional differences in human umbilical vein endothelial cells from twin pairs. Atherosclerosis 291:99–106
    [Google Scholar]
  101. 101.
    Zhang Y, Lingappan K. 2017. Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun. 486:431–37
    [Google Scholar]
  102. 102.
    Lorenz M, Witt E, Volker U, Stangl K, Stangl V, Hammer E. 2022. Serum starvation induces sexual dimorphisms in secreted proteins of human umbilical vein endothelial cells (HUVECs) from twin pairs. Proteomics 22:e2100168
    [Google Scholar]
  103. 103.
    Islam H, Jackson GS, Yoon JSJ, Cabral-Santos C, Lira FS et al. 2022. Sex differences in IL-10’s anti-inflammatory function: greater STAT3 activation and stronger inhibition of TNF-α production in male blood leukocytes ex vivo. Am. J. Physiol. Cell Physiol. 322:C1095–104
    [Google Scholar]
  104. 104.
    Moxley G, Posthuma D, Carlson P, Estrada E, Han J et al. 2002. Sexual dimorphism in innate immunity. Arthritis Rheum. 46:250–58
    [Google Scholar]
  105. 105.
    Torcia MG, Nencioni L, Clemente AM, Civitelli L, Celestino I et al. 2012. Sex differences in the response to viral infections: TLR8 and TLR9 ligand stimulation induce higher IL10 production in males. PLOS ONE 7:e39853
    [Google Scholar]
  106. 106.
    Lefevre N, Corazza F, Duchateau J, Desir J, Casimir G. 2012. Sex differences in inflammatory cytokines and CD99 expression following in vitro lipopolysaccharide stimulation. Shock 38:37–42
    [Google Scholar]
  107. 107.
    Bernardi S, Toffoli B, Tonon F, Francica M, Campagnolo E et al. 2020. Sex differences in proatherogenic cytokine levels. Int. J. Mol. Sci. 21:3861
    [Google Scholar]
  108. 108.
    Oksuzyan A, Gumà J, Doblhammer G 2018. Sex differences in health and survival. A Demographic Perspective on Gender, Family and Health in Europe G Doblhammer, J Gumà 65–100. Cham, Switzerland: Springer International
    [Google Scholar]
  109. 109.
    Bouman A, Heineman MJ, Faas MM. 2005. Sex hormones and the immune response in humans. Hum. Reprod. Update 11:411–23
    [Google Scholar]
  110. 110.
    Madla CM, Gavins FKH, Merchant HA, Orlu M, Murdan S, Basit AW. 2021. Let's talk about sex: differences in drug therapy in males and females. Adv. Drug Deliv. Rev. 175:113804
    [Google Scholar]
  111. 111.
    Patel SK, Valicherla GR, Micklo AC, Rohan LC. 2021. Drug delivery strategies for management of women's health issues in the upper genital tract. Adv. Drug Deliv. Rev. 177:113955
    [Google Scholar]
  112. 112.
    Vukovich RA, Brannick LJ, Sugerman AA, Neiss ES. 1975. Sex differences in the intramuscular absorption and bioavailability of cephradine. Clin. Pharmacol. Ther. 18:215–20
    [Google Scholar]
  113. 113.
    Islam MM, Iqbal U, Walther BA, Nguyen PA, Li YJ et al. 2017. Gender-based personalized pharmacotherapy: a systematic review. Arch. Gynecol. Obstet. 295:1305–17
    [Google Scholar]
  114. 114.
    Soldin OP, Mattison DR. 2009. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 48:143–57
    [Google Scholar]
  115. 115.
    Fadiran EO, Zhang L. 2015. Effects of sex differences in the pharmacokinetics of drugs and their impact on the safety of medicines in women. Medicines For Women M Harrison-Woolrych 41–68. Cham, Switzerland: Springer International
    [Google Scholar]
  116. 116.
    Verbeeck RK, Cardinal JA, Wallace SM. 1984. Effect of age and sex on the plasma binding of acidic and basic drugs. Eur. J. Clin. Pharmacol. 27:91–97
    [Google Scholar]
  117. 117.
    Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U et al. 2003. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 67:25–32
    [Google Scholar]
  118. 118.
    Yang L, Li Y, Hong H, Chang CW, Guo LW et al. 2012. Sex differences in the expression of drug-metabolizing and transporter genes in human liver. J. Drug Metab. Toxicol. 3:1000119
    [Google Scholar]
  119. 119.
    Waxman DJ, Holloway MG. 2009. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol. Pharmacol. 76:215–28
    [Google Scholar]
  120. 120.
    Galloway T, Cipelli R, Guralnik J, Ferrucci L, Bandinelli S et al. 2010. Daily bisphenol A excretion and associations with sex hormone concentrations: results from the InCHIANTI adult population study. Environ. Health Perspect. 118:1603–8
    [Google Scholar]
  121. 121.
    Malik MY, Jaiswal S, Sharma A, Shukla M, Lal J. 2016. Role of enterohepatic recirculation in drug disposition: cooperation and complications. Drug Metab. Rev. 48:281–327
    [Google Scholar]
  122. 122.
    Lock R, Al Asafen H, Fleischer S, Tamargo M, Zhao Y et al. 2022. A framework for developing sex-specific engineered heart models. Nat. Rev. Mater. 7:295–313
    [Google Scholar]
  123. 123.
    Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. 1986. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. PNAS 83:2496–500
    [Google Scholar]
  124. 124.
    Welshons WV, Wolf MF, Murphy CS, Jordan VC. 1988. Estrogenic activity of phenol red. Mol. Cell. Endocrinol. 57:169–78
    [Google Scholar]
  125. 125.
    Park MN, Park JH, Paik HY, Lee SK. 2015. Insufficient sex description of cells supplied by commercial vendors. Am. J. Physiol. Cell Physiol. 308:C578–80
    [Google Scholar]
  126. 126.
    Kim JY, Min K, Paik HY, Lee SK. 2021. Sex omission and male bias are still widespread in cell experiments. Am. J. Physiol. Cell Physiol. 320:C742–49
    [Google Scholar]
  127. 127.
    Clapcote SJ, Roder JC. 2005. Simplex PCR assay for sex determination in mice. Biotechniques 38:702–6
    [Google Scholar]
  128. 128.
    Rich-Edwards JW, Kaiser UB, Chen GL, Manson JE, Goldstein JM. 2018. Sex and gender differences research design for basic, clinical, and population studies: essentials for investigators. Endocr. Rev. 39:424–39
    [Google Scholar]
  129. 129.
    Detwiler A, Polkoff K, Gaffney L, Freytes DO, Piedrahita JA. 2022. Donor age and time in culture affect dermal fibroblast contraction in an in vitro hydrogel model. Tissue Eng. Part A 28:833–44
    [Google Scholar]
  130. 130.
    Decaroli MC, Rochira V. 2017. Aging and sex hormones in males. Virulence 8:545–70
    [Google Scholar]
  131. 131.
    van Houten ME, Gooren LJ. 2000. Differences in reproductive endocrinology between Asian men and Caucasian men—a literature review. Asian J. Androl. 2:13–20
    [Google Scholar]
  132. 132.
    Kim C, Golden SH, Mather KJ, Laughlin GA, Kong S et al. 2012. Racial/ethnic differences in sex hormone levels among postmenopausal women in the diabetes prevention program. J. Clin. Endocrinol. Metab. 97:4051–60
    [Google Scholar]
  133. 133.
    Noyola-Martínez N, Halhali A, Barrera D. 2019. Steroid hormones and pregnancy. Gynecol. Endocrinol. 35:376–84
    [Google Scholar]
  134. 134.
    Natri H, Garcia AR, Buetow KH, Trumble BC, Wilson MA. 2019. The pregnancy pickle: evolved immune compensation due to pregnancy underlies sex differences in human diseases. Trends Genet. 35:7478–88
    [Google Scholar]
  135. 135.
    Wallach JD, Sullivan PG, Trepanowski JF, Steyerberg EW, Ioannidis JP. 2016. Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses. BMJ 355:i5826
    [Google Scholar]
  136. 136.
    Feldman S, Ammar W, Lo K, Trepman E, van Zuylen M, Etzioni O. 2019. Quantifying sex bias in clinical studies at scale with automated data extraction. JAMA Netw. Open 2:e196700
    [Google Scholar]
  137. 137.
    Mirin AA. 2021. Gender disparity in the funding of diseases by the U.S. National Institutes of Health. J. Womens Health 30:956–63
    [Google Scholar]
  138. 138.
    Jorgensen SCJ, Miljanic S, Tabbara N, Somanader D, Tse CLY et al. 2022. Characterizing the inclusion of pregnant and breastfeeding people in infectious diseases randomized controlled trials: a targeted literature review. Clin. Microbiol. Infect. 28:6801–11
    [Google Scholar]
  139. 139.
    Kaye DK. 2019. The moral imperative to approve pregnant women's participation in randomized clinical trials for pregnancy and newborn complications. Philos. Ethics Humanit. Med. 14:11
    [Google Scholar]
  140. 140.
    Franceschini R, Wicks SL. 2022. ClinicalTrials.Gov: Pitfalls for pregnant women looking to enroll in studies. Contemp. Clin. Trials Commun. 26:100890
    [Google Scholar]
  141. 141.
    Frew PM, Saint-Victor DS, Isaacs MB, Kim S, Swamy GK et al. 2014. Recruitment and retention of pregnant women into clinical research trials: an overview of challenges, facilitators, and best practices. Clin. Infect. Dis. 59:Suppl. 7S400–7
    [Google Scholar]
  142. 142.
    Garcia-Sifuentes Y, Maney DL. 2021. Reporting and misreporting of sex differences in the biological sciences. eLife 10:e70817
    [Google Scholar]
  143. 143.
    Denfeld QE, Lee CS, Habecker BA. 2022. A primer on incorporating sex as a biological variable into the conduct and reporting of basic and clinical research studies. Am. J. Physiol. Heart Circ. Physiol. 322:H350–54
    [Google Scholar]
  144. 144.
    Tavakol DN, Fleischer S, Falcucci T, Graney PL, Halligan SP et al. 2021. Emerging trajectories for next generation tissue engineers. ACS Biomater. Sci. Eng. 8:4598–604
    [Google Scholar]
  145. 145.
    Fogg KC, Tseng N-H, Peyton SR, Holeman P, McLoughlin ST et al. 2022. Roadmap on biomaterials for women's health. J. Phys. Mater. 6:012501
    [Google Scholar]
/content/journals/10.1146/annurev-bioeng-092222-030857
Loading
/content/journals/10.1146/annurev-bioeng-092222-030857
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error