{"paper_id":"9e3e8a02-5e2f-4e7f-9075-83a93bc6f66b","body_text":"Biomaterials research has long focused\non solutions to regenerate\ntissue, enable diagnoses, and deliver bioactive molecules. \n − \n \n  Nevertheless, the role of biological sex and sex-influenced disease\nstatus in shaping these innovations remains underexplored, representing\nan untapped opportunity to refine biomaterial design to meet the needs\nof individual patients.\nWe begin with a necessary definition of terminology. The following\ndiscussion on sex-related differences in biomaterial interactions\nand applications refers specifically to biological sex as a physiological\nfactor influencing tissue composition, hormonal environment, immune\nresponses, and relevant diseases. The focus of this article on biological\nsex is separate from, but does not diminish, the importance of gender\nidentity in shaping patient-centered care.  Nevertheless, the term “sex” is often inaccurately\nreplaced with “gender” in scientific discourse, which\ncan introduce ambiguity in describing physiological differences. \n − \n \n  This linguistic inaccuracy creates challenges in research and translation\nof biomaterials incorporating sex-related differences, limiting our\nability to consistently frame and address sex-specific phenomena.\nSex-related differences in tissue structure and function are influenced\nby hormonal variations, genetic expression patterns, and inherent\nimmune system differences which play pivotal roles in body–biomaterial\ninteractions.  Effects of (patho)­physiological\nstates that vary across the lifespan further modulate these processes,\nthus dictating degradation kinetics, biomaterial integration, and\ntherapeutic outcomes. However, the design of biomaterials has historically\nrelied on generalized approaches, overlooking the variability introduced\nby sex.  As a result, therapies fail to\naddress the nuances of varying patient populations, limiting their\nclinical efficacy and scalability. While design principles for sex-specific\napplications can inform biomaterials development across many contexts,\nthis perspective particularly elaborates on female-specific biomaterials\ngiven the especially underexplored potential for innovation in these\nareas.\nSex-related differences\ninfluence a wide range of physiological processes relevant to biomaterials\nresearch, impacting tissue regeneration and inflammatory/immune responses.\nUnderstanding these sex-related differences is critical for designing\nbiomaterials that perform optimally across patient populations.\nTissue regeneration varies significantly\nbetween sexes due to differences in hormonal regulation, cellular\nproliferation and other signaling pathways, and extracellular matrix\n(ECM) composition and turnover. \n , \n  Estrogen upregulates\nfibroblast proliferation, collagen synthesis, osteogenesis, and vascularization,\ncontributing to more efficient tissue healing in premenopausal females,\nwhereas declining estrogen levels in postmenopausal females lead to\nimpaired regenerative capacity. \n , − \n \n \n \n  Meanwhile, testosterone promotes enhanced bone mineral density and\nmuscle (re)­generation, yet is locally metabolized into different end\nproducts for males and femalesdihydrotestosterone or estrogen,\nrespectively. \n − \n \n  These differences alter how biomaterials designed\nto facilitate tissue regeneration interact with host tissues, affecting\ntheir integration, functionality, and long-term success.\nSex-related differences\nin inflammation and the immune system have significant implications\nfor a body’s reaction to biomaterials and thus success of their\nintended application. For example, females often exhibit stronger\ninnate and adaptive immune responses. \n , \n  Consequently,\napproximately 80% of autoimmune and inflammatory conditions occur\nin females, reflecting a markedly elevated risk relative to males. \n , \n  Therefore, females may exhibit higher rates and severity of hypersensitivity\nreactions with resulting failure of biomaterial implants.  Emerging research suggesting sex-related differences\nin microbiome composition also indicates modulation of biomaterial-associated\ninflammation and responses to implant-associated infections.\nMoreover, a key sex-related genetic factor\nis X-chromosome inactivation (XCI), a process in which one of the\ntwo X chromosomes in females is largely silenced to balance X-linked\ngene dosage with males.  This complex\nmechanism is also incompletely manifested due to a phenomenon called\nescape, in which at least 15% of genes on the inactivated X-chromosome\npersist in contributing to the expression of that trait.  In particular, escape leads to differential\nexpression of immune-regulatory genes, such as Toll-like receptor\n7 ( TLR7 ) and CD40 ligand ( CD40L ),\nwhich may contribute to amplified immune responses in females and\nthus greater susceptibility to autoimmune disease. These genetic effects\ninteract with hormonal signaling to modulate whether and how biomaterials\nare perceived as foreign bodies with subsequent remodeling by the\nhost immune system. \n ,\nIn the specific case of\nwound healing, the process induced during\nany biomaterial implantation, females exhibit higher collagen deposition\nand faster re-epithelialization but are more prone to fibrotic scarring\nin response to injury or foreign materials. \n − \n \n  In contrast,\nmales may experience prolonged low-grade inflammation associated with\ntestosterone’s effects on immune signaling, which may slow\nhealing but reduce the likelihood of excessive fibrosis.  For the common application of ventral hernia\nrepair with mesh biomaterials, female patients have been found to\nexperience higher rates than males of adverse wound outcomes including\npoor healing, wound infection, and chronic postsurgical pain with\nassociated sleep disturbances. \n ,\nSex-related differences in metabolism can\ndictate the biodistribution, kinetics, and therefore efficacy of drug\ndelivery from biomaterial-based systems. \n − \n \n \n  Importantly, females tend to\nexhibit a greater volume of distribution and slower clearance of liposomal\nnanoparticles and lipid-soluble drugs or degradation products, largely\ndue to higher average body fat content and consequently enhanced lipid\nuptake. \n , \n  Conversely, water-soluble nanocarriers,\ndegradation products, and drugs display affinity for the higher average\nbody water content of males.\nAdditionally, cytochrome P450 (CYP)\nliver enzymes, which mediate the body’s primary drug metabolism\npathways, exhibit sex-specific activity patterns.  Males and females each show higher activity of distinct\nCYP isoforms, leading to measurable differences in drug clearance\nrates and overall pharmacokinetics.\nThese factors combine to\nresult in sex-related disparities in metabolically\nrelated disease outcomes. For example, diabetes confers a disproportionately\nhigher cardiovascular risk in women than in men.  A large meta-analysis found that women with diabetes had\na 58% higher risk of coronary heart disease mortality and a 13% higher\nrisk of all-cause mortality compared to men with diabetes.  Such differences in metabolic processing and\nsusceptibility to disease complications further underscore the need\nfor biomaterials designed with sex-specific pharmacokinetics and therapeutic\nprecision in mind.\nOne illustrative\ndomain for sex-specific design with significant clinical relevance\nand commercial demand is biomaterials tailored for health conditions\nuniquely affecting patients of female sex. \n , \n  Many of these conditions, such as pelvic organ prolapse, uterine\nwound healing, and endometriosis, result from changes in hormones\nand ECM that require specialized biomaterial solutions. By addressing\nthese sex-specific challenges, biomaterials can offer more effective,\nlong-term therapeutic options that enhance patient quality of life.\nOne critical area of need is\npelvic floor disorders, including organ prolapse, which affects a\nsignificant proportion of postmenopausal women due to the weakening\nof connective tissues and muscle support. \n , \n  Traditional surgical interventions often rely on synthetic biomaterial\nmeshes, which have been associated with complications such as erosion\nand chronic pain.  Therefore, novel biomaterial\napproaches must focus on improving biocompatibility, reducing inflammatory\nresponses, and enhancing integration with host tissues to minimize\ncomplications and ensure long-term success. Advancing these designs\nwith bioactive materials that actively promote tissue remodeling and\nhealing is critical to overcoming the limitations of current synthetic\noptions.\nSignificant\ndemand also exists for optimized biomaterials for breast modification\nand reconstruction following mastectomy or cosmetic procedures. \n , \n  Additionally, contraceptive implants exemplify the application of\ncontrolled release principles for drug delivery.  The hormones are released for years in the case of long-acting\nreversible contraception like intrauterine devices, while localization\nof effect is crucial to minimize systemic side effects. Complementarily,\nanother emerging area of biomaterials for family planning is ovarian\ntissue engineering and fertility preservation for women undergoing\nchemotherapy or premature ovarian failure.\nMeanwhile,\nseveral potential biomaterials applications for female-specific conditions\nwith widespread need remain largely underdeveloped. For example, vaginal\nand urethral tissue regeneration would offer improvements for the\ncommon menopausal conditions of stress urinary incontinence and vaginal\natrophy. \n , \n  Declining estrogen levels during and after\nmenopause lead to thinning of vaginal epithelium, reduced elasticity,\nand increased tissue fragility, often resulting in discomfort and\nfunctional impairment. \n , \n  Additionally, insufficient wound\nhealing after severe perineal trauma during childbirth can result\nin chronic complications such as pain or incontinence.\nBeyond the\npelvic floor, biomaterials also hold promise for addressing uterine\nwound healing following Cesarean sections and other surgeries, such\nas fetal intervention or fibroid removal. \n , \n  Furthermore, endometriosis, a chronic inflammatory condition in\nwhich vasculature-rich tissue of the uterine lining exists outside\nof the uterus, displays a recurrent nature that currently necessitates\nrepeated surgical interventions. This application is overdue for biomaterial\ntherapies that mitigate its recurrence and progression. \n ,\nBy incorporating sex-specific considerations into biomaterial\ndesign, researchers and clinicians can develop therapies that address\nthe distinct physiological and hormonal influences affecting patients\nof different sexes. Advancing these technologies not only enhances\ntherapeutic efficacy and patient satisfaction but also promotes a\nmore adaptive and precise approach to biomaterials-based medicine.\n\nMost studies evaluate biomaterials\nin only a single sex, often due to concerns that biological variabilityparticularly\nhormonal fluctuations in female subjectscould confound results.  While these variations do introduce additional\ncomplexity, excluding one sex from study design ultimately undermines\nthe generalizability and applicability of biomaterials ( Table  \n ). In reality, understanding\nhow biomaterials perform under hormonally dynamic conditions is essential,\nas real-world patient populations include individuals with varying\nhormone levels due to age, puberty, menstrual cycles, pregnancy, or\nhormone therapy. \n , − \n \n  Without accounting\nfor these variables, biomaterials may be designed under conditions\nthat do not fully represent their eventual clinical use, increasing\nthe risk of poor clinical performance or unexpected outcomes in different\nsexes.\nAdditionally, a lack of standardized testing protocols\nacross research\ngroups makes it difficult to compare results, further limiting the\nability to detect sex-related variability in biomaterial performance.\nIn other fields, significant insights have only emerged by aggregating\ndata across multiple research groups, \n − \n \n  yet data sets in biomaterials\nresearch have rarely been compiled and analyzed at scale. This lack\nof integration, combined with inconsistent methodologies and variable\noutcome measures, limits the ability to systematically assess sex-\nand disease-specific effects.  Without\nstandardization, biomaterial properties such as degradation rates,\nmechanical responses, and immune interactions may appear inconsistent\nacross studies, making it difficult to determine whether observed\nvariations are due to true sex-related (patho)­physiological differences\nor artifacts of experimental design.  These\ninconsistencies ultimately hinder the development of biomaterials\noptimized for sex-related differences and prevent a full understanding\nof how sex-specific factors influence biomaterial integration and\nfunction.\nThe U.S. National Institutes\nof Health (NIH) have established a policy on Sex as a Biological Variable\n(SABV) and guidelines on Sex and Gender Equity in Research (SAGER).  However, unlike other biomedical fields for\nwhich SABV compliance is increasingly enforced, the field of biomaterials\nresearch still lacks clear expectations for complying with sex-disaggregated\ntesting and reporting. \n , \n  Additionally, although regulatory\nawareness of sex differences in biomedical research has improved in\nrecent years, this progress has not yet translated into consistent\nexpectations for biomaterials studies.\nFor example, the U.S.\nFood and Drug Administration (FDA) released updated guidance in January\n2025 entitled Evaluation of Sex Differences in Medical Device Clinical\nStudies.  This document outlines the FDA’s\nexpectations for the inclusion, analysis, and reporting of sex-disaggregated\ndata in clinical research. It emphasizes the importance of enrolling\na fair representation of sexes in clinical trials to detect clinically\nsignificant sex-related differences in response. The guidance also\nrecommends collecting pharmacokinetic data on demographic differences,\nbeginning with early phase studies to inform relevant study designs\nfor later trials.\nHowever, such guidelines are not currently\nenforced in the evaluation\nof biomaterials, leaving a critical gap in regulatory oversight. Without\nclear mandates or standardized pathways to incorporate sex-related\nanalyses in biomaterials research, even well-defined frameworks risk\na lack of implementation.\nFurthermore, the lack of specific\nstandardized testing and regulatory\nrequirements further perpetuates gaps in understanding how biomaterials\nperform across different sexes. For example, many biomaterial testing\nprotocols, such as ISO 10993 (biocompatibility evaluation), lack explicit\nguidance on incorporating different sexes in preclinical studies.  Without enforcing a requirement for sex-disaggregated\ndata, potential sex-specific interactions with biomaterials may remain\nunderexplored. \n ,\nCost remains a major\nbarrier to the realization of sex- and disease-specific biomaterials,\nas designing biomaterials for different populations often requires\nadditional research, manufacturing customization, and testing. Limitations\nin available grant funding make it especially challenging to implement\nsex-related research, as studies designed to include sex-related comparisons\nrequire expanding the number of experimental groups, thus increasing\nthe need for additional cells, animals, and research materials. \n , \n  These financial constraints often force researchers to prioritize\nsingle-sex studies to remain within funding constraints, further perpetuating\nthe lack of sex-specific data in biomaterials research.\nAn additional\nchallenge lies in the limited availability of sex-stratified biological\nsamples. For example, sourcing sufficient quantities of primary cells\nand tissues from female donorsparticularly those representing\nspecific hormonal states such as menstruation, pregnancy, or (peri)\nmenopauseremains logistically complex and possibly even prohibitive. \n − \n \n  This limitation hampers the ability to design both rigorously powered\nstudies and biomaterials themselves that are representative of and\ntailored to female-specific physiology and to achieve reproducible,\ntranslatable results across the sex spectrum.\nAdditionally,\nthe increased cost of scaling manufacturing processes\nfor biomaterials tailored to sex-specific needs presents another hurdle\nin translating laboratory findings into clinical applications.  Without targeted funding initiatives or regulatory\nincentives, the financial burden of biomaterials research on sex-related\ndifferences continues to slow progress toward precision biomaterial\nsolutions.\n\nTesting biomaterials on\neach sex of animals or human-derived cells would provide a more comprehensive\nunderstanding of their performance across populations, ensuring balanced\nrepresentation of sex-specific variables.  Beyond simple inclusion, study designs should integrate and report\non sex-related analyses as a predefined variable rather than a post\nhoc consideration. \n , − \n \n  Standardizing\nprotocols to include sex-specific considerations at all stages of\nbiomaterial testingcell culture,  in vivo  models,\nand early phase clinical trialswill ensure meaningful comparisons\nand applicability to different populations.\nAdditionally, experimental\ndesigns should account for hormonal fluctuations that could influence\nbiomaterial interactions differently in each sex’s models. \n , \n  For example, studying biomaterial integration in female models at\ndifferent phases of the menstrual cycle can provide insights into\nhormone-mediated regenerative or inflammatory responses. This approach\nwill help researchers develop biomaterials that are optimized for\nreal-world physiological variability with superior representation\nof potential clinical outcomes.\nTo evolve beyond the fragmented\napproach of only assessing biomaterials within the scope of individual\nstudies, ensuring high-quality data set integration is crucial for\nenabling comprehensive analyses of biomaterial performance across\ndifferent sexes. Addressing this challenge requires a fundamental\nshift in how biomaterial data is generated, moving away from isolated,\nlab-specific methodologies and data storage toward standardized protocols\nthat capture sex-specific effects. \n , \n  Achieving\nthis goal demands rethinking study design from the outset, ensuring\nthat data collection, structuring, and sharing are aligned for large-scale\nanalyses. Data sets should be augmented to achieve balanced representation\nof each sex.  Incorporating structured\nmetadata such as documentation of these variables will further facilitate\nmeta-analysis, reducing inconsistencies across biomaterial studies\nand improving comparability while avoiding overgeneralizations. \n ,\nBeyond data generation, raw data should be shared across research\ngroups to allow for large-scale aggregation and cross-study comparisons.\nStandardizing data formats and ensuring adherence to FAIR (Findable,\nAccessible, Interoperable, and Reusable) data storage principles will\nfacilitate data set integration and reanalysis.  By compiling and harmonizing these data sets, researchers\ncan minimize systematic biases and generate more meaningful insights\ninto sex-related differences in biomaterial performance. Establishing\nopen-access repositories and collaborative data-sharing networks will\nbe key to achieving these goals, ensuring that biomaterials research\ncan advance with greater precision.\nIntegrating artificial intelligence\n(AI) offers an unprecedented opportunity to automate, standardize,\nand scale biomaterial design and evaluations, making traditional manual\napproaches increasingly obsolete. Machine learning (ML), a subset\nof AI, can enable advanced image analysis that extracts quantitative\nmetrics from histological data sets with greater detail and efficiency\nthan human observers, allowing reproducible comparisons of biomaterial\nperformance across preclinical and clinical data sets.  When paired with proper data aggregation practices,  ML can also further uncover subtle sex-related\ndifferences in biomaterial performance that might otherwise be undetectable,\nfacilitating predictive modeling for patient-specific therapies.  These capabilities can guide the design of more\neffective biomaterials tailored to individual patient contexts. \n − \n \n \n \n \n \n \n \n  For example, ML models can predict how specific biomaterial properties\ninteract with sex-specific hormonal profiles or disease-related inflammation. \n ,\nOnce the optimized biomaterial\ndesign properties are identified, additive manufacturing methodologies\nlike three-dimensional (3D) printing can provide precise control over\nbiomaterial geometry, porosity, and localization of bioactive molecules. \n , \n  This capability is particularly relevant for incorporating sex-specific\nparameters into biomaterial design. For instance, 3D printing could\nenable the production of hormone-responsive scaffolds tailored for\npostmenopausal women, adapting to the specific vascularization and\ntissue integration capacities in this patient population.  Similarly, materials with finely tuned microstructures\ncould be designed to support tissue regeneration in diabetic wounds,\nwhere sex-related differences in metabolic regulation and immune response\ninfluence healing dynamics,  as described\nin the following section.\nBoth physiologically\nand pathologically, sex-related factors such as hormones, genetic\nexpression patterns, and inherent immune system differences dictate\na patient’s body’s response to interactions with a biomaterial. \n , \n  These biological variables also influence the incidence, progression,\nmanifestations, and complications of conditions such as osteoporosis,\ncancer, and diabetes. Such disease-driven alterations significantly\nimpact tissue architecture, cellular dynamics, and biomaterial performance.\nImportantly, biomedical disciplines such as cardiology have increasingly\nrecognized and addressed sex-related differences, yielding improved\ndiagnostic tools and therapies tailored to specific populations. \n − \n \n \n  Embracing this perspective shift within the biomaterials field would\ncritically enable progress toward precision medicine. Representative\nexamples of biomaterial technologies incorporating sex-specific design\nfeatures and evaluated in (pre)­clinical trials across relevant disease\ncontexts are summarized in  Table S1 .\nIn the case of osteoporosis, a metabolic\nbone disease characterized by reduced bone density and increased fracture\nrisk, the influence of sex hormones and therefore sex-related disparities\nin disease incidence are well-documented.  Particularly, postmenopausal women experience a disproportionately\nhigher rate of osteoporosis-related fractures compared to men due\nto declining estrogen levels. Global estimates suggest that approximately\none in three women over age 50 will experience osteoporotic fractures,\nversus one in five men. \n , \n  Critically, hip fractures\nin women are associated with a resulting 20% risk of death in the\nyear following a hip fracture, a figure that rivals or exceeds several\ncancers. \n − \n \n  Therefore, while osteoporosis is often downplayed\nas an inevitable experience of aging in women, in actuality it is\na serious, life-threatening condition with profound consequences for\nmorbidity and mortality. These outcomes highlight the urgent need\nfor biomaterial designs that address the sex-specific aspects of disease\nprogression, functionality, drug delivery efficiency, and diagnostic\naccuracy. \n , ,\nThe\ndisproportionate prevalence of osteoporosis in postmenopausal women\nunderscores significant sex-related differences in how those patients’\ntissues will respond to biomaterials attempting tissue regeneration\nor therapeutic delivery.  The interplay\nof hormonal decline, reduced bone density, and diminished healing\ncapacity necessitates tailored biomaterials to improve outcomes. \n − \n \n  For example, biomaterials incorporating estrogen-releasing or hormone-mimetic\ncoatings could locally modulate cell behavior and responsiveness to\nthe biomaterial’s primary effect, counteracting estrogen-deficiency-induced\nimpairments in bone healing and integration.\nAdditionally, load-responsive\nscaffolds tailored for osteoporotic\nbone could feature adaptive stiffness gradients that accommodate weaker\ntrabecular structures, or degradation kinetics that adjust based on\nreduced bone remodeling rates, ensuring prolonged support and enhanced\nintegration in postmenopausal patients. \n − \n \n  Given that osteoporosis is a progressive disease, biomaterials could\nbe designed to dynamically adjust their mechanical properties over\ntime, providing increased support as bone density declines or incorporating\nresorption-modulating elements that respond to ongoing remodeling\ndeficits.\nTumor microenvironments vary significantly between\nsexes due to previously discussed factors such as sex-related differences\nin vascularization, immune responses, and drug metabolism.  Given these differences, biomaterials designed\nfor cancer therapy could incorporate immune-modulating coatings that\nadjust inflammatory responses based on the hormonal environment of\nthe tumor. \n , \n  Such materials could optimize\ntumor-targeting efficacy or biomaterial integration into cancer-altered\ntissues by harnessing immune activation or promoting immune tolerance\nwhen necessary for the intended mechanism of action.\nAdditionally,\nbiomaterials for drug delivery in hormone-responsive cancers could\nleverage sex-specific hormonal biomarkers to enhance targeting precision.  For instance, nanoparticle-based drug carriers\ncould be engineered to respond to estrogen or testosterone levels,\nreleasing therapeutic agents in a controlled manner based on the tumor’s\nmicroenvironment,  thus enabling localized\nand controlled drug release in response to tumor-associated hormone\nfluctuations. This function would be critical in estrogen- or progesterone-receptor\npositive breast cancer as well as androgen-driven prostate tumors. \n , \n  Such an approach could improve drug retention at the tumor site\nand minimize off-target effects, addressing sex-related differences\nin drug metabolism and immune interactions with biomaterials. \n , \n  Alternatively, for the forms of lung and pancreatic cancer exhibiting\nsex-related differences in drug metabolism and immune response, \n − \n \n  biomaterials exhibiting adaptive release rates could optimize therapy\ndifferentially in male or female patients.\nConditions like\nrheumatoid arthritis exhibit sex-related differences in prevalence\nand therapeutic efficacy, altering the performance of biomaterials. \n − \n \n \n  Therefore, biomaterials meant to regenerate tissue or deliver biomolecules\nin female patients with one or multiple autoimmune/inflammatory conditions\ncould incorporate immunomodulatory coatings that selectively dampen\nexcessive immune activation locally, mitigating excessive fibrosis\nwhile preserving regenerative signaling and drug delivery capacity,\nthus promoting improved healing in high-inflammation environments. \n − \n \n \n  Given that these diseases are often progressive,  smart biomaterials could be engineered to release anti-inflammatory\ncompounds over time or in response to immune system fluctuations,\nensuring sustained efficacy and reducing the long-term burden of chronic\ninflammation on the biomaterial’s targeted functionality. Conversely,\nin men, for whom chronic low-grade inflammation is more prevalent,\nbiomaterials could be designed to gradually enhance immune stimulation\nor promote macrophage polarization toward a reparative phenotype,\nimproving long-term biomaterial integration and function.\nThe pathophysiology of diabetes differs between\nsexes due to hormonal, metabolic, and immune factors. \n − \n \n  For example, the differential distribution of fatsubcutaneously\nin females, viscerally in malesinfluences inflammation, drug\nmetabolism, and tissue repair.  These\nfactors in turn compound the characteristic complications of wound\nhealing in diabetes resulting from chronic hyperglycemia.  Given these differences, biomaterials designed\nfor diabetic patients of different sexes could incorporate anti-inflammatory\nor immunomodulatory coatings that could account for the baseline variations\nin inflammatory/immune phenomena.\nFor drug delivery applications of biomaterials for diabetes, biomaterial\ndesigns must account for the sex-related variations in vascularization,\nwhich may determine bioavailability of the biomolecule to the target\norgan.  Different dosages of pro-angiogenic\nfactors may also need to be included in biomaterials for female patients\nto accommodate their microcirculation, given their higher propensity\nfor microvascular complications, \n , \n  while incorporating\nlocal vasodilatory agents into biomaterial implants for male patients\nto counteract their higher risk of cardiovascular complications.\nSex-specific biomaterial\ndesign principles offer transformative potential in addressing a range\nof conditions, including those characteristic of patients with female\nreproductive anatomy. \n ,\nFor pelvic floor\ndisorders, next-generation biomaterial scaffolds with enhanced bioactivity\nand mechanical adaptability could promote tissue integration, reduce\nforeign body reactions, and restore structural integrity. Incorporating\nlocalized growth factors or estrogen-mimetic compounds may further\nenhance tissue regeneration and reduce recurrence rates.\nIn the realm of vaginal and urethral\nrepair, current clinical solutions remain limited, highlighting an\nopportunity for biomaterial innovations. \n , \n  Hormone-responsive hydrogels, injectable biomaterials, or localized\nimplants could support epithelial regeneration, enhance collagen production,\nand maintain tissue hydration. Similarly, biodegradable bulking agents\nfor urethral support could improve continence by reinforcing tissue\nstructure while minimizing complications associated with synthetic\nmaterials.\nAdditionally, fibrosis\noccurs after incision in the uterine muscle during surgeries such\nas Cesarean (C−) sections, fetal surgery, and fibroid removal.  The resulting scar can lead to chronic pelvic\npain and serious complications in subsequent pregnancies. Instead,\nbiodegradable biomaterial scaffolds could play a key role in uterine\nwound healing by preventing adhesions and promoting regeneration.\nInjectable hydrogels and electrospun nanofibrous scaffolds could also\naid in perineal wound healing, particularly in cases of severe tearing\nor fistula formation.\nFurthermore,\nfor chronic gynecological conditions with limited current therapeutic\noptions, biomaterials offer promising avenues for improving treatment.\nEndometriosis, a highly recurrent inflammatory disease, could be managed\nusing implantable biomaterials that release localized therapies in\nresponse to menstrual cycle-regulating hormones or heme detection,\nreducing lesion regrowth postsurgery.\nIn the application of family\nplanning, smart biomaterials could similarly enable responsive drug\ndelivery for contraception, ensuring precise hormone release aligned\nwith endogenous fluctuations. \n − \n \n \n  Meanwhile, for fertility preservation and\ninfertility treatments, biomaterial scaffolds mimicking ovarian stromal\ntissue could support  in vitro  follicle maturation,\nproviding a platform for supporting follicle survival in both research\n(on-chip) and clinical settings.\nFinally, biomaterials for breast\ntissue engineering could enhance reconstruction outcomes following\nmastectomy or cosmetic procedures.  Biodegradable\nscaffolds supporting adipose and glandular tissue regeneration could\nminimize the need for permanent implants, improving long-term functional\nand aesthetic results. These innovations hold the potential to significantly\nimprove postsurgical recovery and patient quality of life.\nIn the biomaterials application\nof cardiac stents, which are inserted in blood vessels to restore\nblood flow upon blockage, a large-scale clinical trial recently determined\nthe sex-related differences in key device performance outcomes.  Females experienced a higher rate of myocardial\ninfarction (colloquially known as a “heart attack”),\nwhich cardiac stents intend to prevent and treat. Meanwhile, males\nreceived more repetitions of the procedures to reopen the blocked\nblood vessel. Given the larger anatomical diameter of male blood vessels,  consequent distinctions in the biomechanical\nenvironment, and previously discussed inflammatory tendencies, sex-specific\ncoatings could be designed for the stent surface to more optimally\nmitigate clotting and promote native endothelial cell migration for\nfemale and male patients, respectively.\nFurthermore, for biomaterials\nthat interface with nerve tissue to provide temporary or permanent\nmeasurements or therapeutic stimulation, male patients have a higher\ndensity of neuroimmune microglia cells and therefore more neuroinflammatory\nreactivity that can cause dysfunctional device encapsulation and disrupt\nsignal transmission.  Neural interface\nbiomaterials for males could be tailored with immunomodulatory, antifibrotic\nsurface chemistries that dampen such aggressive encapsulation.  Meanwhile, biomechanically matched interface\nsurfaces that support natural integration without oversuppressing\nbeneficial immune responses would benefit female patients. \n − \n \n  This sex-specific approach would ensure optimized biocompatibility\nand functional longevity across sexes.\nCollaborating with physician-scientists\nwho witness firsthand the limitations of biomaterials in addressing\nsex-related differences is essential to ensuring clinical relevance. \n , , \n  Engaging clinicians in a continuous\nfeedback loop throughout the biomaterial design processbefore,\nduring, and after market introductioncan refine innovations\nbased on real-world, sex-related variability, bridging the gap between\nresearch and patient outcomes.\nBeyond academic partnerships, industry engagement is critical to\naccelerating biomaterials research that incorporates sex-related considerations.  The biomaterials market has yet to fully capitalize\non the demand for sex-specific products, particularly in areas such\nas osteoporosis treatments, cardiovascular implants, and drug delivery\nsystems for hormone-sensitive conditions. Encouraging investment in\nbiomaterials tailored to different physiological profiles can assist\nwith closing this gap, making sex-specific biomaterials research not\nonly a scientific necessity but also an as-yet largely untapped commercial\nopportunity that enhances long-term healthcare outcomes.\nAdditionally,\nconcrete implementation pathways are critical to\ntranslating interdisciplinary collaboration into lasting change. For\nexample,  The Lancet Women and Cardiovascular Disease Commission  has served as a high-impact model by aligning academic, clinical,\nand policy stakeholders to generate sex- and gender-specific research\npriorities, establish reporting standards, and advocate for institutional\nreforms.  Similar consortia could be\nleveraged in biomaterials to set research agendas, create shared repositories\nof sex-disaggregated data, and inform guidelines for sex-specific\nbiomaterial development.\nExisting initiatives such as the NIH  Office of Research\non Women’s Health  (ORWH) and the European Commission’s  Horizon Europe  framework program also provide structural\nmodels and funding mechanisms that could be adapted or expanded to\nsupport sex-specific biomaterials research. For example, ORWH’s  Strategic Plan for Women’s Health Research  and  Building Interdisciplinary Research Careers in Women’s Health  (BIRCWH) programs explicitly support translational and collaborative\nprojects across scientific disciplines. \n − \n \n \n \n \n \n \n  Likewise, Horizon-funded consortia such as  GENDER-NET Plus  have established templates for incorporating sex and gender analysis\ninto large-scale biomedical projects.  Establishing such structured frameworks would ensure that collaborations\nextend beyond dialogue and lead to systemic improvements in research\nand clinical application.\nAddressing the structural challenges\nthat hinder the integration of sex-related differences in biomaterials\nresearch requires targeted changes in funding priorities and regulatory\nframeworks.  Fortunately, a template\nfor these measures already exists in the form of the SAGER guidelines. \n − \n \n  Ensuring financial and institutional support for studies investigating\nsex-related differences will improve the reproducibility, clinical\napplicability, and long-term impact of sex-specific biomaterial innovations.\nTo overcome the current barriers, innovative funding models are\nnecessary to support the increased costs associated with incorporating\nsex-related differences in research. Since biomaterial studies that\nassess different sexes require additional experimental groups, more\nextensive analyses, and greater statistical power, research budgets\nmust reflect these demands.  Funding\nagencies should establish dedicated grants or matching funds to support\nstudies that explicitly investigate sex as a variable in biomaterials\ndevelopment. Specialized initiatives can be developed to reevaluate\nkey studies that were originally conducted in only one sex, expanding\ntheir scope to include comparative analyses of sex-related differences.\nThese efforts would not only improve the reproducibility of findings\nbut also ensure that developing therapeutic strategies are applicable\nacross populations by addressing sex-related variability in biomaterials\nresearch.\nWhile tailored sex-specific\nbiomaterials development would incur\nhigher upfront costs due to additional preclinical testing and stratified\nclinical studies, these investments can be offset and eventually surpassed\nby longer-term benefits. \n − \n \n  Devices and therapies tailored\nto sex-specific physiological differences are more likely to achieve\nsustained efficacy, reduce rates of failure and revision procedures,\nand minimize chronic adverse effects, thereby lowering downstream\nhealthcare expenditures. \n − \n \n \n \n \n  For example, precision strategies in oncology have demonstrated\nthat stratified approaches often lead to improved clinical outcomes\nand more efficient use of healthcare resources over time.\nCreative public-private partnership models\nand financial healthcare\nreforms have been proposed with the goal of facilitating the development,\nimplementation, and adoption of novel technologies. \n − \n \n  These approaches support shared investment in innovation, equitable\nrisk distribution, and long-term value realization. Analogous frameworks\ncould support sex-specific biomaterials development by encouraging\nthe pooling of financial, infrastructural, and data resources across\nresearch institutions, public health agencies, and private industry.\nSpecifically, harmonized use of preclinical testing platforms and\npatient data registries with shared control groups would reduce duplicated\ninfrastructure and experimentation. \n , \n  Such strategies\nmay also help align economic incentives across payers, regulators,\nand developers to ensure that the added value of sex-specific approaches\nis recognized and reimbursed accordingly.\nAdditionally, regulatory frameworks should evolve to enforce\nrequirements\nfor balanced preclinical and clinical representation among the sexes,\naccompanied by clear guidelines for data disaggregation and reporting\nto ensure transparency and reproducibility, \n , , \n  thus reducing the risks of biased or incomplete\ndata informing product development and regulatory approval.\n\nThe incorporation of sex-related differences\ninto biomaterials\nresearch is a critical step toward advancing precision medicine and\nensuring that biomaterials perform optimally across diverse patient\npopulations. As this perspective has outlined, sex influences key\nbiological processesfrom tissue regeneration and immune response\nto drug metabolismyet biomaterials research has historically\noverlooked these factors. A shift toward sex-specific biomaterial\ndesign will require fundamental changes in study design, data integration,\nregulatory standards, and interdisciplinary collaboration.\nTo\nachieve this, biomaterials research must move beyond the traditional\n“one-size-fits-all” paradigm and instead embrace data-driven,\nsex-specific strategies that improve therapeutic efficacy and patient\noutcomes. Standardizing preclinical testing frameworks to include\nsex-specific analyses, developing biomaterials that account for sex-specific\nphysiological differences, and leveraging AI and computational tools\nto analyze biomaterial–host interactions will be essential\nsteps in this transition. Additionally, regulatory agencies and funding\nbodies should specifically incentivize biomaterials research practices\nfor investigating sex-related differences, ensuring that future innovations\nare designed to be both scientifically rigorous and truly patient-centered.","source_license":"public-domain-us","license_restricted":false}