Convened October 1, 2024

The Intersection of Regenerative Medicine and Women’s Health
Proceedings of a Workshop—in Brief

Historically, women¹ have been excluded from basic, translational, and clinical research, resulting in limited understanding of the impacts of underlying sex-based biological differences on health and disease burden. Regenerative medicine holds the potential to bridge these gaps to better understand the role of sex in health and disease and, ultimately, translate this knowledge into improved clinical care. On October 1, 2024, the National Academies of Sciences, Engineering, and Medicine’s Forum on Regenerative Medicine and Forum on Temporomandibular Disorders jointly convened a workshop to explore strategies to enable the development of regenerative medicine therapies for women. The goals of the workshop, as outlined by Kimberlee Potter, scientific portfolio manager for surgery, trauma, and restorative medicine in the Office of Research and Development at the Department of Veterans Affairs, were to (1) consider gaps within regenerative medicine basic and translational research related to conditions that are female-specific and/or are more common in or differently impact women, (2) explore emerging regenerative medicine therapies and technologies for these conditions, (3) examine the representation of women within the regenerative medicine workforce, and (4) identify obstacles that restrict and opportunities to expand access to regenerative medicine therapies.

KEYNOTE ADDRESS

Sex influences the care and treatment that women receive and how they experience health and disease, said Vivian Ota Wang, deputy director for the Office of Research on Women’s Health at the National Institutes of Health (NIH). Although women tend to live longer than men, they spend more years living with disability. Diseases that disproportionately affect women often present in their teens and midlife, impacting their long-term quality of life. Moreover, with care that can seem like it is based on trial and error, the lag time from presentation to diagnosis for chronic disorders can be as long as a decade (Sun et al., 2023).

Researchers should adopt a life course approach to the health of women, from pre-conception through adulthood, considering the interactions of gender, sex, and epigenetic modifiers and the impacts of both biological factors (e.g., genomic, molecular, cellular, physiological) and contextual factors (e.g., social and psychological determinants of health), Ota Wang said. A “whole person health” approach is needed that acknowledges the interconnectedness of the conditions that impact women and their lived experiences, especially during pivotal periods

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¹ Per the National Institutes of Health Office of Research on Women’s Health, “women” is inclusive of all who identify under this term. https://orwh.od.nih.gov/about-orwh#card-1634 (accessed December 2, 2024).

of a woman’s life, like pregnancy or menopause, that can further exacerbate pre-existing conditions, she added.

While gender is based on social, psychological, and cultural factors and encompasses identity, roles and norms, relations, and power,² sex is defined by biological factors including genetics, anatomy, physiology, and hormones, Ota Wang said. Sex, as an important biological variable, should be included at all levels of biomedical and health related research³ (IOM, 2001). NIH categorizes conditions affecting women’s health into four categories: conditions that are distinctly female-specific (e.g., endometriosis); conditions that disproportionately affect women (e.g., autoimmune disease); conditions that present and progress differently in women (e.g., cardiovascular disease); and conditions that do not disproportionately or differently affect women.⁴ Gaps and incomplete knowledge about these conditions that affect women’s health persist and contribute to disparities. Recently there has been renewed federal attention to closing the gaps and advancing women’s health research, including Executive Order 14120 and the addition of new NIH efforts for women’s health.⁵

Research will further perpetuate the current disparities and injustices if it is not designed to consider equity, said Ota Wang. Ideally, the future of women’s health could entail “a world in which every woman receives evidence-based disease prevention and treatment tailored to her own specific needs, circumstances, and goals,” she said. The data informing evidence-based practice guidelines, though, depends heavily on who is funding, conducting, analyzing, and participating in the research, so more women are needed in decision making and leadership positions in academic medicine, industry, and government, said Linda Goler Blount, president and chief executive officer of the Black Women’s Health Imperative, in reaction to the keynote presentation. Therefore, to reach this ideal, the systems of power that have long determined what is or will be known about women’s health should be addressed.

Furthermore, as the national racial and ethnic demographics continue to shift, the intersection of gender, race, and ethnicity needs to also be considered, Goler Blount said. Regenerative medicine, for example, has been influential in the treatment of sickle cell with the recent approval of the first gene therapy for sickle cell.⁶ Now that patients with diseases such as sickle cell are living longer, more attention is needed beyond survival to quality of life concerns, like reproductive and maternal health, said Teonna Woolford, co-founder and chief executive officer of the Sickle Cell Reproductive Health Education Directive, as she shared her personal experiences of living with sickle cell anemia. Additional strategies to achieve these future ideals could include increased multidisciplinary research and collaborations and enhanced, more accurate coverage of women’s health in medical training, said Ota Wang, Goler Blount, and Woolford.

THE IMPACT OF SEX AND HORMONES ON REGENERATIVE MEDICINE

Gaps in understanding of sex-based biological differences persist due to the historic and continued lack of inclusion of female, trans, and intersex persons in clinical studies, female cells and animals in foundational research, and consideration for the complex hormonal environment, said Monica Laronda, assistant professor in the department of pediatrics at the Ann and Robert H. Lurie Children’s Hospital of Chicago and Northwestern University. This knowledge gap can further exacerbate health complications through misdiagnoses, delayed diagnoses, and restricted access to or adverse effects from treatment, she said.⁷ U.S. Department of Health and Human Services regulations from 2001 supported the inclusion of pregnant and lactating people in clinical trials, explaining that the benefits of including this population were outweighed by anticipated safety risks (Blehar et al., 2013). Yet nearly two decades later, SARS-CoV-2 vaccine trials

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² See https://orwh.od.nih.gov/sex-gender (accessed November 11, 2024).

³ See https://orwh.od.nih.gov/sex-gender/orwh-mission-area-sex-gender-in-research/nih-policy-on-sex-as-biological-variable (accessed November 11, 2024).

⁴ See https://www.mckinsey.com/mhi/our-insights/closing-the-womens-health-gap-a-1-trillion-dollar-opportunity-to-improve-lives-and-economies (accessed December 3, 2024).

⁵ Resources include the NIH Discover Women’s Health Research resource, https://discoverwhr.nih.gov (accessed December 3, 2024), and the Health of Women of U3 Populations Data Book, https://orwh.od.nih.gov/in-the-spotlight/all-articles/fifth-edition-of-health-of-women-of-u3-populations-data-book-is-now-available (accessed December 3, 2024).

⁶ See https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease (accessed December 3, 2024).

⁷ See https://www.weforum.org/publications/closing-the-women-s-health-gap-a-1-trillion-opportunity-to-improve-lives-and-economies/ (accessed December 20, 2024).

excluded pregnant and lactating people despite emerging evidence of associated risks (Brady et al., 2021).

Moreover, reproductive biology is not always binary, as highlighted by intersex conditions where an individual’s anatomy and/or hormones do not fall into discreet male or female categories, Laronda added. Tissues throughout the body express receptors for hormones, as illustrated by disorders such as premature ovarian insufficiency, which can cause co-morbidities that affect mental, cognitive, cardiovascular, and bone health and reduce life expectancy by 2 years. Increased research on the female hormonal milieu across the lifespan and on hormonal conditions in cell cultures and their influence on cellular responses is needed, Laronda said. Such inclusion of sex as a biological variable improves the scientific rigor across cellular, animal, and human models of disease and treatment development, she further emphasized, and regenerative medicine can help provide tools to better investigate these sex-related questions.

Multiple Sclerosis as a Model for Sex as a Biological Variable

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disorder that could benefit from regenerative therapies such as chimeric antigen receptor (CAR) T-cell therapy. Many MS symptoms are invisible to others, such as pain, fatigue, depression, anxiety, and bladder and bowel dysfunction, and women have long been disregarded when raising concerns about these symptoms, resulting in diagnostic delays, said Riley Bove, associate professor of neurology at the University of California, San Francisco. Although the female-to-male ratio for those with MS is 3 to 1, there are many gaps affecting the inclusion of sex as a biological variable in MS research. One challenge is the wide range of cell types and hormones involved in the inflammatory and neurodegenerative processes of MS, with studies often focusing on only one hormone and one cell type. Furthermore, randomized controlled trials often do not include sex-based analyses, despite half of people living with MS being postmenopausal female individuals. Clinicians’ ability to provide equitable care for their patients, though, depends on their knowledge of the reproductive safety of medications, which is currently lacking, she said.

“Reproductive transitions⁸ are windows into mechanisms of disease and resilience,” Bove said. During pregnancy, for instance, women with MS have a decreased risk of relapse; however, up to 30 percent experience a relapse in the postpartum period. Breast feeding is likewise protective, but little is known about the impact of MS treatments on lactation, due in large part to the ethical concerns of research involving pregnant people. It is important to understand the reproductive safety of emerging therapies, including cellular therapies, and the extent to which the cells cross the placenta or are present in breast milk (Cosgrove et al., 2019).

Menopause is another transition to consider with noted overlap between common menopausal symptoms and MS symptoms, Bove said. There are analytical challenges associated with studying the effect of menopause on brain health, such as distinguishing the direct and indirect effects of the loss of gonadal hormones from the roles of other factors like exposures and comorbidities. To fully understand the impact of hormones and menopause, though, it will be important to re-evaluate canonical pathways and knowledge related to hormones since this can impact the mechanisms of regenerative medicine therapies, and further curricular and continuing medical education on the brain and menopause are needed, she added.

The Impacts of Sex on Osteoarthritis

The prevalence of osteoarthritis (OA) is increasing both in the overall population and in women and is consistently more prevalent in women than in men,⁹ said Kimberly Templeton, professor and vice-chair of orthopedic surgery at the University of Kansas Medical Center. Sex-related risk factors for OA of the knee in women include anatomy, gait pattern, the impact of estrogen, inflammatory responses, injury, menopause, and obesity. In response to injury, OA of the knee occurs earlier in women than men, and women with OA are at increased risk for comorbidities, including hypertension, depression, and chronic obstructive pulmonary disease. The most common reason women seek care for OA is chronic

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⁸ “Reproductive transitions” refers to reproductive life stages such as puberty, pregnancy, and menopause. See https://pubmed.ncbi.nlm.nih.gov/24721149/ (accessed December 20, 2024).

⁹ See https://www.cdc.gov/nchs/products/databriefs/db497.htm#:~:text=Data%20from%20National%20Health%20Interview,those%20age%2075%20and%20older (accessed January 9, 2024).

pain, which is more common and severe in women than men, due to sex and gender-based factors, and impacts both function and quality of life, Templeton said. Women are more likely than men to be treated for pain in the 12 months prior to joint replacement surgery, but these treatments do not address the underlying biology or change the disease course. Joint-replacement surgery has limitations, however, with women achieving lower levels of pain relief and functional improvement than men. Such limitations to the current treatment modalities emphasize the potential role of regenerative medicine to develop therapies for women with OA, she said, though issues with the current regenerative technologies, such as the survival of injected cells and the engraftment of cells onto damaged cartilage, need to be addressed.

A challenge for understanding sex differences in OA is that only a minority of studies in the musculoskeletal literature disaggregate data by sex, though the likelihood of data being reported by sex is greater for studies with a woman first or last author, Templeton said (Stumpff et al., 2021). To address this lack of reporting by sex, a recent NIH-funded meeting brought together editorial leadership from different orthopedic journals to collaborate on potential solutions. This resulted in a joint editorial co-signed by 28 journals agreeing to adapt a set of related guidelines, including resolutions to build review process systems that address sex and gender equity in research and calling for authors to disaggregate and analyze data by sex (Leopold et al., 2024).

CELLULAR APPROACHES TO ADDRESS WOMEN’S HEALTH

Endometrial Stem and Progenitor Cells in Regenerative Medicine

The human uterus contains an innate capacity to regenerate its endometrial lining, said Caroline Gargett, professor at the Hudson Institute of Medical Research. A population of rare epithelial progenitor cells and mesenchymal stem cells (MSC) in the human endometrium likely contributes to this regenerative capacity (Salamonsen et al., 2021). Having determined the associated biomarkers, the roles of these cells in endometrial regeneration and endometrial diseases can be further investigated. One means to do so is through endometrial gland organoids generated using menstrual fluid as a non-invasive source of endometrial tissue, she said. These three-dimensional endometrial gland growths might be used in precision medicine by treating organoids formed using patients’ cells with potential therapies.

Endometrial MSCs (eMSCs) are also being incorporated into tissue meshes to treat pelvic organ prolapse, which affects 25 percent of women and has limited therapeutic options for reconstruction, Gargett said. Such engineered products are manufactured using eMSCs purified from endometrial biopsies, expanded and embedded into a novel non-degradable mesh. These constructs have been found to induce angiogenesis, alter the macrophage response, and promote integration of the mesh with the native tissue (Hennes et al., 2021).

Another disorder that could benefit from endometrium regeneration is Asherman’s Syndrome, in which the endometrium thins, likely from damage to or loss of the native stem progenitor cell population, Gargett said. To progress such cell therapies, though, many questions need to be answered concerning which cell type to use, the best delivery method, methods to track cell survival, and the cells’ mechanism of action, she added. Furthermore, investment in product development is driven by anticipated profit, and funding for endometriosis is significantly less than for diabetes, despite similar incidences, potentially from limited interest in conditions like endometriosis (Ellis et al., 2022). To promote women’s health research and draw the attention of funders, awareness needs to be raised about the impact of gynecologic diseases, Gargett said.

Modeling Female Reproductive Tract Diseases

While all model systems can provide advantageous information, some less closely mimic the human condition, as with the current models for endometriosis, said Julie Kim, Susy Y. Hung Professor of Obstetrics and Gynecology in the Division of Reproductive Sciences at Northwestern University. One challenge facing current models of endometriosis is the low availability of surgical endometrial tissue from which to harvest cells. Furthermore, modeling the interplay between different cell types can be crucial, yet studies are typically conducted using a single cell type or in monolayer, which is not reflective of human physiology, she added. Induced pluripotent stem cells (iPSCs) and microfluidics can be used to address these concerns and study endometriosis in a more physiologically relevant manner, Kim said.

A tissue chip consortium was created to collaboratively develop a multi-organ, microphysiological system to model the female reproductive tract and study interactions among different tissue types using iPSCs.¹⁰ Derived from adult somatic cells reprogrammed into stem cells using pluripotent stem cell factors, iPSCs can be induced to differentiate into any cell type of the body, Kim explained. In this model, iPSCs derived from white blood cells of women with endometriosis, for example, can be differentiated into different endometrial and immune cells. Since iPSCs can be expanded in culture and frozen for future use, they provide a renewable source of primary human cells. The resulting microfluidic, three-dimensional EVATAR¹¹ system developed by a consortium of researchers incorporates ovary, endometrium, fallopian tube, and ectocervix cell types into individual tissue modules and uses a controlled pump to distribute culture media containing secreted paracrine factors between these different cells, Kim said. Such microfluidic organ-on-a chip models can be used to study endometriosis in the context of the whole body and to evaluate the impact of different compounds on iPSC-derived tissues in a personalized manner.

Urinary Sphincter Regeneration

Stress urinary incontinence (SUI) occurs in up to 49 percent of women and can significantly impact psychological, physical, and sexual health and overall quality of life, said Melissa Kaufman, professor in the department of urology and chief of the Division in Reconstructive Urology and Public Health at Vanderbilt University Medical Center and global principal investigator with Cook MyoSite. Proposed etiologies for SUI span a range of different pathophysiologic mechanisms, including intrinsic sphincter deficiency due to the estrogen reduction associated with menopause. Current guideline-based treatments include pelvic floor exercises, devices for mechanical occlusion, and other surgical interventions to manage symptoms, but all have potential drawbacks, she said. An ideal therapy, in contrast, would be durable, broadly applicable, minimally invasive, and produce low no pain and low morbidity, she added.

One new paradigm for SUI treatment focuses on developing regenerative cellular therapies using terminally differentiated, autologous muscle-derived cells, thus addressing disease progression without the use of foreign bodies. While the mechanisms of action are not fully understood and there are associated ethical, economic, and health concerns with stem cell therapies (e.g., malignancy, rejection, contamination), she said, proof of concept has been shown in animal models. In summary, this therapy uses autologous muscle progenitor cells obtained from skeletal muscle tissue which are then expanded, frozen, transported to study sites, and injected into the external urethral sphincter. These quiescent satellite cells are activated in response to injury and regenerate muscle fiber. Studies in animals have demonstrated that the injection of muscle-derived cells can promote reinnervation of contractile muscle tissue and recovery of some sphincter muscle functional capacity (Chermansky et al., 2004). Clinical trials of this treatment for SUI are ongoing, and the treatment has been granted regenerative medicine advanced therapy designation by the Food and Drug Administration (FDA).¹² The hope, Kaufman said, is to make “regenerative medicine part of everyday medicine.”

Inclusion of Women in Regenerative Medicine

Regenerative medicine has an opportunity to help women in a variety of areas, but to do so, women should be better included in the research, said Doris Taylor, chief executive officer of Organamet Bio. One such area is cardiovascular disease (CVD), which is the leading cause of death of women worldwide. Despite known sex differences in the prevalence, development, and mechanisms of CVD, analyses of sex-specific differences are lacking in animal research and clinical trials. In response to this gap in CVD research, Taylor offered a list of “R’s” for improving the inclusion of women in regenerative medicine: recruit and retain women, report data, and research women.

Inclusion of Women in Research

First, she said, recruit women, both as participants in clinical studies and as leaders of cardiovascular clinical research. Women account for 38 percent of CVD clinical

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¹⁰ See https://news.northwestern.edu/stories/2017/march/female-menstrual-cycle-reproductive-system/ (accessed January 10, 2024).

¹¹ See https://ncats.nih.gov/pubs/features/evatar (accessed December 4, 2024).

¹² See https://www.biospace.com/fda-grants-rmat-designation-for-cook-myosite-s-investigational-autologous-muscle-derived-cells-for-urinary-sphincter-repair (accessed December 20, 2024).

trial enrollment on average but only 18 percent in regenerative medicine CVD trials; furthermore, trials are not sufficiently powered to assess effects in women or to facilitate subgroup analyses. Barriers to equitable enrollment include underdiagnosis, lower levels of recruitment from a lack of understanding of how CVD impacts women, and misconceptions that recruiting and studying CVD in women requires more time and money, Taylor said. Notably, studies led by women more frequently enroll women. One solution would be to recruit and develop women leaders in cardiology, she said. An increased representation and advancement of women in the biomedical workforce could help influence the research questions being asked and drive more inclusive, equitable care, Bove added. Furthermore, women also drop out of clinical trials more frequently than men, thus requiring improved retention of female research participants. Retention of female faculty is likewise needed, as the attrition rate for tenure-track and tenured female professors exceeds that of men at every career age, with the workplace climate being cited most frequently as the reason for leaving (Spoon et al., 2023).

Inclusion of Sex when Reporting Data

Increased reporting of data by sex is also necessary since less than 2 percent of regenerative medicine CVD studies in 2024 to date reported data by sex, Taylor said. Lack of reporting by sex can lead to overlooked outcomes. For example, a retrospective analysis by sex of autologous cell therapy trials found that women treated with the therapy had lower incidences of stroke, acute myocardial infarction, and death than female placebo-treated controls, whereas the therapy produced no difference in men (Haller et al., 2021). By not aggregating the data by sex, such sex-based differences in the efficacy of regenerative medicine therapies are not apparent, impacting the clinical approval and thus women’s access to these therapies, she remarked.

Inclusion of Women and Sex as a Variable in Research

The final “R” is research, indicating the need for more research on women and the impact of sex as a biological variable. Sex-based differences exist beyond cells and can also be observed in biological tissues as seen, for instance, in the differences in the mechanical properties of male and female tissues. Thus, regenerative medicine therapies should use proteins and scaffolds derived from the appropriate sex, Taylor said. One way to improve the inclusion of women and sex in research is educating review panels and study sections about the importance of including sex as a biological variable and funding research accordingly, she said.

CAR T-Cells to Treat Autoimmune Disease

Autoimmune disease affects 4 to 7 percent of the global population, with women being 4 or more times more likely to be affected than men, depending on the condition, said Samik Basu, chief scientific officer at Cabaletta Bio. The current standard of care for lupus includes either broad, systemic therapies (e.g., immune suppressants) or targeted therapies (e.g., monoclonal antibodies, such as rituximab). These therapies, though, are non-curative, require ongoing treatment, and can leave patients chronically immune-suppressed, he said. In addition, the efficacy of monoclonal antibodies can be suboptimal due to limited tissue penetration.

CAR T-cell therapy, which has been used in the treatment of cancer, is now being investigated for treatment of autoimmune disease.¹³ In essence, this therapy is created from T-cells genetically engineered to target and kill B-cells, Basu said. Studies have demonstrated that CD19-directed CAR T-cells penetrate tissues and deplete B-cells better than rituximab and produce significant improvement and long-term remission for several autoimmune diseases (Schett and June, 2024). Moreover, pre-clinical investigational new drug–enabling studies for CAR T-cell therapies can be designed to account for sex differences through the use of female human T-cells from patients with autoimmune disease or mice, he said.

NON-CELLULAR INNOVATIONS IN WOMEN’S HEALTH

Microphysiologic Systems to Model for Lupus and Uterine Fibroids

In the United States, 90 percent of patients with lupus are women, with the highest rates occurring in African American and Hispanic women, said Erika Moore, assistant professor in the Fishell Department of Bioengineering at the University of Maryland. Lupus vasculitis is a complication of lupus which can lead to tissue and organ damage. The associated alterations in monocyte function and effects on microvessel structure can be better

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¹³ See https://www.lupusresearch.org/investigational-car-t-cell-gets-fast-tracked-by-u-s-fda/ (accessed December 4, 2024).

characterized using microphysiological platforms, she said (Ryan et al., 2022). These platforms, which encapsulate cells of interest into a polymer structure, are used to create a microenvironment that mimics immune cell function in vivo. One finding from this preclinical model was that monocytes from lupus patients had increased angiogenic function compared to healthy controls. Another such biomaterial model is focused on evaluating the efficacy of different treatments for a given patient: mononuclear cells are isolated from peripheral blood of a patient with lupus and introduced into a microfluidic system lined with endothelial cells embedded in hydrogel. Different treatments are then introduced into the system to assess their impact on monocyte-endothelial cell interactions and vascular inflammation.

These static and flow microphysiologic systems are also being used to model uterine fibroids, which are very prevalent but not well understood, Moore said. Fibroids are stiffer than the myometrial tissue they arise in, have higher levels of transforming growth factor beta 3 (TGF-β3), and have a higher density of macrophages than healthy tissue. By seeding primary human uterine fibroblasts into a hydrogel, researchers replicated uterine fibroid growth and mimicked physiological aspects such as the mechanics and cell density, she said; this can be used for screening fibroblasts.

The precision medicine field has an opportunity to move towards a more holistic approach, starting at the bench with these types of models, Moore continued. For example, researchers can work with clinicians to better consider ancestry when recruiting patients and focusing on who is burdened most by the disease. Consider “who you study and why,” she said, making sure to acknowledge whom the disease more disproportionately effects and how researchers can address these disparities.

Proteases as Diagnostics and Therapeutic Targets in Women’s Health

With their involvement in tissue remodeling, proteases, such as cathepsin, can serve both as functional biomarkers and as therapeutic targets for tissue remodeling diseases, said Manu Platt, director of the Center for Biomedical Engineering Technology Acceleration at the NIH National Institute of Biomedical Imaging and Bioengineering. For instance, increased levels of cathepsins have been observed in endometriotic lesions in a mouse model and in human samples. Treatment of mice with a protease inhibitor reduced attachment of these lesions, highlighting their potential as therapeutic targets, he said. Additionally, multiplex cathepsin zymography can be used to quantify active protease, providing a very low-cost assay feasible for use in low resource areas, Platt said. Using this diagnostic, cathepsin K was found to be 50-fold higher in breast cancer tumor samples than in healthy tissue from the same patient (Chen and Platt, 2011).

The assay has also been used to monitor a set of enzymes known to be involved in cardiovascular and bone-disruptive diseases and cancer metastasis and to calculate predictive risk scores for metastasis. A similar protease assay was used for the early detection of aggressive breast cancer in young women in Ethiopia. Local graduate students and professors were trained to run the assay and published a study of its application, providing an example of using technology to empower communities, Platt said. Moving forward, he continued, the medical device field needs to ensure that therapies are developed to benefit broader reaches of humanity.

Precision Biomaterials for Research and Treatment

Human tissues are complex and exhibit large amounts of cellular heterogeneity, but biomaterials can provide a model system to help study this complexity as well as disease progression, said Brendan Harley, the Robert Schaefer Professor of Chemical and Biomolecular Engineering at the University of Illinois at Urbana–Champaign. For example, a craniofacial bone regeneration model consisting of porous, sponge-like collagen scaffolds can be developed by implanting the material into a jaw, in which the physiologically relevant microenvironment stimulates the regeneration of craniofacial bone. By providing mechanical and structural signals, the biomaterial can promote the differentiation of stem cells along different musculoskeletal cell trajectories without the need for exogenous morphogens in the basal media, he said.

This biomaterial can also be used to investigate variability across stem cells from different donors. Growing adipose stem cells from a variety of donors within the scaffold and in the presence of only a basal media without stan-

dard osteogenic supplements revealed donor variability, such as increased proliferation of stem cells from male donors versus cells from female donors, Harley said. Cells from female donors also had increased alkaline phosphatase activity, produced mineral at a faster rate, and secreted different amounts of cytokines compared with the male cells (Kolliopoulos et al., 2024). Coupled with reports of the presence of low levels of sex steroid hormones in the basal media, these findings suggest the potential necessity to fully strip cell culture media of sex-steroid hormones and highlight the importance of questioning assumptions about cell cultures and models. When using adipose stem cells, the donor age should also be considered, Harley added, since characteristics such as cell distribution, metabolic activity, and regenerative potency can change across the lifespan, particularly during perimenopause and menopause. This project also emphasized the importance of considering the role of gender/sex beyond reproductive tissues, such as in musculoskeletal and orthopedic tissue injury and repair.

Likewise, these biomaterial systems can be used to study the complexities of endometrial diseases and model a healthy endometrium, making it possible to investigate the activity of endometrial-derived endothelial and stromal cells, the role of matrix environment on endometriosis lesion initiation, and the physiologic and pathological responses of endometrial cell types to reproductive toxicants during short timeframes, Harley said. A challenge for these systems, though, is the multifactorial nature of sex, which is not always binary, he added. Moving forward, the field should consider potential biomaterial solutions to better account for donor variability and consider who is being excluded with narrow definitions of women’s health, he said. To make space for a new generation of regenerative medicine products, Harley added, it will be important to center research at the margins of current discourse and account for gender, sex, age, and social factors and cultivate spaces that facilitate interdisciplinary scholarship, integrating social scientists, engineers, life scientists, and the humanities.

Regenerative Therapies for Temporomandibular Disorders

Temporomandibular disorders (TMDs) are a group of at least 30 different conditions affecting the temporomandibular joint (TMJ) and are two to three times more prevalent in women than in men and appear most commonly between the ages 20 to 50, said Alejandro Almarza, professor of oral and craniofacial sciences at the University of Pittsburgh. Symptoms range from acute or chronic pain to joint erosion and osteoarthritis. Comorbidities are common and include chronic low back pain, fibromyalgia, irritable bowel syndrome, endometriosis, headaches, and rheumatological diseases as well as psychosocial comorbidities. TMDs are complex and not well studied, and diagnostics are lacking, he said.

As the biologic causes of the chronic pain associated with TMDs are unknown, regenerative therapies for TMDs focus on restoring function, Almarza said. Extracellular matrix scaffolds offer a promising acellular material since they are capable of remodeling TMJ-like tissues and promoting constructive tissue remodeling and are already FDA approved for clinical use, he added. In a pilot pre-clinical study, an acellular extracellular matrix scaffold was implanted to promote TMJ disc regeneration. This was followed by a long-term study, in which the implant promoted constructive tissue remodeling that resembled the native disc both histologically and mechanically. To produce such outcomes, a biomaterial must induce a robust inflammatory response, inducing macrophage infiltration of the scaffold, Almarza said. The short-term safety of the device was likewise demonstrated in another preclinical study (Chung et al., 2022). Translation into the clinic, though, faces several challenges: The financial incentive for industry is lacking due to low patient numbers, as only about 3,000 to 5,000 patients per year would benefit from this technology; all TMJ implantable technologies are categorized as Class III devices by FDA, which require the highest level of clinical evidence, and thus, increased financial investment; and no claims regarding pain relief can be made since there is still a limited understanding of the relationships between anatomy, disease, and pain or the mechanisms of pain, he said.

Pro-Regenerative Biomaterials

Pro-regenerative biomaterials, defined as biomaterials capable of influencing the immune response to promote tissue repair, offer a promising alternative to cellular therapies, said Karen Christman, Pierre Galletti Endowed Chair for Bioengineering Innovation in the Jacobs School

of Engineering at the University of California, San Diego (Christman, 2019). Biomaterials can be more cost effective than cell-based therapies; easier to prepare, ship, store, and sterilize, as there is no living material; more reproducibly manufactured; and, in some cases, regulated as devices rather than biologics, she said. Extracellular matrix scaffolds are an example of a naturally derived pro-regenerative biomaterial. The decellularized natural matrix product can be formed into an injectable hydrogel that self-assembles into a porous, fibrous scaffold in vivo.

One potential application for these pro-regenerative biomaterials is treating pelvic floor disorders, in which overstretching of the pelvic floor muscles during vaginal delivery can result in injury, skeletal muscle degeneration, atrophy, and fibrosis. Despite its high prevalence, many women have never heard of pelvic organ prolapse, Christman said. Therefore, she added, there is a need for increased awareness among both the general public and researchers in the regenerative medicine field. In a model of simulated birth injury, injecting an extracellular matrix hydrogel into skeletal muscle promoted tissue restoration and decreased fibrosis compared with control animals.¹⁴ These types of biomaterials can also be used to treat other conditions that affect women, such as genitourinary syndrome of menopause, she said.

One challenge to translating pro-regenerative biomaterials for women’s health, though, is the gap in understanding of the molecular, cellular, and tissue level pathologies and disease progression of pelvic disorders, Christman said. The optimal time for the delivery of regenerative therapies for pelvic disorders is likewise unknown. Other challenges are the limited precedence for the development of these products and a lack of knowledge regarding the established regulatory pathways, outcome measures for clinical trials, and the target populations that would most benefit compared with fields like cardiology, Christman said. There are also barriers to funding the development and commercialization of these new technologies, she continued. More guidance from FDA on the preclinical pathway to investigational new drug approval for regenerative biomaterials for women’s health, such as acceptable models, could be beneficial, she said.¹⁵

EXPLORING FUTURE OPPORTUNITIES

Increasing Representation of Women in the Regenerative Medicine Workforce

During a panel discussion, speakers proposed strategies to attract women to the regenerative medicine field. Such strategies include increasing funding for regenerative medicine and women’s health research, since women tend to study women’s health topics more than men, and establishing special fellowships for women’s health research, Goler Blount said. Those in the field can also be role models and “set the example of how to speak truth to power” about the need for equity and fairness in women’s health research, she said. There is also benefit in intentionally communicating the reality of conditions that disproportionately impact women and the impact of regenerative medicine to those not in the field, Moore said. Research universities and medical centers could also establish a board that focuses on women in the workforce, women as participants in research, and general women’s health initiatives, said Akua Roach, program manager for the Peer-Reviewed Orthopedic Research Program, Arthritis Research Program, and Orthotics and Prosthetics Outcomes Research Program at the Department of Defense Congressionally Directed Medical Research Programs.

The “hidden curriculum” in higher education, defined as information on how to successfully navigate the system drawn from family, career, or other experiences and hence only known by some, should be better communicated, Moore added. These curriculum gaps in practical knowledge can be addressed starting at the undergraduate or high school level as well as with periodic programmatic professional development, she said. The next generation of women could also benefit from mentorship on how to facilitate their academic success in conducting research and running a laboratory, said Goler Blount and Taylor. Business education modules can be made available online to further increase accessibility and should be part of the college curricula, Taylor said. Women’s health

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¹⁴ See https://www.eurekalert.org/news-releases/997024 (accessed January 10, 2024).

¹⁵ Since the date of the workshop, FDA published a women’s health roadmap to provide more guidance on the regulatory pathways for women’s health; see https://www.fda.gov/consumers/about-owh-research/womens-health-research-roadmap (accessed December 4, 2024).

should be a routine part of overall medical and biomedical curricula, including continuing medical education, suggested Roach and Moore, especially since women’s health affects everyone. Exposing all students to women’s health topics also helps to generate allies and inform students about careers.

Increasing Access to Regenerative Medicine Therapies

Access should be considered during the development of regenerative medicine therapies by designing and testing products with the intended treatment population in mind, said Goler Blount and Eric Sid, program director at the National Center for Advancing Translational Sciences. While people of color are willing to participate in clinical trials, they are often underrepresented because they are not asked by their clinicians to participate or they drop out after feeling disrespected and disregarded by researchers, said Platt and Goler Blount. Clinician bias can also influence whether a clinician offers research participation opportunities to patients, which may limit patient access to therapies, Roach added. To address medical mistrust, researchers can better approach communities with honesty and humility and a desire to listen and learn, Goler Blount said. Mistrust is often a biproduct of ineffective communication, which can be addressed through more thoughtful communication, Roach added.

A new ecosystem may be needed to better scale regenerative medicine technologies, Taylor said, helping increase the supply and thus accessibility of regenerative medicine therapies for women’s health. This will likely require bringing together vendors, scientists, and engineers across diseases and sectors and improving upon the current manufacturing of regenerative medicine therapies, she said. Existing resources and infrastructure can also be leveraged along with knowledge from other fields, said Roach and Taylor. “Extensive networking,” including building and learning from those within your network, can help with this knowledge and resource sharing, Moore added.

Moving the Field Forward

Information sharing can often be limited because of concerns about competition, thus creating a need for pre-competitive collaboration opportunities in regenerative medicine and women’s health, Taylor said. One option is providing increased transparency and precise language regarding the cells used for studies, helping contextualize the findings, said Moore and Harley. The field should also be building trust with communities through honest communication and precise language about the development of regenerative medicine products, Harley said. Resources such as samples, cells, and data can also be better shared, perhaps though a database or biobank, commented Harley, Platt, and Taylor. Issues such as scalability and donor privacy should also be addressed, Harley added.

FINAL REFLECTIONS

Unlike traditional drug therapies, regenerative medicine products are “forever” because they are incorporated into the body; therefore, researchers have an elevated responsibility to patients that is worth keeping in mind when developing these products, Taylor said. While more work is needed, Roach encouraged participants to build upon the momentum of the workshop. Opportunities to advance the development of regenerative medicine therapies for women’s health presented by individual speakers are summarized in Box 1. In closing the workshop, Ota Wang stressed the need to stretch beyond one’s bioscience area of focus and consider biopsychosocial factors in the development of model systems. She encouraged participants to think beyond the financial drivers of biomedical research and to think of health care as a basic human right. Moreover, advancing this field will require researchers to be thoughtful and deliberate about their work and be willing to move beyond what is comfortable, Ota Wang concluded.-

REFERENCES

DISCLAIMER This Proceedings of a Workshop—in Brief has been prepared by Michelle Drewry, Theresa M. Wizemann, and Sarah H. Beachy as a factual summary of what occurred at the meeting. The statements made are those of the rapporteurs or individual workshop participants and do not necessarily represent the views of all workshop participants; the planning committee; or the National Academies of Sciences, Engineering, and Medicine.

*The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop—in Brief rests with the institution. Planning committee members: Kimberlee Potter, Department of Veteran Affairs; Vivian Ota Wang, NIH Office of Research on Women’s Health; Alejandro Almarza, University of Pittsburgh; Cristina H. Amon, University of Toronto; Tammy R. L. Collins, Burroughs Wellcome Fund; Margot Damaser, The Cleveland Clinic; Elizabeth Garner, KNI Health Consultants and American Medical Women’s Association; Juan Gnecco, Tufts University; Eric Sid, NIH National Center for Advancing Translational Sciences; Katherine Tsokas, Johnson & Johnson Innovative Medicine; and Kathleen Zackowski, National Multiple Sclerosis Society.

REVIEWERS To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Fabrisia Ambrosio, Spaulding Rehabilitation Hospital, and Sohel Talib, California Institute of Regenerative Medicine. Leslie Sim, National Academies of Sciences, Engineering, and Medicine served as the review coordinator.

SPONSORS This workshop was partially supported by contracts between the National Academy of Sciences and Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Academy of Oral Medicine; American Academy of Orofacial Pain; Academy of Orthopaedic Physical Therapy; American Medical Women’s Association; American Society of Gene & Cell Therapy; American Society of Temporomandibular Joint Surgeons; Burroughs Wellcome Fund (Grant No. 1325461); California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; Department of Veterans Affairs (Contract No. 36C24E21C0011); Food and Drug Administration: Center for Biologics Evaluation and Research (Contract No. 1R13FD008396-01 ) and Center for Devices and Radiological Health (Contract No. 75F40122D00002); International Society for Cellular Therapy; International Society for Stem Cell Research; Johnson & Johnson; National Institute of Standards and Technology; National Institutes of Health (Contract No. HHSN263201800029I; Task Order No. 75N98024F00002 and 75N98023F00008), including: National Center for Advancing Translational Sciences; National Eye Institute; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; and National Institute of Diabetes and Digestive and Kidney Diseases; New York Stem Cell Foundation; Orofacial Therapeutics, Inc.; The TMJ Association, Ltd.; and United Therapeutics Corporation. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

STAFF Sarah H. Beachy, Senior Program Officer; Michelle Drewry, Associate Program Officer; Kathryn Asalone Shively, Associate Program Officer; Ashley Pitt, Senior Program Assistant; and Rebecca English, Senior Program Officer.

For additional information regarding the workshop, visit https://www.nationalacademies.org/event/43007_10-2024_the-intersection-of-regenerative-medicine-and-womens-health-a-workshop.

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2025. The intersection of regenerative medicine and women’s health: Proceedings of a workshop—in brief. Washington, DC: National Academies Press. https://doi.org/10.17226/29088

Health and Medicine Division Copyright 2025 by the National Academy of Sciences. All rights reserved.