Abstract
Decades of progress in biomedical research and engineering have transformed the field of oncology, shifting cancer from a largely terminal diagnosis to a more manageable disease. This is especially evident in breast cancer, where survival rates have improved due to life-saving procedures like mastectomies and lumpectomies. Every year, 1.3 million breast cancer patients receive lumpectomies which is a breast-conserving surgery that removes tumors while preserving surrounding breast tissue. However, this procedure leaves a void cavity that can cause poor cosmetic outcomes, fat necrosis, and seroma formation. Current reconstruction options have risks and do not fully address the problem. Thus, there is a clinical need for a minimally invasive, biocompatible, and effective material to fill these tissue voids and promote tissue regeneration. At the same time, ensuring patient safety, particularly for women who are disproportionately affected, requires critical evaluation of the preclinical models used to test and translate new therapies.
Injectable hydrogels offer a unique solution to address post-lumpectomy voids. They are water-swollen polymer networks that resemble soft tissue and can act as a scaffold for native adipose cells adhesion and proliferation. Their ability to be injected and facilitate tissue regeneration offers a favorable alternative to reconstructive breast surgery. Furthermore, fiber-reinforced hydrogels are an emerging biomaterial for tissue regeneration. A voltage-driven fabrication process called electrospinning is used to create nanofibers from a polymer solution. These nanofibers can be incorporated into hydrogel scaffolds to yield mechanically robust biomaterials mimicking the native fibrous architecture of the extracellular matrix (ECM). These fibrous-hydrogels have demonstrated enhanced cell growth and vascularization compared to traditional non-fibrous hydrogels. Current research on injectable, fibrous hydrogels often relies on photocrosslinking methods to achieve increased stiffness, however, many clinicians are hesitant to apply ultraviolet (UV) light to previously cancer-effected tissues due to perceived safety concerns, such as the potential for DNA damage.
To address this limitation, our team successfully created a fiber-enforced microparticle (FEMP) scaffold that can be injected, conforms to irregular cavities, and crosslinks in situ without UV light. The scaffold consists of hydrogel microparticles, electrospun nanofibers, and sacrificial gelatin that creates porosity. A polyethylene glycol-thiol (PEG-SH) crosslinker enables gel formation through a Michael-type addition reaction following injection. We fabricated scaffolds with varying gelatin concentrations (0%, 25%, 50%) to modulate porosity and compared them to UV-crosslinked controls. Material properties, porosity, and cytocompatibility were evaluated using rheology, fluorescence imaging, and fibroblast encapsulation.
Before clinical translation, our FEMP scaffolds must undergo extensive preclinical testing, currently conducted in mouse models. However, small animal models often fail to accurately replicate human physiology, particularly in women’s health. These limitations are compounded by historical gender bias in research, which has restricted the inclusion of female subjects.
Thus, the goal of my STS research project was to assess the efficacy of animal models as preclinical research tools for women’s health, specifically by studying their evolution in use and accuracy throughout the 20th and 21st centuries, with particular attention to the NIH’s 2016 Sex as a Biological Variable (SABV) policy. The main conclusion of this research is that the implementation of SABV has significantly increased the inclusion of female animal models, helping to challenge an entrenched male-only paradigm. However, women’s health research remains limited, as female rodent models lack the complexity needed to accurately represent human reproductive anatomy. Additionally, the species-dependent nature of sex differences restricts the translation of findings on sex-specific disease markers and behaviors to humans. This is true even for breast cancer, which is historically the most funded and inclusive area of women’s health. Emerging computational and tissue engineering technologies such as ex vivo disease models, 3D bioprinting, microfluidics, and organ-on-a-chip may help address these gaps and should be used alongside animal models to improve outcomes in women’s health.
The synthesis of my technical and STS projects highlights the importance of biomedical innovation that advances research and improves quality of life as well as critical evaluation of the systems used to test and develop such innovations. Successful innovation depends not only on technical performance but also on the accuracy and inclusivity of research practices. Ultimately, this work underscores the ethical responsibility to ensure that new therapies are both safe and truly representative of the populations they are intended to serve.
