Novel biomimetics promote dynamic cell-driven remodeling of their microenvironment


Three-dimensional (3D) cell culture systems have been extensively used to mimic the complexity of human tissues and organs in vitro. They represent a powerful biomedical technology for disease modeling, tissue engineering and regenerative medicine. Organoids consist of a 3D collection of cells able to self-renew and self-organize that recapitulate key features of developed organs; they are explored for drug design and screening assays. Biological cell models strongly rely on biomaterials to recreate a microenvironment with compatible properties that resemble the extracellular matrix (ECM). Biomimetic materials are the materials developed by taking inspiration from nature to support a complete or a portion of a living structure that accomplishes, enhances, or substitutes a natural function. These biomaterials are usually engineered for medical biotechnology and pharmaceutical applications. Several concerted efforts have been made in the area of synthetic biomaterials for tunning bioactivity through mixing of materials, degradable crosslinks, and adoption of adhesive molecules such as RGD. Unfortunately, integrin-mediated cell adhesion and proteolytic matrix degradation are known to contribute only a fraction of features of extracellular matrix reported to mediate cell behavior.

During extracellular matrix modelling, the matrix is degraded and deposited, thereby allowing cells to alter the structure and composition of nearby extracellular matrix. Also, extracellular matrix serves as a hub for biochemical cues and growth factors that are presented to cells as tethered molecules. The limitations of current biomaterials present the need for clinically translational synthetic biomimetics with controllable biomechanics that recapitulate the structural features and biological functions of the native extracellular matrix and the possibility of sequestering growth factors.

Biomimetic hydrogel-based cultures can serve as a treatment option for infertility caused by cancer radio- and chemotherapies by supporting the growth and maturation of ovarian follicles to yield fertilizable eggs. These therapies are cytotoxic to ovarian follicles, and it’s impossible to regenerate the non-renewable ovarian follicular reserves once degraded. The only viable yet experimental fertility preservation option which would be applicable to a broad range of cancer survivors is ovarian tissue cryopreservation before the anti-cancer treatments, succeeded by culture and maturation of follicles to obtain fertilizable oocytes. This option could also help avoid the potential transfer of cancer cells back into the patient in the case of leukemia and ovarian cancer.

Despite the impressive progress made in the culture of large murine follicles adopting biomaterials such as degradable poly(ethylene-glycol) hydrogels, it’s still challenging to culture small follicles and achieve clinical translation by yielding supreme oocytes. The lack of endogenous extracellular matrix in the current systems is partly to blame for this shortfall.

To address these challenges, University of Michigan researchers, Claire Tomaszewski, Katarina DiLillo, Brendon Baker, Kelly Arnold, and led by Professor Ariella Shikanov proposed that peptides from native extracellular matrix or growth factors and tethered to a poly(ethylene-glycol) (PEG) hydrogel would sequester and retain extracellular matrix molecules secreted by an encapsulated follicle. They designed these hydrogels with an objective of recapitulating the native extracellular matrix for culture and maturation of follicular organoid. Their research is published in the journal Acta Biomaterialia.

To regenerate the extracellular matrix of ovarian tissues, the authors adopted four peptides, laminin-derived peptide (AG73), heparin-binding peptide (HBP), basement membrane binder (BMB) peptide and the extracellular matrix binding region of placental growth factor 2 (RRR). The authors observed that the peptides they adopted considerably improved ovarian follicle growth, survival, and maturation compared to an inert control, PEG-Cys. By performing an immunohistochemical analysis of the hydrogels near the cultured follicles, the authors were able to see sequestration and retention of laminin, fibronectin, perlecan, and collagen I in the ECM-sequestering hydrogels but not in the bioinert hydrogels.

The research team demonstrated that follicles cultured in hydrogels functionalized with AG73, BMB, or RRR peptides posted higher concentrations of follicle development regulating factors than PEG-Cys. AG73 and BMB peptides were the most crucial in enhancing follicle maturation mainly because they take after basement membrane activity, which is necessary for follicle development.

The outcomes of the study report improved folliculogenesis, presenting a fertility preservation avenue for women put under anti-cancer treatments. They also give a potential solution for other tissue engineering options, for it was possible for encapsulated cells to reinstate their native microenvironments in vitro.

Novel biomimetics promote dynamic cell-driven remodeling of their microenvironment - Medicine Innovates Novel biomimetics promote dynamic cell-driven remodeling of their microenvironment - Medicine Innovates Novel biomimetics promote dynamic cell-driven remodeling of their microenvironment - Medicine Innovates Novel biomimetics promote dynamic cell-driven remodeling of their microenvironment - Medicine Innovates

About the author

Claire Nason-Tomaszewski recently completed her PhD in Biomedical Engineering at the University of Michigan. With a background in materials science and a particular interest in hydrogels, Claire spent her PhD engineering biomimetic matrices for ovarian tissue engineering with a focus on recapitulating the ovarian microenvironment for in vitro follicle culture. Claire has designed a fully synthetic, ECM-sequestering PEG matrix to act as an artificial ovary, restoring critical cell-cell and cell-matrix interactions for preserving fertility of female cancer survivors. Claire is an avid advocate for women and underrepresented groups in STEM, coordinating and participating in several on-campus outreach events which introduce students and educators at all levels to basic engineering principles and reproductive biology. Claire’s research and contributions to her community have been recognized through several national and university awards including a Ruth L. Kirschstein Predoctoral Individual Fellowship (F31), Tissue Engineering and Regeneration T32 fellowship, the Richard and Eleanor Towner Prize for Outstanding PhD Research and the Marian Sarah Parker Prize for academic excellence, leadership, and community service.

About the author

Ariella Shikanov is an Associate Professor at the Department of Biomedical Engineering at the University of Michigan, with appointments at the Department of Obstetrics and Gynecology, Cellular and Molecular Biology Program and Macromolecular Science and Engineering. She joined UM in Fall 2012 as an Assistant Professor after completing her postdoctoral fellowship at Northwestern University in Chicago in a multidisciplinary collaboration called the Oncofertility Consortium aiming to address infertility induced by chemotherapy in cancer survivors.

The Shikanov laboratory focuses on treatment of premature ovarian insufficiency (POI), which is a common complication of cytotoxic treatments due to extreme ovarian sensitivity to chemotherapy and radiation. The research in Shikanov lab aims to create artificial constructs that direct tissue regeneration and restore biological function by combining approaches from engineering, materials, chemistry and life sciences.

Dr. Shikanov is the recipient of The Hartwell Foundation (2014), NSF CAREER (2016), Cellular and Molecular Bioengineering Young Innovator (2018) awards and is currently funded by NIBIB and NICHD. Dr. Shikanov was also nominated for the Golden Apple Teaching award (2017) and was voted an Outstanding Undergraduate Research Opportunity Program mentor (2014). In 2020 Dr. Shikanov founded the start-up company, “ArtOva Therapeutics, Inc”, with the goal to bring the technology developed in her lab into the clinic.


Claire E Tomaszewski, Katarina M DiLillo, Brendon M Baker, Kelly B Arnold, and Ariella Shikanov. Sequestered cell-secreted extracellular matrix proteins improve murine folliculogenesis and oocyte maturation for fertility preservation. Acta Biomaterialia, issue 132 (2021), pages 313–324.

Go To Acta Biomaterialia