Biology subjects

Weber, M. H.

Publications and source records attributed to Weber, M. H..

6 recordsLinked to original sources

bioRxiv2026

3D-Printed Scaffolds for Local Chemotherapeutic Delivery in Resected Spine Metastases

Spinal metastases often occur secondary to breast, lung and prostate cancer and lead to instability, pain and poor quality of life. Standard care for spine metastases includes a multidisciplinary approach with surgery playing a major role in tumor resection, stabilization and decompression. Surgical resection with adjuvant is an effective treatment, yet it is often accompanied by tumor recurrence from residual disease. Furthermore, acrylic cements applied to defect sites provide stability, but they do not promote bone repair and can become destabilized during recurrence events. Developing new tools to stabilize defect sites, promote bone repair and locally deliver therapeutics may circumvent these limitations. We have previously developed mechanically competent 3D printed lactide/mineral scaffolds conducive to bone repair in vivo. We have also developed 3D printed nanoporous scaffolds conducive to both bone repair and chemotherapeutic delivery. Here, we set out to assess doxorubicin and cisplatin uptake and release rates and efficacy of drug delivery in 2D and custom physiological 3D cultures of two human cancer cell lines associated with metastases, MDA-MB-231 (human breast) and C42B (human prostate). Composite scaffolds had a compressive modulus close to trabecular bone, and could sustainably and effectively release doxorubicin and cisplatin as measured against both breast and prostate cell lines in 2D and 3D custom physiological metastases models. As a proof-of-concept, doxorubicin loaded composite scaffolds were implanted into rat caudal vertebrae following MDA-MB-231 xenograft resection. Following 6 weeks of implantation, no adverse events were noted and microCT analysis revealed boney integration of the construct. Taken together, these data indicate that our composite scaffolds may be an appropriate alternate therapy to stabilize bone defects, promote bone repair and effectively inhibit cancer recurrence post-tumor resection. Future work will test composite scaffolds using in vivo bone metastases models.

bioengineering↗

bioRxiv2026

Targeting therapy-induced senescence across multiple breast cancer subtypes in a metastatic bone-like microenvironment

Chemotherapeutic treatment of breast cancer with Doxorubicin (DOX) can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Exposure of triple-negative breast cancer (MDA-MB-231), hormone-responsive (MCF-7) and HER2+ (MDA-MB-453) cells, and primary spine osteoblasts to DOX showed significant induction of p21-positive senescent cells. DOX and senolytics (RG-7112, o-Vanillin) treatment of co-culture spheroids showed a significant additive effect in reducing tumor sphere viability and growth, indicating reduced metastatic potential. This was correlated with reduced SASP in triple-negative and hormone responsive lines and decreased levels of senescent cells in all subtypes and primary stromal cells, while proliferation was decreased, and apoptosis increased across all breast cancer subtypes. Future chemotherapeutic treatment in breast cancer models may be optimized by adding senolytic drugs to more effectively clear senescent tumor and stromal cells, reducing risk for relapse and metastatic potential, while allowing for tissue regeneration in the bone metastatic environment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/724653v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@c4cb8forg.highwire.dtl.DTLVardef@105219org.highwire.dtl.DTLVardef@17e0517org.highwire.dtl.DTLVardef@802bd2_HPS_FORMAT_FIGEXP M_FIG C_FIG Senolytics selectively eliminate senescent cancer and stromal cells and enhance Doxorubicin efficacy in a 3D bone-like tumor microenvironment model.

cancer biology↗

bioRxiv2025

Targeting breast cancer senescence in 3D models of bone metastasis

Chemotherapeutic treatment of breast cancer with Doxorubicin can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Treatment of both triple-negative breast cancer (MDA-MB-231) cells, and primary spine osteoblasts 0.25 {micro}M Doxorubicin showed significant induction of senescence indicated by p21 positive cells. Doxorubicin and senolytics (RG-7112, o-Vanillin) treatment of mono-culture and co-culture spheroids showed a significant additive effect on decreased tumor sphere viability and growth. This was correlated with decreased p21 and Ki67 proliferation marker in both the breast cancer and osteoblast cells. In all cases, combined Doxorubicin and senolytics significantly reduced sphere size and cancer cell outgrowth, indicating reduced metastatic potential. Future chemotherapeutic treatment of breast cancer patients may be optimized by adding senolytic drugs to more effectively clear tumors and help regenerate surrounding stroma tissue such as in the bone metastatic environment.

cancer biology↗

bioRxiv2024

Cold Atmospheric Plasma Selectively Disrupts Breast Cancer Growth in a Bioprinted 3D Tumor Microenvironment Model

Spine metastases are the most common bone site for breast cancer, with evolving surgery and multidisciplinary care improving outcomes. Current treatments, including chemotherapy and invasive surgery, may damage healthy tissue and may leave residual tumors that lead to recurrence. Cold atmospheric plasma (CAP) offers a non-invasive alternative by delivering reactive oxygen and nitrogen species (RONS) locally to tumor sites, selectively targeting cancer cells while sparing healthy tissue. To assess the impact and selectivity toward tumor cells adjacent to bone-like tissue, we develop a 3D bioprinted tumor-stroma model using a 1% alginate and 7% gelatin cell-laden hydrogel to mimic a bone-like microenvironment. The model co-cultures triple-negative MDA-MB-231 human breast cancer cells with primary human bone marrow mesenchymal stromal cells to simulate tumor-stroma interactions. The effects of CAP treatments are assessed through metabolic activity and viability assays over three days. Results show significant selectivity for cancer cells in both 2D and 3D cultures. CAP minimizes damage to healthy cells, offering the potential for localized treatment over systemic chemotherapies such as doxorubicin. Our novel bioprinted model, combined with a plasma source controlling RONS composition, enables detailed studies of redox-based cancer cell inactivation and highlights CAP as a personalized, non-invasive treatment for bone metastases.

bioengineering↗

bioRxiv2023

Nanoparticle-Functionalized Acrylic Bone Cement for Local Therapeutic Delivery to Spinal Metastases

Polymethylmethacrylate bone cement is often used to reconstruct critical-sized defects generated by surgical resection of spinal metastases. Residual tumor cells after a resection can drive recurrence and destabilization. Doxorubicin (DOX) is a common chemotherapeutic drug with unwanted side-effects when administered systemically. Mesoporous silica nanoparticles are gaining attention for targeted drug delivery to bypass the negative side effects associated with systemic drug administration. We developed a nanoparticle-functionalized cement for the local release of DOX and tested its ability to suppress cancer cells. DOX was loaded onto nanoparticles which were then mixed into the cement. Drug release profiles were obtained over a period of 4 weeks. Cement constructs were incubated with 2D and 3D cultures of breast and prostate cancer cell lines, and cell metabolic activity and viability were evaluated. Cell migration and spheroid growth were assessed in collagen-coated spheroid cultures. Nanoparticles were homogenously dispersed and did not alter cement mechanical strength. A sustained DOX release profile was achieved with the addition of nanoparticles to the bone cement. The release profile of DOX from nanoparticle cement may be modified by varying the amount of the drug loaded onto the nanoparticles and the proportion of nanoparticles in the cement. Cells treated with the cement constructs showed a dose- and time-dependent inhibition. Cell migration and spheroid growth were impaired in 3D culture. We show that nanoparticles are essential for sustained DOX release from bone cement. DOX-loaded nanoparticle cement can inhibit cancer cells and impair their migration, with strong potential for in vivo translation studies.

bioengineering↗

bioRxiv2022

Continuous two-phase in vitro co-culture model of the enthesis

The enthesis is the interfacial tissue between ligament or tendon, and bone, which connects tissues of distinctly different mechanical properties. Although ligament and enthesis injury is commonplace, the development and healing mechanisms of these tissues are yet unclear. Current models for investigating these mechanisms are primarily in vivo animal models as in vitro models have been limited. In this study, an in vitro enthesis model was developed using a modified gel aspiration-ejection (GAE) method. Continuous two-phase aligned dense collagen (ADC) hydrogels with an overlapping interface were fabricated within 2 hours. The mechanical properties of acellular two-phase ADC confirmed the continuous nature of this model, as the mechanical properties showed no significant difference compared to single-phase ADC and maintained comparable structural and mechanical characteristics of immature ligaments and unmineralized bone. Human anterior cruciate ligament (ACL) fibroblasts and human spine vertebral osteoblasts were isolated from donor tissues and were seeded to form the enthesis model. These were cultured for 14 days, at which the viability and proliferation was observed to be 85 {+/-} 7.5% and 230 {+/-} 52%, respectively. Histological and immunofluorescence analyses at day 14 revealed extensive cell-driven matrix remodelling, and the seeded fibroblasts and osteoblasts maintained their phenotype within their compartments of the layered co-culture model. These results demonstrate the rapid fabrication of a two-phase co-culture system that can be utilized as an in vitro model to further understand the degenerative and regenerative mechanisms within the enthesis.

bioengineering↗