The latest funding complements a landmark $3.5 million NIH grant awarded in 2025 to Luiz Bertassoni, D.D.S., Ph.D., director of the Knight Cancer Precision Biofabrication Hub at OHSU, bringing the total NIH commitment to nearly $9.2 million. These grants, led by Bertassoni and Alexander Davies, D.V.M., Ph.D., represent a strategic thrust by OHSU’s Knight Cancer Institute to meld bioengineering, oncology, and precision medicine. This initiative underscores the transformative potential of sophisticated tissue engineering to elucidate the complex microenvironments encountered by cancers invading bone, facilitating research that had previously been unattainable.

At the heart of this research are microphysiologic systems, diminutive yet intricate devices roughly the size of USB drives, composed of living human cells organized in three-dimensional arrays to faithfully recapitulate tissue architecture and function. These chip-based models integrate multiple cell types, including bone osteoblasts, endothelial cells constituting blood vessels, and neural components, enabling dynamic, real-time observation of cancer cell behavior, signaling interactions, and responses to therapeutics at unparalleled single-cell resolution. This biofabrication approach addresses a critical shortfall in conventional cancer models, which often fail due to oversimplification or species differences inherent in animal studies.

Alexander Davies leads a $3.17 million project focusing on osteosarcoma, a highly aggressive and rare pediatric bone cancer with a stagnant survival rate, especially in patients with pulmonary metastases. By engineering bone and ex vivo lung microenvironments within these microfluidic chips, Davies’ team enables visualization and monitoring of metastatic tumor cells as they colonize lung niches and interact with the surrounding microenvironment. This allows researchers to dissect metastatic processes and evaluate drug responses in a controlled yet physiologically relevant setting, a significant leap beyond static cultures or animal models.

A particularly promising avenue investigated within these osteosarcoma models targets MCL-1, an anti-apoptotic protein that aids cancer cell survival in the metastatic lung microenvironment. Previous collaborative studies utilizing animal and lab models demonstrated that MCL-1 inhibitors, especially when combined with cyclophosphamide chemotherapy, substantially impair metastatic tumor viability and sometimes eradicate lung tumors entirely. However, the precise action mechanism, specificity, and safety profiles remain to be fully elucidated in human-relevant models, which Davies’ cutting-edge organ chips provide.

Meanwhile, Bertassoni’s $2.5 million NIH award aims to unravel the biomechanical and neurovascular determinants that govern prostate cancer metastasis to bone, a phenomenon clinically observed in over 80% of men with advanced prostate cancer. His lab’s bone-on-a-chip systems incorporate live blood vessels and nerve cells within engineered human bone tissue, creating an unprecedented platform to investigate how mechanical forces—such as shear stress and vessel wall compression—and neural signaling synergistically facilitate tumor cell extravasation, survival, and aggressive growth within the bone niche.

The integration of vasculature and neural elements into a single microphysiologic device represents a significant bioengineering accomplishment. This holistic platform enables detailed mechanistic studies on how physical and biochemical cues influence gene expression patterns in metastatic cancer cells and their crosstalk with the resident bone microenvironment. Bertassoni emphasizes the active role of bone as a dynamic tissue whose hemodynamic and neural features critically shape cancer progression, challenging the traditional view of bone as a passive metastatic site.

Beyond prostate cancer, this organ-on-chip technology demonstrates adaptability to various cancer types, including head and neck cancers that aggressively invade bone tissue, as reflected by prior NIH funding to Bertassoni’s lab. The modularity of these platforms facilitates exploration of diverse tumor-stroma interactions, drug screening, and personalized medicine applications, positioning OHSU at the forefront of biofabrication-driven cancer research.

These NIH awards epitomize an intentional interdisciplinary ecosystem cultivated at OHSU, where bioengineers, cancer biologists, clinicians, and imaging specialists collaborate synergistically within the Knight Cancer Institute’s Precision Biofabrication Hub. This collaborative framework accelerates innovation and amplifies the translational impact of research, with the ultimate aim of improving clinical outcomes for patients afflicted by challenging bone-metastatic cancers.

In summary, the integration of advanced biofabrication, microfluidics, and cellular engineering embodied in these NIH-funded projects heralds a new era in oncology research. By recreating physiologically relevant human tissues on microchips, scientists can probe cancer metastasis mechanisms with unprecedented clarity, evaluate therapeutic interventions more effectively, and pave the way towards novel, targeted treatments tailored for bone-invading malignancies.

Envisioning the profound implications, Bertassoni notes, “Our biofabrication models enable an in-depth exploration of cancer complexity and therapeutic vulnerabilities that were inaccessible before. These efforts mark a pivotal step in translating engineered human tissue technologies into meaningful clinical insights.”

Davies concurs, emphasizing the translational promise: “Our osteosarcoma models resolve long-standing challenges in studying metastatic progression and therapy resistance. They hold great potential to transform patient care by enabling safer, more effective treatment strategies grounded in robust, human-relevant science.”

Collectively, these projects underscore the NIH’s strategic shift towards promoting human-relevant experimental platforms and signal a transformative advance in understanding, treating, and ultimately overcoming bone metastatic cancers.

Subject of Research: Development and application of microphysiologic systems (organs-on-a-chip) to study cancer growth, metastasis, and therapeutic response in bone and bone-associated tissues.

Article Title: Revolutionizing Bone Cancer Research: Engineering Human Tissues on a Chip to Decode Metastasis and Treatment Response

News Publication Date: Not specified in the source content.

Web References:

• Knight Cancer Precision Biofabrication Hub: https://www.ohsu.edu/knight-cancer-institute/precision-biofabrication-hub
• NIH Funding Announcement for Bertassoni: https://news.ohsu.edu/2025/07/28/ohsu-research-team-lands-federal-funding-to-study-aggressive-head-and-neck-cancer
• Osteosarcoma Lung Metastasis Research Publication: https://pubmed.ncbi.nlm.nih.gov/37676378/
• Prostate Cancer Bone Metastasis Statistics: https://www.sciencedirect.com/science/article/pii/S0046817700800350?via%3Dihub

References: Relevant NIH grant numbers: R01CA300732-01A1 (Davies), R01CA310177 and R01DE035326 (Bertassoni).

Image Credits: OHSU/Christine Torres Hicks

Keywords: Bone cancer, osteosarcoma, prostate cancer metastasis, organs-on-a-chip, microphysiologic systems, biofabrication, tissue engineering, biomedical engineering, cancer metastasis, microfluidics, MCL-1 protein, cancer therapeutic development

Hepatocellular carcinoma remains one of the deadliest cancers worldwide due to its aggressive nature and limited treatment options. One of the critical challenges in studying HCC has been the inability to faithfully replicate the tumor’s microenvironment ex vivo, which includes not only cancer cells but also surrounding stromal cells, immune components, and the extracellular matrix milieu. Traditional two-dimensional culture systems fail to offer the spatial and biochemical complexity required to understand tumor-stroma interactions, immune modulation, and drug responses. The newly developed microenvironment-on-a-chip overcomes these obstacles by integrating multiple cell types within a dynamically perfused microfluidic device that recapitulates HCC’s structural and functional attributes.

At its core, the chip technology advances beyond static culture by introducing a finely tuned microfluidic network that simulates blood flow conditions, enabling nutrient and oxygen gradients similar to those found in vivo. This feature is crucial since tumor hypoxia and metabolic heterogeneity significantly influence HCC progression and therapeutic resistance. By incorporating liver-specific endothelial cells, stellate cells, and immune cells alongside carcinoma cells, the model allows for real-time assessment of cellular crosstalk under physiologically relevant shear stress and chemical gradients. Such dynamic interactions are pivotal in tumor growth, angiogenesis, and immune evasion.

The study highlights detailed characterization of the tumor microenvironment simulated on the chip, including extracellular matrix remodeling and cytokine profiles characteristic of liver malignancies. Using high-resolution imaging and transcriptomic analyses, the researchers verified that the tumor cells on-chip expressed hallmark molecular signatures of HCC and exhibited phenotypic behaviors such as invasiveness and proliferation rates comparable to clinical observations. Intriguingly, immune cell infiltration patterns were also faithfully mirrored, providing novel insights into the tumor-immune interface that are difficult to capture with conventional models.

By harnessing this technology, researchers demonstrated the ability to simulate and dissect the multifaceted responses of HCC tumors to various chemotherapeutic agents and immunotherapies. Rather than relying on static endpoint measurements, the chip enables longitudinal monitoring of drug efficacy and resistance evolution by tracking changes in cell viability, migration, and secretome dynamics over time. This capability ushers in a new era of personalized medicine approaches for liver cancer, where treatments can be tailored and optimized using patient-derived cells within these microengineered platforms.

Incorporating patient-specific biopsies into the organ-on-a-chip system opens doors for precision oncology applications. It empowers clinicians and researchers to generate bespoke tumor models that account for genetic and epigenetic heterogeneity, ultimately predicting individual patient responses to therapy with a level of accuracy unattainable by current preclinical models. Moreover, the scalability of the chip design promises potential for high-throughput drug screening, accelerating the discovery of novel anticancer compounds and combination regimens that are effective against resistant HCC subtypes.

The integration of microengineering, cell biology, and computational modeling was critical to the success of this platform. Sophisticated design considerations ensured optimal cell compartmentalization, mechanical properties consistent with hepatic tissue, and modulation of biochemical signaling pathways to authentically mimic the chronic inflammatory and fibrotic cues that often accompany hepatocellular carcinoma development. These technical refinements reflect a maturation of organ-on-a-chip technology from proof-of-concept to application-ready systems in cancer biology.

Furthermore, the microfluidic chip also facilitates exploration of metastasis and cancer stem cell niches within HCC. By manipulating spatial configurations and fluid shear forces, the study elucidates mechanisms by which tumor cells detach, invade surrounding matrices, and potentially intravasate into bloodstream analogs within the device. Understanding these steps under controlled conditions lays foundational work for strategic intervention points that may inhibit HCC dissemination and improve patient prognoses.

The multidisciplinary approach adopted by the authors merges experimental data with computational analyses of signaling networks, metabolic fluxes, and immune cell dynamics, paving the way for predictive modeling of tumor evolution and therapeutic outcomes. These insights provide a systems-level perspective crucial for designing next-generation therapeutics that target not just tumor cells, but the entire ecosystem that sustains malignancy and mediates drug resistance.

Importantly, this development addresses ethical and logistical drawbacks of animal models by providing human-relevant results without the complexity and variability often seen in in vivo systems. This paradigm shift aligns with global efforts to reduce animal testing and enhance translational fidelity from bench to bedside, ultimately accelerating clinical advancements for HCC patients worldwide.

Looking forward, the authors suggest that continued refinement of the model—including integration of vasculature-on-a-chip components, immune checkpoint modulations, and real-time biosensors—could further elevate the platform’s utility. Such enhancements will enable comprehensive dissection of therapeutic mechanisms, synergy effects, and emergent resistance patterns with temporal resolution previously unattainable, heralding a transformative era in cancer research.

This microenvironment-on-a-chip represents not only a technological triumph but also a conceptual leap in oncology, fundamentally redefining how complex liver tumors can be studied in controlled yet biologically faithful settings. The convergence of this platform with personalized medicine, high-throughput screening, and computational oncology promises to deliver breakthroughs in diagnosis, prognosis, and treatment strategies that save lives and improve quality of life for millions affected by hepatocellular carcinoma.

In light of these findings, the broader scientific community is poised to embrace organ-on-chip systems as indispensable tools for studying tumor biology. As the study by Mocellin and colleagues demonstrates, bridging the gap between microengineering and cancer biology opens fertile ground for innovation with profound clinical implications.

Ultimately, this advance underscores the vital importance of interdisciplinary collaboration to tackle the formidable challenge presented by hepatocellular carcinoma—a malignancy notorious for its complexity and therapeutic intractability. With sustained research and development spurred by this new model, a future where HCC can be routinely studied, understood, and effectively managed at the individual patient level draws increasingly near.

Subject of Research: Modeling hepatocellular carcinoma and its tumor microenvironment using organ-on-a-chip technology.

Article Title: Modeling hepatocellular carcinoma and its microenvironment on a chip.

Article References:

Mocellin, O., Treillard, S., Robinson, A. et al. Modeling hepatocellular carcinoma and its microenvironment on a chip.
Cell Death Discov. (2025). https://doi.org/10.1038/s41420-025-02917-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02917-8