The Three-Cell Problem: How Justin Jadali Studies the Biology Behind Microvessel Formation

Building a blood vessel from scratch requires more than the right materials. It requires the right cells — in the right arrangement, communicating with each other through the right signals. Tissue engineers who work on vascularization quickly discover that the biology of blood vessel formation is not a single-cell story. It involves a coordinated cast of cell types, each with a distinct role, and the interactions between them are as important as the behavior of any one cell in isolation. Justin Jadali, a researcher at Yale University studying microvessel self-assembly in engineered tissue, works at the center of this multi-cellular problem.

 

Why Vascularization Is the Central Problem in Tissue Engineering

The mechanics of the problem are straightforward, even if the solution is not. Every cell in living tissue must sit within roughly 200 micrometers of a blood vessel to receive adequate oxygen and nutrients by diffusion. Below that threshold, cells survive. Beyond it, they do not.

For thin tissue constructs — a single cell layer, a thin membrane — diffusion alone is sufficient. For anything thicker, it is not. The inability to vascularize thick engineered constructs is the primary reason tissue engineering has produced functional thin tissues — skin grafts, corneal replacements — while thicker, more complex organs have proven far more difficult to engineer for clinical use. Heart tissue, liver tissue, kidney tissue: each requires a dense, hierarchical vascular network to function. Without one, any thick construct implanted in the body will undergo necrosis at its core before the surrounding vasculature can grow in.

The field has pursued two broad strategies in response. The first involves pre-vascularizing constructs before implantation — engineering vascular networks into the construct itself. The second involves designing materials that recruit the body’s own vessels to grow into the construct after implantation. Jadali’s research engages with the first approach: studying how to promote microvessel self-assembly within engineered constructs using alginate microparticles and a defined set of cell types.

 

The Three Cell Types at the Core of the Work

Microvessel formation — the spontaneous organization of cells into vessel-like tubular structures — is driven by the coordinated activity of three cell types: endothelial cells, pericytes, and fibroblasts. Jadali’s research uses all three. Understanding what each contributes clarifies why the system works the way it does, and why studying their interactions is the central scientific question.

Endothelial cells are the primary architects of blood vessels. They line the interior of every vessel in the body — from the aorta to the smallest capillary — and they are responsible for forming the tubular structures that define a functional vascular network. In culture, endothelial cells are capable of organizing into vessel-like structures on their own under certain conditions, but those structures are typically unstable and short-lived without the support of other cell types. The presence of endothelial cells in the system is non-negotiable. They are the structural unit of the vessel.

Pericytes are perivascular support cells that wrap around capillaries and small vessels, providing mechanical stabilization and paracrine signaling that promotes vessel maturation. A capillary stabilized by pericytes is more durable and better regulated than one formed by endothelial cells alone. Pericyte coverage is one of the markers used to assess whether a newly formed microvessel network is maturing into a stable, functional state rather than remaining in a transient, immature configuration. Their presence in a tissue engineering system is what differentiates preliminary vessel-like structures from something closer to a stable network.

Fibroblasts provide the stromal — or connective tissue — context within which the vascular network forms. They produce extracellular matrix components, secrete growth factors that promote endothelial cell behavior, and contribute to the mechanical environment of the construct. Fibroblasts do not form vessels, but they create the conditions in which vessel formation is possible. In vivo, the relationship between fibroblasts and endothelial cells is essential to wound healing, tissue remodeling, and vascular development. In engineered constructs, fibroblasts serve a similar function: they are the supporting environment, not the structure itself.

The three-cell system is not arbitrary. It reflects the actual cellular composition of vascularized connective tissue, which is why it produces more physiologically relevant vessel formation than simpler, single-cell approaches.

 

How Microparticles Enter the Picture

Jadali’s contribution to this system is the alginate microparticle — a small, crosslinked hydrogel bead embedded within the gel matrix alongside the three cell types. The microparticles are not passive. Depending on how they are fabricated, they release ions, present mechanical cues, or alter the local biochemical environment in ways that influence how the surrounding cells behave.

His current experiments compare two crosslinking conditions: calcium and zinc. The difference matters because these ions do not behave identically in biological environments. Calcium is a ubiquitous signaling ion in mammalian physiology — it is involved in cell adhesion, cytoskeletal organization, and numerous signaling cascades, including those relevant to endothelial cell behavior. Zinc has a distinct biological profile; it is a cofactor for hundreds of enzymes and plays roles in cell proliferation, apoptosis, and immune function.

When alginate microparticles crosslinked with calcium or zinc are placed in the three-cell culture system, they introduce different ionic conditions into the local microenvironment. Those conditions, in turn, may promote or inhibit microvessel self-assembly by influencing endothelial cell organization, pericyte recruitment, or fibroblast matrix production. Determining precisely how — and how much — is the experimental question Jadali is working to answer.

 

Microscopy as the Primary Measurement Tool

Understanding how cells respond to the microparticles requires seeing what they do. Jadali uses microscopy to visualize microvessel formation, capturing images of the three-cell system over time to assess whether vessel-like structures form, how they branch, how they mature, and whether pericyte coverage develops.

Microscopy in this context is both a skill and a discipline. Images must be acquired consistently — same settings, same timepoints, same fields of view — to allow meaningful comparison across experimental conditions. Analysis requires distinguishing true vessel formation from nonspecific aggregation, quantifying network characteristics such as branch length and junction density, and interpreting what the images show in light of the underlying biology.

For Jadali, whose research depends on being able to compare calcium-crosslinked and zinc-crosslinked conditions with confidence, the quality of the imaging data is inseparable from the quality of the conclusions. This is where his emphasis on standardized protocols and careful experimental design connects directly to the biology: if the measurement process introduces variability, the biological signal is obscured.

 

What the Research Is Actually Trying to Establish

The practical goal of Jadali’s research is to identify a material design parameter — specifically, crosslinking ion identity — that reliably influences microvessel self-assembly in a defined, reproducible way. If calcium-crosslinked microparticles consistently promote more robust vascular network formation than zinc-crosslinked particles, or vice versa, that is a finding with direct implications for how tissue engineers design the biomaterial component of vascularized constructs.

It is a specific question, deliberately scoped. Grand claims about tissue engineering applications tend to outpace what the underlying science can currently support. What Jadali’s work contributes is not a clinical product but a mechanistic data point — a controlled comparison that answers, under defined conditions, whether the ionic environment created by a particular microparticle crosslinking strategy influences how endothelial cells, pericytes, and fibroblasts organize themselves into vessel-like structures.

That kind of data point is the currency of early-stage research. It is what allows the field to build progressively more sophisticated systems, each generation of experiments grounded in what the previous one demonstrated. A researcher who generates clean, reproducible data on a well-defined question contributes more to the field’s long-term progress than one who attempts a broader question without the experimental infrastructure to answer it rigorously.

 

A Research Profile Grounded in Both Engineering and Biology

What distinguishes Jadali’s position in this work is that he approaches the cellular biology from an engineering foundation — not as a biologist who learned to fabricate materials, but as a mechanical engineer who deliberately acquired the biological knowledge required to work meaningfully on this problem. His year of biology and year of organic chemistry at UCLA, taken alongside his mechanical engineering degree, were preparation for exactly this kind of research: one where the relevant questions sit at the interface of material properties and cellular behavior.

Understanding why endothelial cells respond differently to calcium and zinc requires both chemistry and cell biology. Designing microparticles that deliver a controlled ionic stimulus requires materials science and fabrication precision. Imaging and quantifying the resulting vascular networks requires microscopy competence and analytical rigor. Jadali has worked to develop all of these capabilities, which is what allows him to participate meaningfully at each stage of the research process rather than contributing only to one.

The three-cell problem — how to get endothelial cells, pericytes, and fibroblasts to form stable microvessels in an engineered construct — is one of the foundational challenges in tissue engineering. Jadali’s research does not solve it. What it does is produce rigorous, material-specific data that the field can use to make better decisions about how to design the biomaterial environment in which that biology occurs.

 

About Justin Jadali

Justin Jadali is a mechanical engineer and biomedical engineering researcher specializing in tissue vascularization, biomaterials, and microvessel self-assembly. He holds three Associate of Science degrees from Irvine Valley College and a B.S. in Mechanical Engineering from UCLA (Class of 2025). He is currently completing his M.S. in Mechanical Engineering and Materials Science at Yale University, where his research focuses on alginate microparticle fabrication, calcium and zinc crosslinking systems, and the behavior of endothelial cells, pericytes, and fibroblasts in 3D gels and bioprinted skin constructs. He serves as a Teaching Assistant for the Yale Mechanical Engineering Capstone and is based in New Haven, Connecticut.