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Engineering biomaterials, culturing tolerance.

From Holly’s lab diary:

Prior to joining the Segura Lab, my world was in the operating room. As a surgery resident at Duke, I’ve performed many procedures, and as you know, surgery requires cutting through the patient’s healthy tissues to gain access to internal structures. After we close them up, the wound healing process begins and usually a scar forms – but in some unfortunate cases, the wound never properly heals and takes much longer to close. We are trying to understand the molecular signals that lead to healthy wound healing and a return to normal function.

Before I was a surgeon, I spent my PhD investigating the roles of adult stem cells as well as their anti-inflammatory properties, and I later learned that biomaterials could be designed to mimic the pro-healing actions of stem cells. Since I was drawn to transplantation surgery during residency, I became interested in developing a biomaterials-based approach for improving the immune response to soft tissue transplants – and this brought me to the Segura lab. When I first approached Prof. Segura, I was struck by her welcoming attitude toward new applications of her MAP hydrogel technology. Although she was not familiar with the challenges of soft tissue transplantation, I explained what I wanted to do, and she was immediately on board. The plan is to use MAP scaffolds to promote immune tolerance. As you may have already read, MAP scaffolds promote blood and lymphatic vessel formation in healing tissues, both of which are critical processes in reconstructive and transplant surgeries like skin grafting and kidney transplantation, respectively.

Skin grafting (my current topic) is a cornerstone of reconstructive surgery. Over 160,000 skin grafts are performed annually for patients after burns, trauma or vascular disease (Serebrakian, et al. Plast Reconstr Surg Glob Open, 2018). Despite various FDA-approved dressings, up to half of skin grafts are rejected. Repeated skin grafting requires multiple surgeries, which increases risk of morbidity and mortality. Although a variety of cadaveric and synthetic alternatives exist, they are limited by allogeneic responses, dysregulated inflammatory reactions, worse scarring, poor functional outcome, and just overall lower quality of life. My research aims to improve the outcome of soft tissue reconstruction through the development of hydrogel biomaterials that can coordinate the interactions of immune cells to improve tolerance in the wound bed of allotransplantation.

If working on a biomaterials-based approach to promote tolerance in soft tissue transplants is of interest to you, contact us and add in the message that you’re interested in my project! #holly #culturingtolerance

Extending the window for cellular change

We’ve explored this approach the most. During the latter stages of wound healing, the microenvironment is in a state of endogenous plasticity, which means the tissue is still undergoing changes as it heals. The goal here is to place materials into wounds that extend the plastic time period by recruiting progenitor cells and other important factors. We primarily do this by designing materials that promote blood vessel formation. Blood vessels are a key component in tissue repair – they deliver important nutrients, regulate the immune response, and guide cell migration and tissue deposition. By maintaining and controlling the process of vessel formation with our materials, we’re thinking we can extend the window of plasticity and promote tissue regeneration. You can learn more about our approaches to promote vessel formation by reading the articles on Our Publications page that deal with therapeutic angiogenic material (filter by Topic: angiogenesis)!

Another way we’re extending endogenous plasticity is by designing materials that allow for rapid cellular infiltration while maintaining structural support. We do this by forming a microscopic scaffold made of packed hydrogel microparticles that are stuck together, which forms pockets of void space that are large enough for cells to fit. Alright, you guessed it – we’re describing MAP… you might as well read about it here.

Glycobiology of stroke

From Juhi’s lab diary:

Did you know that our body uses sugars to regulate its activity? In the brain, sugar molecules are everywhere – they’re attached to biomolecules and covering all of the cells. Sugars, which are called glycans in our world, can help cells communicate with each other and with their environment. And cells will display different glycans depending on their current state. As you may imagine, the glycans that get added and displayed during disease or injury are different to those that get displayed during a healthy state.

I am interested in understanding how glycosylation changes with aging and after a stroke, and I want to understand if part of the success of our previous materials are because of changes in the glycosylation profile. My ultimate goal is to design novel glycan-decorated materials to promote recovery after stroke.

If you’re a student who agrees that glycans > proteins and nucleic acids and you’re interested in their impact on stroke recovery, contact us and add in the message that you’re interested in my project! #juhi #sweetbrain

Microporous annealed particles (MAP) scaffolds

The magic of MAP comes from interlinking the HMPs in a granular scaffold so that the particles get stuck in place. There are many, many different techniques for doing this, but the very first MAP scaffold was designed to naturally crosslink in the body. This was great because it meant we could load a syringe with HMPs, inject into the body to form a granular scaffold, then wait for the body’s natural clotting factor to chemically link the particles together. Since then, we’ve also become fond of interlinking using UV light. The benefit of interlinking (or annealing) HMPs is that we create a stable structure that sticks around for longer and makes cells extra happy. We’ve seen MAP scaffolds promote aspects of wound healing in disease models like stroke, myocardial infarction, skin wounds, and spinal cord injury. And once the MAP scaffold has completed its job, it naturally gets degraded by the body.

Inter-subunit descriptors

We have 7 descriptors that measure features of the scaffold that do not refer to the subunits of the space – hence the term ‘inter-subunit’ because they exist between or across multiple subunits. (Recall that subunits are the pockets of empty space throughout the scaffold.) For example, we study pathways that can be traveled by cells inside the scaffold. The measurements taken for each pathway give rise to inter-subunit descriptors.

Return descriptor data

LOVAMAP does some powerful computing to generate an ever-growing list of descriptors that quantitatively characterize the MAP scaffold. These measurements describe features of the void space between the particles, the pathways throughout the scaffold, integrin-binding hotspots, and more. By quantifying the microarchitecture of our scaffolds, researchers can study how scaffold geometry affects other measurable properties, like infiltrating cell behavior and material mechanics. Ultimately, these types of analyses will help us optimize our material for the best possible therapeutic effect.

Generate images and GIFs

Coming soon!

Global descriptors

LOVAMAP computes 12 global descriptors for each scaffold. ‘Global’ refers to the fact that a single value is reported for the descriptor, which captures information spanning the entire scaffold. For example, the most common global descriptor reported in the literature for granular biomaterials is Void-Volume Fraction, where the top of the fraction is the volume of scaffold that’s occupied by empty space and the bottom of the fraction is the total volume of the scaffold.

Subunit descriptors

Coming soon!

Outer porosity

Coming soon!

Hydrogel microparticles (HMPs)

The first step is to design the particles that compose our MAP material. Each particle is actually a network of entangled polymers (like a microscopic hairball), and we typically work with hydrogel polymers that swell in water – hence the term HMPs. The process starts with some good ‘ole polymer chemistry, where we customize our material to fit the therapeutic application. Once the polymers are just right, we form them into the desired shape, then lock the shape into place through a process called polymerization. Most of our MAP experiments use spherical HMPs produced through emulsion or microfluidic techniques, but we’ve been experimenting with other shapes as well. (I know we just dropped some technical terms, so if you’re unfamiliar and want to learn more about HMPs, click here, we won’t tell anyone 🤫)

Inner porosity

Coming soon!

Granular scaffolds

The word ‘scaffold’ implies a supporting structure or framework, so at this step, we’re creating a framework using the HMPs as building blocks. The term ‘granular’ has a specific definition as well, but we’ll leave you to read this review for the nitty-gritty details. The take-home point is that granular materials transition from a ‘liquid-like’ state to a ‘solid-like’ state when particle jamming occurs – so to create a solid structure from HMPs, we pack them together. Now we have a granular scaffold with empty space in between the particles to support cell ingrowth. But remember, a granular scaffold is just a collection of particles jammed together, so it’s still a dynamic system where everything can slosh around.

Wound healing

We are inspired by our body’s ability to heal. This occurs through a process called endogenous regeneration, which takes advantage of the activation of ‘plasticity’ upon injury. Plasticity is the ability to transform local cells into tissue factories that produce extracellular matrix and other multicellular structures that got destroyed. The goal of plasticity is to produce brand-spanking-new tissue. As you may have guessed, these pathways are usually dormant and only awaken once the body recognizes that an injury has occurred. So this begs the question – if tissues have the ability to fix themselves back to working order, why do some injuries cause permanent damage? This is because there are two competing forces in healing: plasticity and scarring. Scarring is a pro-survival mechanism that evolved to ensure that we survive an injury. Regenerating tissue takes time and resources – time that we may not have if the injury starts inhibiting important bodily functions or introducing deadly bacterial infections. Thus, at the same time that pro-regenerative pathways are activated to promote functional recovery, there are also pro-survival mechanisms activated that favor a quick-fix. Usually, scarring wins, and scar tissue gets deposited that is not completely functional.

Our main goals are to 1) scale-down scarring so that our tissues have a chance to regrow, and 2) deliver key signals that promote tissue regeneration. Luckily we know that our body actively works to repair itself after injury, so we only have to deliver the pro-healing components that are low or lacking in the wound environment. And the good news is that biomaterials can be designed to do just that – modulate the pathways that are responsible for scarring, while at the same time deliver key therapeutics to promote functional tissue deposition.

Extract spatial landmarks

LOVAMAP relies on accurately identifying key spatial landmarks within the void space of MAP scaffolds. These landmarks are subtypes of the medial axis, which are central locations in space, and they serve as a starting point to orient LOVAMAP to the space. Our custom algorithms are highly effective at locating these landmarks because we takes advantage of information stored within the graphical representation of granular material. Once the information has been stored, we’re ready to start dissecting and analyzing the MAP scaffold.

Heterogeneity

MAP is a collection of tiny particles, but nobody says we have to use the SAME particles throughout our scaffold. In fact, having the option to easily combine different types of particles into one scaffold is a big plus with our material. We can include particles of different shapes, sizes, and stiffnesses…made from different polymers…with different degradation rates…carrying different types of drugs… Really the world is our MAP-oyster! And not only can we precisely choose the proportion of these particle types, but we can also vary where in the scaffold they lie. Do you want everything to be mixed like rainbow Dippin’ Dots? Do you want particle types to be nicely layered like a cake? You choose. This is all to say, the heterogeneity offered by MAP allows for a highly personalized, versatile therapeutic material.

Injectability

In the same way that it would be difficult to fit a sponge into a needle, it’s difficult for a non-granular matrix to be injected. And if something can’t be injected, then getting it to the right place might require some surgery. Luckily MAP is granular, so all of the tiny particles can fit inside a syringe. And – thanks to the concept of particle jamming – after injection, the particles reform into a scaffold that perfectly conforms to the shape of the wound. Once the material has been deposited, the last step is to perform some chemistry magic to interlink the particles so they don’t go anywhere. The injectability of MAP makes it much more convenient for physician’s to use, and patients can avoid undergoing unnecessary surgery – everyone wins!

Stroke variation by age and sex

From Kevin’s lab diary:

As you have probably guessed by looking at our website, my lab is interested in coming up with new approaches to reduce the physical disability caused by stroke. However, before getting into material development, I became interested in the differences across sex and age when treating stroke. All of our previous work was studied in young male mice, so we don’t know how well our technology works in female mice or old mice. It’s important to study our materials in all contexts so that we can identify any differences among patient groups and develop therapies that work for everyone who needs them.

Aside from sex and age, my work focuses on further development of a dual-function angiogenic biomaterial, CLUVENA, that previous lab members developed (Sean, Shiva, and Lina). When injected intracranially into the stroke cavity, CLUVENA can both restore blood vessel density and decrease inflammation. This material was also able to reduce physical disability in a rodent model of stroke. My goal is to better understand the mechanism of action of CLUVENA in order to design a novel approach that further reduces physical disability. I also want to make sure our materials can be easily manufactured, shipped, and stored.

If you’re a student who wants to work on cutting-edge technology in the stroke recovery space, contact us and add in the message that you are interested in my project! #kevin #stroke

CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

Non-invasive therapeutics

We’re motived to develop non-invasive treatment options so that patients can avoid invasive surgical procedures whenever possible. Although surgery is oftentimes the best and only option for treating a condition, the process introduces secondary surgical wounds that both increase the risk for bacterial infections and also require additional energy and resources to heal. Technological advances are tending toward minimizing how much cutting has to be done, but even in the field of biomaterials, surgical procedures are often required to implant therapeutic materials. This is because many products on the market are bulk materials, such as sponges or mesh sheets, that have to be cut to the appropriate shape and physically placed into the wound site.

Our lab has been focused on a different approach – generating materials that are flowable so that they can be injected via needle or catheter to the target location without the need for extensive surgery. Even for sites that are easily accessible, such as skin wounds, our flowable materials offer a benefit because upon injection, they naturally fill the shape of the wound for a seamless interface between the material and surrounding tissue – even if the tissue is moving!

Aside from injectable hydrogel materials, we are also working on intravenous (IV) delivery and transdermal delivery of nanoparticles. IV delivery is a very common route of administration for many therapeutics today, so it makes sense to use this approach when delivering nanosized materials. Transdermal delivery across the skin barrier removes the need for needles and enables home therapy using patches. Of course, the skin has evolved to be a tough barrier to penetrate, so we need to outsmart evolution and find a side door.

Ninjabyte Computing

If you’ve ever watched a Marvel movie or played a video game like Witcher 3, you know graphics have come a long way. But you may not know how much serious math and research goes into 3D animation. Technologies in simulation and visual effects are incredibly powerful, yet most scientists don’t have access to them because software engineers in animation don’t often chill with scientists. Ninjabyte Computing was founded to connect the science community with high-performance animation tools used in industry.

The company is headed by Peter Cheng, PhD, who offers the perfect blend of expertise in mathematics, computer science, and animation. Ninjabyte Computing uses professional visual effects software, like SideFX Houdini, to generate physically-accurate simulations of randomly packed particles with varying shapes, sizes, stiffness, and textures. These simulations are fantastic mimics of a range of MAP scaffold types, which makes the data perfect to analyze with LOVAMAP in order to study our scaffolds. Ninjabyte Computing also renders beautiful images and videos of our material to help explain our work. One of their images was featured on the cover of Nature Materials!

While our collaboration focuses on MAP simulations, this only scratches the surface of animation technology. We’re happy to share the love for Ninjabyte, and we recommend reaching out to ninjabytecomputing@gmail.com for any inquiries.

Biomaterial scaffold

A biomaterial scaffold is exactly what it sounds like – a structure made from building blocks that provides support. In this case, the building blocks we use are nanoscopically small because our scaffolds interact with tissue at the microscopic level. The scaffolds act as a supplemental extracellular matrix that provides physical support in compromised tissue, and they also serve as a framework to help nearby cells move around and do their job. You can see below that a typical scaffold looks like a little slab of clear Jello.

The scaffold itself can also behave as a drug and influence biological processes in the tissue surrounding it. This is possible because cells in the tissue are mechanoresponsive, which means that they can sense the structural features around them and respond to any changes. We can engineer the structural features of our scaffold to influence cell behavior, which leads to therapeutic action.

When we make scaffolds out of hydrogel microparticles and link these particles together, we create MAP – but you can read more about that here.

Read in formatted data

LOVAMAP is a software designed for analyzing granular material. For this reason, LOVAMAP takes in a specific data format that highlights individual particles – basically each voxel (3D pixel) associated with a particular particle should be labeled with a unique identifying number. This ensures that our software is analyzing exactly what you intended. Alternatively, if you’re simulating spherical particles with a known center and radius, go ahead and input the sphere data – our code can handle it.

Re-opening the window for cellular change

The most difficult wounds to treat are those that are chronic or well-past the phase of endogenous plasticity – when tissue is still being remodeled. For these wounds, we want to re-activate plasticity so that the body has another opportunity to heal itself properly. As you can imagine, this is harder to achieve than when wounds are still fresh in the acute or sub-acute phase. Our strategy is to first identify the molecules that are present in wounds during endogenous plasticity. We will then introduce materials that induce blood vessel formation as a source for replenishing the molecules that are present during plasticity. The goal is to determine the minimum molecular signals needed to re-open the window for cellular change.

Tweaking the immune system

The goal with this approach is to design materials that communicate with our body’s immune system and urge it to generate a lasting pro-regenerative response in the wound. The immune system is most commonly known for helping us fight disease. When external objects enter our body, specialized cells will recognize them as foreign and trigger a specific immune response depending on the type of invader. Viruses, for example, often trigger a danger! danger! response that causes the immune system to produce antibodies against the virus for long-lasting defense. This means you’re protected from getting sick if you get infected with the same virus again. Materials made in lab, however, don’t always elicit the same immune response, which means our materials can be explicitly engineered to tweak the immune system in a certain direction.

It turns out that in addition to fighting foreign invaders, immune cells are also primary players in healing the body. Inflammation, for example, is an early-stage part of wound healing that relies on the hustle and bustle of immune cells. As you probably know, too much inflammation can be a bad thing that actually delays healing. This is why RICE (Rest, Ice, Compression, Elevation) is used to treat twisted ankles and sprained knees. RICE helps keep inflammation down and is often accompanied by the administration of anti-inflammatory drugs such as ibuprofen, which helps our body heal faster. I’m sure it comes as no surprise that modulating inflammation is one of the key features of our materials. In fact, it has recently been discovered that the same cells involved in creating immunity against viruses could be used to promote healing, so we’re learning how our materials can transition from controlling inflammation to generating long-lasting immune responses.

LOVAMAP: LOcal Void Analysis of MAP scaffolds

From Lindsay’s lab diary:

I get the fun computational project in the lab 😀 Remember that our MAP technology is a bunch of interlinked particles… Well cells like to crawl into the empty space (or void space) between the touching particles, and once inside, they start checking out the new pad. Is it too tight? Are the walls too stiff? Depending on what they find, they’ll change their behavior accordingly. We want to better understand how cells interact with the void space of our MAP scaffolds because influencing cell behavior is the key to therapeutic success.

The goal of this computational project is to develop software that can analyze microscope images of real MAP scaffolds and return data that describes geometrical features of the scaffold. As a starting point for this goal, we are working with simulated MAP scaffolds that are created by running powerful software to simulate spheres falling into a container. This requires knowledge about animation software, and it doesn’t hurt to have a mathematical background. Once we have our simulated scaffolds, we can move forward with void space analysis.

LOVAMAP is the name of our current software package that takes in simulated MAP scaffolds and segments the void space into natural pockets of open space. The software then performs numerous computations to characterize the space. This is an ongoing project because we are continually looking for bigger and better metrics to describe local geometry that capture more complicated features like curvature.

The next stage in this computational work will incorporate machine learning techniques to convert microscope images of MAP into formats that can be read by LOVAMAP. We are also simulating more advanced particles shapes, stiffnesses, and textures. In the future, we plan to use mathematical modeling to study fluid flow and cell migration within the void space.

If you’re a student who wants to apply your math and coding skills to questions in wound healing, contact us and add in the message that you’re interested in my project! #lindsay #computational

Injectable and long lasting delivery of genes to brain tissue

From Evan’s lab diary:

You all are probably very familiar now with the goals of non-viral gene delivery after the pandemic. If you are not, then great. I get to give you some new information. The goal of gene delivery is to use genetic information (like mRNA or DNA) as drugs. Our cells are designed to know what to do with genetic material, so if you can get this material to the right cellular compartment, the cell will use it as intended – generally to make a therapeutic protein. In the case of COVID vaccines, either mRNA or DNA was delivered depending on the manufacturer. But in all cases where genetic material was delivered, the vaccine expressed the spike protein of the SARS-CoV-2 virus, and this spike protein was able to give us immunity against COVID-19. The difficulty has been to deliver enough genetic material to the right cellular compartment so that enough therapeutic protein is expressed to reach the required dose.

My lab has worked for over a decade on approaches to deliver genetic material from hydrogel biomaterials (heck even my advisor’s thesis was on this topic, along with past lab members Leo, Quinn, Talar, Anandika, Cynthia, and Norman). These approaches have led to high levels of protein expression in vitro, but not in test animals. Also, previous approaches did not load genetic material into injectable gels…and just like a vaccine, if our gene therapy isn’t injectable, it limits applicability. My thesis work is focused on improving our delivery strategies to achieve effective genetic material delivery from injectable hydrogels into the brain. Once this is achieved, my goal is to express proteins that can regulate endogenous protein expression of pro-repair factors to promote recovery after stroke.

If you’re a student who recognizes that non-viral gene delivery is trending, contact us and add in the message that you’re interested in my project! #evan #genedelivery

Using pro-repair matrices to fight cancer

From Alex’s lab diary:

My lab primarily works on designing novel biomaterials to help heal our body after injury or disease. So, when I first approached Prof. Segura about wanting to work on cancer, she was not super receptive. She eventually said that if I could figure out how to use our pro-repair matrices for cancer, then she would be ok with it. It turns out that using pro-repair matrices to fight cancer is a brand-new approach that has only begun in the last decade! This approach treats cancer as a wound that won’t heal and uses materials to change the tumor microenvironment towards a healing rather than inflammatory state. The tumor microenvironment has evolved to evade the body’s defenses so that it can grow without containment – meaning if one could normalize the tumor microenvironment so that the body can recognize it, then the body could prevent its growth and kill the cancerous cells. Our plan is to inject our material either inside the tumor core or in a resected-tumor cavity and use the material to promote tumor microenvironment normalization. In particular, I am focused on designing materials to promote normal vasculature so that therapeutics and host immune cells can penetrate the tumor core.

Since MAP scaffolds are a highly versatile biomaterial that have been shown to support cell growth, we are hoping they can be used to combat cancer as well. So far, we have experimented with different polymer types, as well as varying material stiffness, and our custom MAP scaffolds are already showing promising results – with more functionality on the way.

Our focus is on glioblastoma multiform, an aggressive brain cancer with particularly low survival rates. If you’re a student with a passion to fight cancer using pro-repair matrices, contact us and add in the message that you are interested in my project! #alex #healingcancer

Macrophages in repair and regeneration

From Yining’s lab diary:

When a material is implanted inside of our body, it’s recognized as a foreign object, which sets off alarm bells that call our immune system to investigate. If the material is determined to be a pathogen or dirty substance, our body rejects it and causes an inflammatory reaction that may lead to immunity against the material (like how the COVID vaccines work). However, if the material is not recognized as bad, then our immune response is much friendlier, and our body allows it to stick around in the tissue for a long time without any issue (take orthopedic implants, for example). One of our lab goals is to develop biomaterials that can guide the foreign body response towards regeneration – which is the ultimate form of wound healing. Previous work in our lab has shown that our traditional MAP scaffolds are somewhat immune-stealthy where they trigger a very minimal foreign body reaction that eventually resolves (similar to what is seen with hernia meshes). But what’s crazy is that even the smallest change to how we make MAP can set off alarm bells and call in the immune system.

At the risk of sounding nerdy…I have a favorite immune cell: the macrophage. Macrophage cells are such an important mediator in our immune system, and I’ve always been fascinated by their many roles in healing wounds. I want to understand how MAP can modulate macrophage phenotype toward different behaviors – like promoting wound closure vs. causing implant rejection. In particular, my thesis is following up on leads that suggest that the degree of confinement dictates the phenotype of macrophages. My work revolves around using the unique microstructure of MAP to answer questions related to immune activation and regenerative wound healing. I am also changing the biochemical properties of MAP to study its range from immune-stealthy to immune-reactive.

If you’re a student who is equally as intrigued by the role of microstructure on macrophage phenotype and wound healing, contact us and add in the message that you’re interested in my project! #yining #macrophages

Engineering components of the amniotic membrane for wound healing

From Drew’s lab diary:

Our lab uses hyaluronic acid (HA) as a base for many of our materials because it is naturally found in the human body and because it can be recombinantly produced, which makes it easier for translation. Finding natural ways to modify HA to introduce novel functionality would make it an even better material. One day Prof. Segura asked me to look into natural covalent modifications of HA. She knew that most modifications of hyaluronic acid are non-covalent, but she had come across a covalent modification. Although our original plan to use this chemistry to modify HA was not feasible (it was more complicated than we expected…), it turns out that the covalent modification of HA with proteins is involved in the scarless healing of the amniotic membrane. I was super intrigued with amniotic membrane biology, and I am basing my thesis on the design on synthetic placenta biomaterials. My goal is to use these matrices to promote scarless healing of skin wounds.

Since the amniotic membrane is used to promote healing of non-healing wounds, I will incorporate components of the amniotic membrane – which I will produce recombinantly – into HA hydrogels.

If you’re a student who’s excited about scarless healing and synthetic placenta biomaterials, contact us and add in the message that you’re interested in my project! #drew #syntheticplacenta

Modified building blocks

Our starting materials are hydrogel polymers, such as

hyaluronic acid
polyethylene glycol
poly(propylene sulfide)
heparin
poly(allyl mercaptan)

We chemically engineer these polymers to precisely fit our needs, like adding handles that allow the strands to link to one another and form a gel. Our polymer modifications include end-group modifications, side-chain modifications, and even attachment of biologically relevant ligands that make our materials more biocompatible and useful for therapeutic applications. We also use these polymers to create higher-level building blocks called hydrogel microparticles, which you can read more about on our MAP Scaffolds page.

In vivo work

In vivo studies are performed in a living organism and are an essential and exciting part of the research we do. These types of experiments are invaluable because they not only teach us about biocompatibility, but we also get the full effect of a living tissue. This means we gain access to the complicated signaling pathways that would be impossible to recreate in a test tube, and therefore, we get a complete picture of the healing process. Understanding our in vivo results bring us one step closer to developing a product that can help real patients.

During an in vivo study above, we injected one of our biomaterial scaffolds into a controlled skin wound.

Trapping the pro-repair environment

From Shangjing’s lab diary:

I’m currently a postdoc in the lab, and my previous PhD project revolved around designing biomaterials (actually MAP gels) for bone tissue engineering. I delivered stem cells from the material to promote bone formation. I joined the Segura lab because I wanted to learn from the creators of MAP scaffolds and challenge myself to design materials for neural applications, which is completely new to me. The project Prof. Segura proposed sounded really interesting, and with some reading, we have a really cool approach.

The fact that brain injury may actually help you learn new things fascinates me. This occurs through a process called plasticity. When we are first born, our brain is very plastic, and we are able to learn many new things. However, as we age, our brains are less plastic, meaning neurons in the brain aren’t able to form as many new pathways and connections. On the one hand, having our brains settle on stable connections helps us become good at things, but unfortunately, it also hinders us from picking up new things easily. It turns out that after injury, our body turns on plasticity as a way to heal the injury.

My project is to leverage this plasticity window with a ‘repair soup’ to promote healing after stroke. In particular, I am working on strategies that would trap locally-secreted plasticity-proteins into our biomaterial in an effort to extend the window of cellular change. The end goal of course is to reduce physical impartment caused by stroke.

If you’re a student who wants to work on promoting recovery after stroke – particularly using biomaterial approaches that sequester plasticity-proteins – contact us and add in the message that you are interested in my project! #shangjing #repairsoup

Do these lipids make my brain look fat?

From Briana’s lab diary:

I’m a chemist, and I love the art of synthesis – creating new polymers from scratch with unique designs. I also have experience making nanoparticles, so Prof. Segura and I discussed using nanoparticles as drug carriers that would target the brain after stroke. Before joining the lab as a postdoc, I worked on developing dendritic polymers that have both a hydrophobic (‘fat-loving’) and a hydrophilic (‘water-loving’) part, so I’m incorporating this chemistry into my current project. By using these amphiphilic polymers to form nanocapsules, we could not only co-deliver both hydrophobic and hydrophilic drugs, but we could also leverage the lipid (fat) content of the nanocapsules to cross the blood-brain barrier. In this way, our material could reach the brain through IV injection into the arterial system as opposed to direct injection into the brain, making it even less invasive.

After talking with Prof. Segura, I also learned that the brain is 50% lipids by weight. Lipids do much more than make us fat – they’re active players in signaling and normal tissue function. I’ll be reading and learning about lipid biology, especially in the context of stroke, so that I can guide my synthesis to include brain-active materials. By using self-assembling lipids, I aim to make nanoparticles that are entirely bioactive.

If you’re a student who has an inkling for chemistry and who wants to work on drug delivery to the brain after stroke, contact us and add in the message that you’re interested in my project! #briana #fatbiomaterials

Crosstalk between hydrogel microstructure, neuroprogenitor cells, and angiogenesis

From Kat’s lab diary:

My brain heroes are neural progenitor cells (or NPCs, for short). They are involved in brain repair and normal brain function to keep us sharp throughout our life, so I wanted to focus on them for my thesis work. Previous lab members (Elias and Lina) showed that our biomaterials can promote the proliferation (cell division) of NPCs as well as their migration into the material. My goal is to capitalize on these findings by further improving our material to promote NPC migration and to then guide the phenotype of these NPCs when they get to our material/stroke core. The end goal of course is to promote recovery after stroke by reducing the physical impairment observed after stroke.

Although their name would imply that NPCs become neural cells (e.g., nerves), I am interested in how these cells also play a role in blood vessel formation. There is a synergistic relationship between growing blood vessels in the brain and NPCs. Low blood vessel growth results in low NPC migration, but also NPCs secrete factors that are essential for blood vessel sprouting and maturation. My studies revolve around the use of MAP scaffolds as well as our VEGF delivery technology CLUVENA to promote NPC migration and vascularization. In addition, I am changing the physical and biochemical cues of the scaffold to modulate NPC phenotype and mature vessel formation.

If you’re a student interested in working on strategies to promote recovery after stroke focusing on NPCs and vascularization, contact us and add in the message that you’re interested in my project! #kat #brainheroes

VEGF – vascular endothelial growth factor
CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

In vitro work

In vitro studies are performed in the lab outside of a living organism – think test tubes and petri dishes. These types of experiments allow us to characterize important properties of our scaffolds, like how much they deform or how well the molecules we’ve attached get released. It also offers us the luxury of studying the effects of our material on specific phenomenon, like cell behavior and vessel growth, in a controlled environment. It’s basically Step 1 in understanding what we’ve created.

Look how our gel squishes during compression testing to measure its stiffness!

Ischemic Stroke Project

Ischemic strokes are characterized by a sudden stop of blood flow to the brain due to a clot. The lack of blood flow rapidly kills brain tissue leaving > 40% of patients with a physical disability. There are currently no therapies to decrease stroke related disabilities. Although all current therapeutic treatments for stroke are administered immediately after stroke onset and focus on preventing tissue death, our goal is to develop materials to treat stroke related disability that can be administered days to months after the stroke occurs. Our materials are delivered intracranially, directly into the stroke core, to promote and encourage the brain plasticity needed to form new brain tissue and reduce disability.

Although their name would imply that NPCs become neural cells (e.g., nerves), I am interested in how these cells also play a role in blood vessel formation. There is a synergistic relationship between growing blood vessels in the brain and NPCs. Low blood vessel growth results in low NPC migration, but also NPCs secrete factors that are essential for blood vessel sprouting and maturation. My studies revolve around the use of MAP scaffolds as well as our VEGF delivery technology CLUVENA to promote NPC migration and vascularization. In addition, I am changing the physical and biochemical cues of the scaffold to modulate NPC phenotype and mature vessel formation.

If you’re interested in working on strategies to promote recovery after stroke focusing on NPCs and vascularization, contact us and add in the message that you’re interested in my project! #kat #brainheroes

VEGF – vascular endothelial growth factor
CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

Stem cell delivery

Tbd

We injected MAP into a skin wound, and you can see cells infiltrating between the particles.

Stroke-induced disability

A stroke is like a heart attack of the brain – it occurs when oxygen can’t get delivered to the organ. But unlike a heart attack, a stroke will leave a patient with substantially increased risk for lifelong disabilities [1]. In fact, stroke is one of the leading causes of serious long-term disability in the United States [2], and in 2018 alone, over 7.8 million individuals suffered from a stroke [3]. Sadly, although thrombolytic drugs are used to minimize damage within the first few hours of stroke onset, there are no therapeutic drugs available to treat damaged brain tissue after stroke. Patients must therefore rely on rehabilitation efforts like physical therapy and video-assisted training to reduce their disability and regain independence.

After a stroke, the brain tissue that was starved of oxygen is irreversibly injured, and the body attempts to repair the injury by forming a scar – but scar tissue is no longer functional. Patient disability is the direct result of non-functional scar tissue at the stroke site. Rehabilitation efforts attempt to recover function by training the brain to rebuild neuronal connections that bypass the stroke site. The brain is an adaptive organ, so figuring out new ways to form connections without the original tissue is challenging, but not always impossible.

Instead of working around scar tissue, we’re motivated to develop a material that can be placed directly into the stroke cavity to promote endogenous tissue regeneration, which is the body’s way of rebuilding functional tissue after injury. Theoretically, the body has all of the tools necessary to replace injured tissue with healthy tissue, and our material will offer physical and chemical cues to help guide this process in the stroke cavity. The end-goal is minimal scar tissue and maximal functional recovery.

[1] Dhamoon MS, et al. (2017) Disability Trajectories Before and After Stroke and Myocardial Infarction The Cardiovascular Health Study. JAMA Neurology. 74(12): 1439-1445.

[2] Centers for Disease Control and Prevention (CDC). (2009) Prevalence and most common causes of disability among adults: United States, 2005. MMWR Morb Mortal Wkly Rep. 58: 421–426.

[3] NCHS, National Health Interview Survey, 2018. Table A-1a: 1-9.

Poorly healing wounds

We all know that tearing your skin creates a wound. And even though skin wounds are a pain (literally), most heal right up – possibly with the help of some stitches. But the bigger and deeper the wound, the harder it is for the body to heal. What’s worse – if a patient has an underlying disease that stunts wound closure, like diabetes, wounds are more susceptible to chronic inflammation, infection, and poor healing. For some perspective, in 2014 there were 8.4 million claims for wound healing related diagnosis codes in Medicare patients alone [1]. Although there is a long history of therapies that have been developed to improve wound healing (check out reference [2] below), there is no universal approach to treat the ones that fail to close up. This means that despite the thousands of products available, many individuals continue to suffer from painful, long-lasting wounds that severely impact their quality of life.

The challenge of fixing a disrupted natural process in the body motivates us to develop a biomaterials-based approach that can break the inflammatory cycle and turn a non-healing environment into a healing one.

[1] Nussbaum SR, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value in Health. (2018) 27 – 32.

[2] Han, G and Ceilley, R, 2017. Chronic wound healing: a review of current management and treatments. Advances in therapy, 34(3), 599 – 610.

Scarless healing

You could call this the Holy Grail of wound healing – everyone dreams of applying a topical cream that miraculously prevents scarring. It’s no wonder scar treatments are a $17.94 billion market [1]. But we’re motivated by more than cosmetic benefits. Many people hear ‘scar’ and think of visible scars that tell an interesting story. But scarring is a physiological process that can occur at any site of injured tissue, including internal organs. Think of scarring like the body filling up the injured site with cement. On the one hand, the cement (or scar tissue) has prevented further damage locally…but on the other hand, the region that contains the cement is no longer normal tissue, and it can’t function properly. Depending on the size and location of the scar, this can lead to compromised organ function and serious health issues.

The medical field is in need of a material that can prevent scarring and recapitulate* the native tissue environment. We are developing biomaterials that are intended to be placed in a wound prior to the formation of a scar. The goal is for our material to modulate the wound environment in a way that promotes normal tissue deposition while reducing scar formation. This means less cement and more healthy, functioning tissue.

[1] Grand View Research: Market Analysis Report. Scar Treatment Market Size, Share & Trends Analysis Report By Scar Type (Atrophic, Hypertrophic & Keloid Scars, Stretch Marks), By Product (Injectables, Topical, Laser), By End Use, And Segment Forecasts, 2019 – 2026.

* Fun fact: Lindsay in our lab was responsible for changing the official Merriam-Webster definition of the word ‘recapitulate’ to include the way scientists have been using it for years:

Wound healing

Tbd

We injected MAP into a skin wound, and you can see cells infiltrating between the particles.

Bells and whistles

We hate to be boring, so we’re always exploring new features to incorporate into our materials. Most of our scaffolds include additional bioactive signals that help make our material more effective at promoting healing, like:

peptides / proteins
nucleic acids
small molecules
cells

These additions can be used to attract and influence cells that make their way into the scaffold, or the material can be designed as a drug depot that releases factors at desired time points.

Above you can see DNA nanoparticles (highlighted in green) that have been loaded into a scaffold.

Sept 2015 – June 2019

Elias Sideris

Clearview Healthcare Partners

Elias obtained his PhD from the Segura Lab in 2019 with a thesis titled “Hydrogel scaffolds and their influence on the brain.” He is now a consultant at Clearview Healthcare Partners based in San Francisco.

Sept 2015 – June 2019

Elias Sideris

Clearview Healthcare Partners

Impact Factor:

02.02.20
Nature Materials

Hydrogel micopraticles for
Biomedical aplications

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Engineering biomaterials, culturing tolerance.

If working on a biomaterials-based approach to promote tolerance in soft tissue transplants is of interest to you, contact us and add in the message that you’re interested in my project! #holly #culturingtolerance

Extending the window for cellular change

Glycobiology of stroke

If you’re a student who agrees that glycans > proteins and nucleic acids and you’re interested in their impact on stroke recovery, contact us and add in the message that you’re interested in my project! #juhi #sweetbrain

Microporous annealed particles (MAP) scaffolds

Inter-subunit descriptors

Return descriptor data

Generate images and GIFs

Coming soon!

Global descriptors

Subunit descriptors

Coming soon!

Outer porosity

Coming soon!

Hydrogel microparticles (HMPs)

Inner porosity

Coming soon!

Granular scaffolds

Wound healing

Extract spatial landmarks

Heterogeneity

Injectability

Stroke variation by age and sex

If you’re a student who wants to work on cutting-edge technology in the stroke recovery space, contact us and add in the message that you are interested in my project! #kevin #stroke

CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

Non-invasive therapeutics

Ninjabyte Computing

While our collaboration focuses on MAP simulations, this only scratches the surface of animation technology. We’re happy to share the love for Ninjabyte, and we recommend reaching out to ninjabytecomputing@gmail.com for any inquiries.

Biomaterial scaffold

When we make scaffolds out of hydrogel microparticles and link these particles together, we create MAP – but you can read more about that here.

Read in formatted data

Re-opening the window for cellular change

Tweaking the immune system

LOVAMAP: LOcal Void Analysis of MAP scaffolds

If you’re a student who wants to apply your math and coding skills to questions in wound healing, contact us and add in the message that you’re interested in my project! #lindsay #computational

Injectable and long lasting delivery of genes to brain tissue

If you’re a student who recognizes that non-viral gene delivery is trending, contact us and add in the message that you’re interested in my project! #evan #genedelivery

Using pro-repair matrices to fight cancer

Our focus is on glioblastoma multiform, an aggressive brain cancer with particularly low survival rates. If you’re a student with a passion to fight cancer using pro-repair matrices, contact us and add in the message that you are interested in my project! #alex #healingcancer

Macrophages in repair and regeneration

If you’re a student who is equally as intrigued by the role of microstructure on macrophage phenotype and wound healing, contact us and add in the message that you’re interested in my project! #yining #macrophages

Engineering components of the amniotic membrane for wound healing

Since the amniotic membrane is used to promote healing of non-healing wounds, I will incorporate components of the amniotic membrane – which I will produce recombinantly – into HA hydrogels.

If you’re a student who’s excited about scarless healing and synthetic placenta biomaterials, contact us and add in the message that you’re interested in my project! #drew #syntheticplacenta

Modified building blocks

Our starting materials are hydrogel polymers, such as

In vivo work

During an in vivo study above, we injected one of our biomaterial scaffolds into a controlled skin wound.

Trapping the pro-repair environment

If you’re a student who wants to work on promoting recovery after stroke – particularly using biomaterial approaches that sequester plasticity-proteins – contact us and add in the message that you are interested in my project! #shangjing #repairsoup

Do these lipids make my brain look fat?

If you’re a student who has an inkling for chemistry and who wants to work on drug delivery to the brain after stroke, contact us and add in the message that you’re interested in my project! #briana #fatbiomaterials

Crosstalk between hydrogel microstructure, neuroprogenitor cells, and angiogenesis

If you’re a student interested in working on strategies to promote recovery after stroke focusing on NPCs and vascularization, contact us and add in the message that you’re interested in my project! #kat #brainheroes

VEGF – vascular endothelial growth factor CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

In vitro work

Look how our gel squishes during compression testing to measure its stiffness!

Ischemic Stroke Project

If you’re interested in working on strategies to promote recovery after stroke focusing on NPCs and vascularization, contact us and add in the message that you’re interested in my project! #kat #brainheroes

VEGF – vascular endothelial growth factor CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

Stem cell delivery

Tbd

We injected MAP into a skin wound, and you can see cells infiltrating between the particles.

Stroke-induced disability

[1] Dhamoon MS, et al. (2017) Disability Trajectories Before and After Stroke and Myocardial Infarction The Cardiovascular Health Study. JAMA Neurology. 74(12): 1439-1445.

[2] Centers for Disease Control and Prevention (CDC). (2009) Prevalence and most common causes of disability among adults: United States, 2005. MMWR Morb Mortal Wkly Rep. 58: 421–426.

[3] NCHS, National Health Interview Survey, 2018. Table A-1a: 1-9.

Poorly healing wounds

The challenge of fixing a disrupted natural process in the body motivates us to develop a biomaterials-based approach that can break the inflammatory cycle and turn a non-healing environment into a healing one.

[1] Nussbaum SR, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value in Health. (2018) 27 – 32.

[2] Han, G and Ceilley, R, 2017. Chronic wound healing: a review of current management and treatments. Advances in therapy, 34(3), 599 – 610.

Scarless healing

[1] Grand View Research: Market Analysis Report. Scar Treatment Market Size, Share & Trends Analysis Report By Scar Type (Atrophic, Hypertrophic & Keloid Scars, Stretch Marks), By Product (Injectables, Topical, Laser), By End Use, And Segment Forecasts, 2019 – 2026.

* Fun fact: Lindsay in our lab was responsible for changing the official Merriam-Webster definition of the word ‘recapitulate’ to include the way scientists have been using it for years:

Wound healing

Tbd

We injected MAP into a skin wound, and you can see cells infiltrating between the particles.

Bells and whistles

VEGF – vascular endothelial growth factor
CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

VEGF – vascular endothelial growth factor
CLUVENA – Clustered VEGF Nanoparticle hydrogel (developed by our lab!)

02.02.20
Nature Materials