Super Skin: UCLA's Hydrogel Innovations in Wound Healing and Tissue Regeneration

Introduction

UCLA researchers are at the forefront of developing innovative hydrogels, often referred to as "super skin," with remarkable properties that mimic and even enhance the natural capabilities of human skin. These advancements hold significant promise for revolutionizing wound care, tissue regeneration, and various biomedical applications. This article delves into the groundbreaking research conducted at UCLA, focusing on the development of novel hydrogels and their potential to transform medical treatments.

Clay-Enhanced Hydrogels for Bone Regeneration

Bioengineers and dentists at the UCLA School of Dentistry have achieved a significant breakthrough by creating a new hydrogel that surpasses existing hydrogels in promoting tissue repair and regeneration. Published in Nature Communications, their research highlights the development of a more porous hydrogel that effectively induces the migration of naturally occurring stem cells to accelerate bone healing in a mouse model.

Current experimental applications often involve introducing hydrogels and stem cells or expensive biological agents into the body, which can lead to undesirable side effects. This new hydrogel system aims to mitigate these issues and improve biomaterial-based therapeutics for bone defect repair.

Hydrogels are biomaterials composed of a three-dimensional network of polymer chains. Their ability to absorb water and their structural similarities to living tissue make them ideal for delivering cells to damaged areas to regenerate lost tissue. However, the small pore size of traditional hydrogels limits the survival, expansion, and tissue formation of transplanted cells, hindering their effectiveness in tissue regeneration.

To address this limitation, the researchers incorporated clay, a naturally occurring mineral, into their hydrogel. Clay has become a popular additive in medical products due to its biocompatibility and availability, with no reported negative effects. The layered structure and negative surface charge of clay are crucial to its function. Through a process called intercalation chemistry, the hydrogel is inserted into the clay layers, resulting in a clay-enhanced hydrogel with a more porous structure that facilitates bone formation.

Read also: Comprehensive NCAA Softball Guide

The researchers then used photo-induction, exposing the material to light, to transform the clay-enhanced hydrogel into a gel form suitable for injection into a mouse model with a non-healing skull defect. After six weeks, the model exhibited significant bone healing due to the migration and growth of its own naturally occurring stem cells.

According to Min Lee, professor of biomaterials science at the UCLA School of Dentistry and a member of the Jonsson Comprehensive Cancer Center, this research will contribute to the development of next-generation hydrogel systems with high porosity, significantly improving current bone graft materials. Lee envisions that their nanocomposite hydrogel system will be useful for therapeutic delivery, cell carriers, and tissue engineering.

Future research will focus on understanding how the physical properties of nanocomposite hydrogels affect cell migration, function, and blood vessel formation. This injectable combination of living cells and bioactive molecules using hydrogels offers a less invasive alternative to surgery for treating unhealthy or damaged areas of the body.

Self-Healing Hydrogels: Mimicking the Properties of Human Skin

Scientists from Aalto University and the University of Bayreuth have collaborated to develop a self-healing, flexible, and strong hydrogel, marking a major milestone in materials science. Human skin possesses unique properties, combining strength and flexibility with the ability to heal itself within 24 hours after injury. Replicating these properties in artificial materials has been a significant challenge.

The researchers used ultra-thin clay nanosheets to achieve these features in a rigid hydrogel. These nanosheets create a dense, entangled network of polymers that strengthens the hydrogels and prevents them from being too soft. The process involves mixing a powder of monomers with water containing nanosheets, with the subsequent interactions of the polymers being crucial.

Hang Zhang from Aalto University explains that the thin polymer layers twist around each other like tiny wool yarns in a random order, leading to entanglement. When the polymers are fully entangled, they become indistinguishable from each other. The healing process is remarkably fast, with the hydrogel achieving 80-90% repair within the first four hours and full restoration after twenty-four hours.

This work demonstrates how biological materials can inspire the creation of synthetic materials with new combinations of properties. Developing stiff, strong, and self-healing hydrogels has been a long-standing challenge, and this discovery provides a mechanism to strengthen conventionally soft hydrogels.

The innovation involves embedding ultra-thin, high-aspect-ratio clay nanosheets that align into co-planar structures. During UV-induced polymerization, using a UV lamp similar to those used for gel nail polish, polymer chains become densely entangled within the nanosheet framework. According to Dr. Chen Liang, a postdoctoral researcher at Aalto University, the UV radiation causes the individual molecules to bind together, transforming the material into an elastic solid - a gel. When cut, mobile segments diffuse and re-entwine, closing gaps without external input.

Polymer Entanglement

Polymer entanglement occurs when chains in dense networks weave around each other, restricting motion like threads in a ball of yarn. Unlike chemical crosslinks, entanglements are dynamic and reversible. In hydrogels, they improve strength and toughness but must remain mobile to enable self-healing.

The healing rate is approximately 80-90% recovery within 4 hours, typically completing in 24 hours. Side-by-side cuts heal almost fully (94-100% recovery by tensile strength), while end-to-end cuts show lower recovery (~33%). Mechanical benchmarks include a Young’s modulus up to ~50 MPa and tensile strength up to ~4 MPa.

Read also: The Benefits of SAT Super Scoring

Although the material's stiffness makes healing more challenging, the carefully designed confinement and entanglements ensure effective healing.

Testing and Analysis

Hydrogel studies commonly employ various methods to probe nanoscale ordering, viscoelasticity, and toughness:

UV polymerization: Monomers crosslinked under UV exposure.
Shear alignment: Induced nanosheet orientation before polymerization.
Mechanical testing: Tensile strength, modulus, and healing efficiency.
Adhesion testing: Lap-shear experiments to measure bonding.
Fluorescence recovery after photobleaching: Confirmed polymer chain mobility in confinement.
Small-angle X-ray scattering
Transmission electron microscopy
Rheology
Fracture testing

Potential Applications

The hydrogel super skin's stiffness and self-healing capacity make it suitable for various applications:

Artificial skin for robots: The material can serve as an artificial skin material for robots.
Synthetic skin bandage: As a synthetic skin bandage, the hydrogel could cover wounds, resist tearing during movement, and autonomously repair micro-tears.
Controlled-release drug delivery: The hydrogel can serve as a scaffold for controlled-release drug delivery, maintaining mechanical integrity while enabling diffusion of therapeutic molecules.
Electronic skin (e-skin) systems: A stiff, self-healing hydrogel provides a substrate that can house conductive elements and recover from mechanical damage in emerging e-skin systems.

Challenges and Future Directions

Several challenges remain in the development and application of hydrogel super skin:

Biocompatibility and cytotoxicity: Ensuring the hydrogel (including nanosheets, initiators, residual monomers) is non-toxic to cells and tissues.
Long-term stability and fatigue: Repeated mechanical cycling and aging may degrade performance or healing capacity.
Scalability and reproducibility: Aligning nanosheets over large areas, consistent confinement architectures, and manufacturing yield.
Integration with electronics/vascularization: Embedding conductive elements or integrating with live tissues demands chemical/physical compatibility.
Standards and benchmarking: New performance metrics (healing efficiency, modulus-healing tradeoff) must become standardized across labs.
Regulatory approval: For clinical devices, regulatory pathways demand thorough biocompatibility, sterilization stability, and in vivo validation.

The hydrogel super skin demonstrates how clay nanosheet nanoconfinement and polymer entanglement can yield a material that is both stiff and self-healing.

Microporous Annealed Particle (MAP) Gels for Scar Reduction

UCLA scientists, in collaboration with colleagues at Duke University and other institutions, have developed a wound-healing biomaterial that reduces scar formation, allowing skin tissue to regenerate into healthier and stronger skin. This advance builds upon UCLA’s previous development of wound-healing gels made of injectable microporous annealed particles, or MAPs.

MAP gels, when applied to a wound, create a type of scaffolding that allows new skin tissue to latch on and grow within the cavities between the linked particles, reducing scarring. The team discovered that the new hydrogel triggers an immune response normally involved in long-term immunity to pathogens or vaccines, which is critical for the hydrogel to induce tissue regeneration. The researchers suggest the gel could be used to heal injuries such as burns and deep cuts, as well as diabetic ulcers and other wounds that generally heal with significantly noticeable scars that are more susceptible to re-injury.

The advance, published in Nature Materials, builds upon UCLA's 2015 research development of injectable microporous annealed particle (MAP) gels. Composed of microscopic spheres and applied to a wound, the gel acts as a highly porous scaffold that allows new tissue to latch on and grow within the cavities between the gel’s linked spheres. As the gel gradually dissolved, however, it started to lose porosity, thereby limiting support needed for the tissue to repair properly.

Rather than creating an entirely different gel with new materials, the researchers hypothesized that by slowing down the gel-degrading process, it would allow new tissue more time to grow into the scaffold. They switched in a different type of amino acid, the mirror image of the ones typically used to make proteins within the body, to act as the chemical link to other molecules in the gel. Much to their surprise, the modified gel placed in mouse wounds actually disappeared from the wound site almost entirely within three weeks, leaving behind just a few particles.

Dr. Philip Scumpia, an assistant professor in the division of dermatology at UCLA Health and the West Los Angeles VA Medical Center, explained that there are two types of immune responses that can occur after injury - a destructive response and a milder regenerative response. When most biomaterials are placed in the body, they are either pushed out like a splinter or walled off by the immune system and degraded or destroyed, but in this study, the immune response to the gel induced a regenerative response in the healed tissue.

With the new gel, the regenerated tissue is much stronger, with hair follicles and sebaceous glands - instead of scar tissue - forming correctly over the scaffold. The researchers determined that the amino acid they used, one not found naturally in the body, was the key behind the regenerative immune response and improved healing.

Dino Di Carlo, a senior author on the study and professor of bioengineering at the UCLA Samueli School of Engineering, noted that the modularity of the chemical and physical properties of the spherical gel building blocks, which they manufacture using scalable microfluidic chips, is a key advantage of the system that enables precise tuning for an optimal tissue response.

The technology is licensed by Tempo Therapeutics, a UCLA startup, which is commercializing the MAP hydrogel to regenerate tissue in complex wounds. As the researchers continue to study the regenerative immune response to the new MAP hydrogel, they are also exploring the possibility of using the gel as an immunomodulatory platform for tissue regeneration and vaccine development.

LUT017: A Topical Gel for Chronic Wound Healing

UCLA physician-scientist Dr. Antoni Ribas has received a grant of more than $5 million from the California Institute for Regenerative Medicine to further the development of a novel gel, called LUT017, that could help heal chronic wounds. The grant will support Ribas’ efforts to complete the testing and manufacturing necessary to apply to the Food and Drug Administration for permission to start a clinical trial in patients.

If the objectives of the grant are met, Ribas hopes to launch a trial evaluating the topical gel as a treatment for venous leg ulcers, which are sores on the legs that heal very slowly due to restricted blood flow. Venous leg ulcers affect 1 to 3% of Americans and can last anywhere from a few weeks to years.

Ribas, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and director of the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center, notes that this condition has a disproportionate effect on underserved populations and is common among people with diabetes, obesity and limited movement. Venous leg ulcers can cause chronic pain, loss of function and mobility, social isolation and lead to increased time spent in hospitals. They can take a severe toll on patients’ quality of life and there are no currently approved drugs to treat them.

In studies in mice models of skin wounds, the compound was found to stimulate skin stem cells to produce all kinds of skin cells and regenerate damaged tissue, thus accelerating wound healing.

Ribas, a world leader in the development of immunotherapies for cancer, discovered the potential of this treatment from a surprising side effect he observed among patients with melanoma who were being treated in a clinical trial of a therapy he helped develop called vemurafenib, marketed as Zelboraf. This treatment falls into a category of targeted cancer drugs called BRAF inhibitors, which can shrink or slow the growth of metastatic melanoma in people whose tumors have a mutation to the BRAF gene.

Ribas noticed that in the first two months of taking this BRAF inhibitor, patients would begin showing a thickening or overgrowth of the skin. It was somewhat of a paradox - the drug stopped the growth of skin cancer cells with the BRAF mutation, but it stimulated the growth of healthy skin cells. After developing a strategy to overcome this side effect in patients with melanoma, Ribas realized that the drug’s skin stimulating effect could be put to good use for a whole other group of patients - those with chronic wounds.

Ribas had to work hard to convince somebody in his lab to follow his crazy idea and take time away from immunotherapy research to do wound healing experiments. For help with these experiments, the Ribas lab tapped into the expertise of colleagues who study wound healing and bioengineering, UCLA professors William McBride, Roger Lo, Phillip Scumpia and Tatiana Segura, who is now at Duke University.

Using their mouse models of wound healing to test their hypothesis, they found that their drug worked in every one of the animals they tested. On average, the wounds of mice treated with the drug healed between 40 and 50% faster than the wounds of mice that did not receive the treatment. Because the safety of BRAF inhibitors has been studied in humans for over 10 years, Ribas is optimistic that there will be a clear path for the therapeutic gel candidate to reach the clinic.

tags: #super #skin #ucla #research