Finding Inspiration in Origami and Eggshells

10/15/2019
By Edwin L. Aguirre

Tissue engineering – the field of biomaterials research and development that combines living cells with 3D scaffolds and biologically active molecules to grow fully functional tissues – has made tremendous progress in recent years, with advances in microfabrication techniques and 3D printing. Scientists, engineers and physicians are applying these new technologies to develop tissue replacement therapies in patients as well as prototypes of tissue substitutes for complex organs such as the liver or the heart.  

Among the researchers worldwide who are at the forefront of this cutting-edge bioengineering technology is Asst. Prof. Gulden Camci-Unal of the Department of Chemical Engineering. Camci-Unal and her team of student researchers are designing novel biomaterials and using unconventional raw materials like paper and pulverized eggshells to construct 3D scaffolds that mimic the biological, chemical and mechanical properties of native human tissues. Their goal is to grow new cells and blood vessels that can help restore or repair damaged tissues or whole organs, a process that only a short time ago was thought to be impossible.  

“The biomaterials we are developing can offer a solution to the acute global shortage of donors for tissue and organ transplants,” says Camci-Unal, who worked at MIT, Harvard University and Harvard Medical School before joining UMass Lowell in 2016.  

Camci-Unal and her team are currently developing new “breathable” biomaterials that can repair heart muscle damaged by disease, injury or heart attack. They are synthesizing biodegradable polymeric materials to serve as stable 3D scaffolds for growing new blood vessels in heart tissue implants. The work is supported by a three-year grant worth nearly $300,000 from the American Heart Association.  

According to Camci-Unal, biomaterials with high oxygen content represent a major step toward creating functional tissues with well-connected blood supplies that can restore damaged heart tissue.  

“Our new biomaterial can provide oxygen on demand up to several weeks to enhance cell survival and function. The material is also biocompatible with cardiac cells, which means it will not trigger a reaction from the body’s immune system,” she says. “The technology can be applied not only to repairing damage due to cardiovascular disease, but also to heart degeneration, aging or trauma.”  Current biomaterials that provide oxygen are limited by their inability to administer enough oxygen in a controlled and sustained fashion into thick tissues such as the heart muscle, Camci-Unal notes.  

“Our goal is to develop biomaterials that can provide oxygen on demand, similar to breathing. Our unique polymeric material will be able to supply the cardiac muscle cells, called cardiomyocytes, with oxygen slowly when they need it, and we will be able to fine-tune the biomaterial’s properties,” she says.  

Responding to a Health Crisis  

Heart disease is the leading cause of death in the United States, claiming more lives – over 840,000 every year – than all forms of cancer and chronic illnesses combined, according to a report released this year by the American Heart Association.  

About half of the country’s population (nearly 122 million people) suffers from some form of cardiovascular disease, the report states. And the direct and indirect costs of treating heart disease, stroke and cardiovascular disease in America are estimated to total more than $350 billion. This includes health care services, medications and lost productivity.  

A common cardiovascular disease is ischemic heart disease, which occurs when the cardiac tissue is deprived of oxygen. “This could lead to progressive loss of function and death of cardiac cells, formation of scar tissue, thinning of the ventricular wall and progressive heart failure in later stages,” Camci-Unal says. A major problem associated with today’s biomaterials used in heart repair is that they typically are not only non-biodegradable and not adequately porous, but they also contain an insufficient amount of oxygen, which can cause cell damage. “Some of the available materials supply a burst release rather than providing a controlled supply in the long term. Adequate oxygen must be provided to the cells for an extended period of time to help promote the formation of blood vessels, especially in thick tissue implants,” explains Camci-Unal.  

Assisting her in the lab at the Saab Emerging Technologies and Innovation Center on North Campus are biomedical engineering and biotechnology Ph.D. students Sanika Suvarnapathaki and Xinchen Wu and biomedical engineering sophomore Alexander Viglione.  

“We are applying for a patent for our breathable biomaterials technology,” says Camci-Unal.  

Combining Old Technologies with Advanced Tissue Engineering  

Camci-Unal has also been using common raw materials to design new biomaterials for tissue engineering. In 2018, using origami – the Japanese art of paper folding – as inspiration, she and her student researchers used plain paper to create tiny 3D scaffolds where biomaterials can grow, and then applied microfabrication techniques to engineer new tissues. These could someday be used to repair, replace or regenerate skin, bone, cartilage, heart valves, heart muscle and blood vessels.  

“Paper is a low-cost, widely available and extremely flexible material that can be easily fabricated into 3D structures of various shapes, sizes and configurations,” says Camci-Unal.  

The team uses origami-folded paper to grow bone cells, called osteoblasts, which produce the matrix that gets deposited with minerals to form bone. The paper can then be implanted to treat patients with bone defects of irregular sizes and shapes, or those with tissue damage caused by disease or trauma. Based on the results of their experiments, Camci-Unal notes, the implants are biocompatible – that is, they are not expected to be rejected by the body’s immune system.  In addition to paper, Camci-Unal also works with hydrogels – Jell-O-like flexible and squishy materials made up of mostly water that can be used as tissue models.  

“Their physical, chemical and biological properties can be tailored to fit in various tissue engineering applications,” she says. “However, hydrogels have relatively weak mechanical properties, so they tend to be not as easy to handle and manipulate when they are in large, very thin sheets.”  By combining hydrogels laden with cells with stacked sheets of paper, Camci-Unal is able to create sufficiently strong support structures that can be used for tissue engineering.  

Using Eggshell Particles for Growing Bone Tissue  

“This is the first study that uses eggshell particles in a hydrogel matrix for bone repair. We have already filed a patent application for it this year.” -Asst. Prof. Gulden Camci-Unal

Earlier this year, Camci-Unal also investigated the use of powdered eggshells for engineering bone tissue that could be applied to treat and repair bones in patients who have suffered injuries due to aging, cancer and other diseases, as well as in accidents or in combat. The technique can also be used to grow cartilage, teeth and tendons, she says.  

Camci-Unal and her team used microscopic eggshell particles – which are composed mainly of calcium carbonate crystals – to reinforce gelatin-based hydrogels, which then serve as stable 3D scaffolds for growing bone cells.  “This is the first study that uses eggshell particles in a hydrogel matrix for bone repair,” notes Camci-Unal. “We have already filed a patent application for it this year. We are very excited about our results, and we anticipate a lot of impactful applications of our invention.”  

According to Camci- Unal, more than 2 million bone-graft procedures are performed each year worldwide. “Bone repair is crucial to restoring a patient’s functionality and self-esteem following an injury,” she says.  

However, she notes that there are limitations to existing bone-graft materials and procedures, including the risk for infection, rejection by the body’s immune system and the limited availability of bone donors.  

She says the team’s experiments demonstrate that their eggshell particle-reinforced biomaterial can significantly increase the mineralization by the bone cells compared to using hydrogels alone, resulting in faster healing. Also, since the biomaterial is combined with cells obtained from the patient and then cultured and allowed to mature in a tissue incubator before being implanted into the patient, problems of rejection by the patient’s immune system are not expected using this method, she says.  

Camci-Unal points out that eggshell particles can also be incorporated easily into 3D scaffolds in a range of new biomedical applications, such as in dental implants as well as in reconstructive surgeries of the skull, jaw and face. “In addition to its role in tissue regeneration, eggshell particles can also be used as a possible vehicle for delivering small molecules such as growth factors, proteins, peptides, genes and therapeutic drugs,” she says.  

She adds, “Our ultimate goal is to improve human health and the quality of life.”