Of Bone, Cells, and Standards
What sparked your interest in materials engineering for medical applications?
In high school, I wrote a science report about bone. I had to describe the structure of bone and how it worked. I became interested then — and still am — in conducting research in the medical field, particularly in the area of bone.
When I went to college in the ‘80s, the field of tissue engineering as we know it now did not exist, and the field I chose to study, biomedical engineering, was at that time mainly electrical engineering, which I found I didn’t like.
I changed my major to mechanical engineering, which had a large materials component. I enjoyed learning about materials and particularly about the structure of materials. After graduating with my undergraduate degree, I worked in the aerospace industry for a couple of years on materials used to coat airplanes and missiles and then went to graduate school for further study in the field of materials engineering.
I have always been amazed by the structure- function relationships in natural materials such as the layers of a seashell that allow the mollusk to survive being tossed by waves. Gems and minerals of all types fascinate me. I have always enjoyed and wanted to find out more about the minutiae of materials.
The Kuhn Biomaterials Lab at your university “works at the interface of materials science and medicine.” Tell us about some of your work.
My goal is to develop new medical products made from biomaterials in order to help patients. At UConn Health, I run a research lab in which bone-like mineral provides the basis for a variety of possible new medical products. For example, we have found calcium phosphate nanoparticles function as a lymp node targeted drug delivery vehicle for chemotherapy. In mouse studies, we have shown that when the cancer is at the stage of a primary tumor without metastasis, direct injections of chemotherapy into the tumor, with or without our mineral carrier, eliminate drug side effects and shrink the tumor so that after it is removed it doesn’t grow back. We tested the efficacy of this approach on breast, head, and neck cancers, and osteosarcomas — a variety of different types — with human and mouse cell lines to create tumors in mice, and it worked well in all tumor types.
This approach has a very low cost, and would be easy for a doctor to administer before surgical resection, so-called neoadjuvant use. With a human patient and given concern about metastasis, the standard IV approach is a good one, but for an early stage tumor, this direct injection approach has lots of promise. I’m now trying to interest veterinarians in this approach for treating dogs or cats with cancer. It’s much harder to give chemotherapy intravenously to a pet; so this would be a good option.
In addition to anti-cancer research, I’m directing a project funded by the National Institutes of Health through their National Institute of Dental and Craniofacial Research to investigate how to improve bone healing outcomes in the elderly. I’ve been working on strategies to regrow bone in conjunction with dental implants. If a tooth is lost, a metallic screw is placed in the bone, and bone needs to grow around it. That is challenging, especially if the person is older.
Over the last several years, we’ve been investigating the potential of the molecule fibroblast growth factor 2 (FGF-2) to overcome problems with slow bone healing in the elderly. We tested the approach in mice with bone defects, and we have confirmed that FGF-2, in very low, nano-size doses, increases bone regeneration when combined with bone morphogenetic protein-2, particularly in older mice that have depleted levels of FGF-2.
To make this system work in younger animals we needed a new timed release delivery system to administer the two molecules in a sequential manner because concurrent delivery of these two molecules inhibits bone formation. That’s where I was able to use a biomineral coating in a novel way. We applied a bone-like calcium phosphate barrier layer within a multi-layer coating that contains both factors to a bone graft, and we recently published information about our work showing how it enhances bone formation in mice. This is an example of the effective use of biologics or biological molecules to communicate to the patient’s own cells so that they recreate the damaged tissue. This is in contrast to a traditional orthopaedic implant, for example, that simply replaces the missing tissue with a synthetic material.
I see my contribution to the field as using materials engineering in combination with basic biological discoveries to discover new ways of healing bone. The goal is tissue regeneration rather than replacing a bone with something that is not living.
Tissue regeneration involving products with growth factors and cells and biomaterials is the topic of standards writing in ASTM F04 Division 4. I’m leading efforts related to growth factors themselves and the biomaterials delivering growth factors to cells and characterization of cells.
Why are standards important for medical products?
Standards are essential for medical products.
I’ve learned this by participating in ASTM as an industry participant and also as an academic participant. I’ve seen firsthand how essential it is to have balance in standards writing and the need for making sure that informed partiipants are there providing input to the standard being developed.
When I first joined ASTM, I was a co-owner of a small company that was seeking to develop a bone graft material. I came to ASTM meetings because I knew that standards can help differentiate between products, and I wanted to use the ASTM process to help show our product was better because it met a higher standard than I could see in existing products.
Jack Parr, Wright Medical, and Jack Lemons, University of Alabama, supported me early in my ASTM activities, encouraged my participation, and offered me task force chair positions. I’m grateful to those two gentlemen for mentoring me about the process and for helping me to understand and navigate it so well. Now I’m doing that in turn for others.
ASTM standards serve to delineate important properties that impact performance, like device dissolution or degradation, properties that depend on material structure. One of the first standards I was involved with was the anorganic bone standard (F1581). I revised the standard based on new structural and chemical information discovered by my mentor Dr. Melvin Glimcher, Boston Children’s Hospital, that helped to distinguish anorganic bone product performance.
ASTM guidance documents provide important background information that can help with product development. Guidance documents identify important properties to maintain during processing and manufacture and potential pitfalls. They’re essential at the early stage of product development. Realizing their importance led me to become the task force chair of F2027 [the guide for characterization and testing of raw or starting materials for tissue-engineered medical products TEMPs]. It was one of the first guidance documents from F04.04 related to TEMPs.
My belief in the therapeutic benefit of tissue engineered products and my desire to help get them to patients faster has kept me involved in ASTM and led me to become task force chair of the published standards F2739, F2997, and F3106 that cover aspects of bone tissue engineering, e.g., cell viability, calcium deposits, and osteogenic differentiation. I am glad that I have been able to apply my passion for bone and bone regeneration to ASTM standards.
You were president of the Society for Biomaterials for 2016-2017. What were your priorities, and what progress was made?
One of my priorities was to increase knowledge about and participation in ASTM standards.
The Society for Biomaterials (SFB) is the premier professional society for people involved in biomaterials research. The medical applications discussed at our meetings range widely: antibacterial, orthopaedics, cardiovascular, ophthalmology research, and more; quite a broad range. Members include people from industry and academia and clinicians; the majority are basic scientists working at universities. Many SFB members have know-how that could be applied to help write ASTM standards.
My goal was to increase participation by SFB members in standards writing. To encourage this I’ve written about ASTM International for the SFB news magazine. I’ve guided and participated in annual meeting programming about standards at the SFB annual meeting. For the April 2018 annual SFB meeting, I’ve organized a session that I hope will help gather new ideas about cell-biomaterial assays that would be good topics for ASTM standards. The plan is to initiate work items around those topics at the May 2018 ASTM committee meeting.
If a university professor has figured out a new way to do an assay related to tissue engineering product characterization, for instance, that may be a great topic for an ASTM standard that the professor could initiate. Through the standards development process, industry, clinicians, and regulatory agency participants would weigh in on what’s reasonable or not reasonable about the assay. There is also a need for more academics to be involved in ASTM because we need more general interest members to allow more industry reps to participate while maintaining roster balance.
As SFB president, I have also sought to increase opportunities for education and training for young scientists in the first 1 to 5 years of their first real job, whether in industry or as a professor. The Society for Biomaterials now provides opportunities for young scientists to take a lead in annual meeting programming, reviewing abstracts and organizing sessions. I wanted to create more opportunities for mentoring because I am grateful to my mentors, who allowed me to take a leading role in societies such as ASTM.
I am also trying to increase use of ASTM standards by the SFB community. I firmly believe in the value of ASTM standards and that their use in the medical field and in the research laboratory increase rigor and help accelerate research discoveries and new product approval.
How do academic institutions help prepare the next generation to contribute to organizations such as ASTM and the Society for Biomaterials? Why is that important?
As a professor, I use ASTM International standards in the courses that I teach. I make students aware of ASTM, the process, how the standards are used in industry and laboratories and by the FDA [U.S. Food and Drug Administration] for regulation, and that standards are a way to get medical products approved more rapidly. There are specific ASTM tests that I have my Ph.D. students use in the lab – because the standards are written clearly, and various points are explained well. This is something I don’t find in textbooks.
I also send my students to present their research at professional societies and to volunteer to help with programming. That’s how they get hooked: They meet interesting people, enjoy the content, feel they learn something, and most importantly feel their contribution is valued. This teaches them the value of volunteer efforts in professional societies.
I haven’t yet influenced clinical practice through my research laboratory discoveries. However, I feel that when I help write a medical product standard, I may help the FDA to realize that a new product is well-characterized and consistent and can be approved for use on human patients in combination with safety data. While the standard might not be about a particular product I discovered, by writing ASTM standards I am indirectly helping to get new, improved products to patients. That’s the major reason I find it rewarding to work at ASTM.
Liisa Kuhn, Ph.D., is associate professor of reconstructive sciences, Center for Regenerative Medicine and Skeletal Development, UConn Health, Farmington, Connecticut. An ASTM International member since 1995, Kuhn is currently chair of the subcommittee on biomaterials and biomolecules for TEMPs (F04.42) in the committee on medical and surgical materials and devices (F04). She has been honored by F04 with the Manny Horowitz Award, the Patrick G. Laing Award, and the Award of Merit.