Developing personalized, bioengineered bone grafts: an interview with Giuseppe Maria de Peppo and Martina Sladkova

In this interview, Giuseppe Maria de Peppo and Martina Sladkova discuss their recent paper on a novel method for producing engineered bone tissue for transplantation.

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Sep 19, 2018
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Dr Giuseppe Maria de Peppo received a BSc in Biotechnology at La Sapienza University and a MSc in Medical Biotechnology at Bicocca University, with a thesis on biomaterial engineering from Politecnico di Milano (all Italy). Following that, he was awarded a Marie Curie fellowship at the University of Gothenburg (Sweden) where he received an international PhD in Tissue Engineering.

Giuseppe is now the NYSCF – Ralph Lauren Senior Principal Investigator at The New York Stem Cell Foundation (NYSCF) Research Institute, where he leads the Stem Cells and Tissue Engineering group. The major goal of his research team is to engineer patient-specific bone grafts for basic and applied research, and ultimately, for use in the clinic. Other research directions include manufacturing and testing biomaterial scaffolds, design and validation of bioreactors, intelligent monitoring of the culture environment, prosthetics and implantology research, drug delivery, organ-on-a-chip, and stem cell-based therapies.

Dr Martina Sladkova received a BSc in Biology and a MSc in Animal Physiology and Ethology at Comenius University (Slovakia) with a thesis on mechanical changes of blood vessels to various pharmacologic agents from Slovak Academy of Sciences. Following this, she was a Marie Curie fellow at Paris Diderot University (France) where she earned her PhD in Tissue Engineering for her work on engineering bone substitutes using human mesenchymal stem cells in perfusion bioreactors. She also holds a Diploma in Hyperbaric Medicine from the University of Paris North (France). Martina is now Staff Scientist at the NYSCF Research Institute and a member of the Stem Cells and Tissue Engineering group. Her research focuses on scaling up the size of engineered grafts, testing and developing implant materials, and engineering replacement cartilage tissues.

Founded in 2005, the NYSCF Research Institute is an independent, non-profit organization focused on accelerating cures and better treatments for patients through stem cell research. The NYSCF global community includes over 150 researchers at leading institutions worldwide and is an acknowledged world leader in stem cell research, in developing pioneering stem cell technologies, including the NYSCF Global Stem Cell ArrayTM, and in manufacturing stem cells for scientists around the globe. NYSCF focuses on translational research in a model designed to overcome barriers that slow discovery and replace silos with collaboration.

How did this work come about?

After many years working in the field of tissue engineering, it has become evident that a number of different issues were limiting the ability to construct segmental bone grafts effectively and reproducibly. These include the inability to grow large tissue products ex vivo, the lack of standard operating procedures, the customization of bioreactor design each time the tissue geometry and size change, and other issues that impede technology transfer and implementation.

The Segmental Additive Tissue Engineering (SATE) strategy addresses all these issues and enables the construction of segmental bone grafts with geometrical requirements for individual patients that could facilitate a tissue engineering approach to segmental bone defect therapy. We are hopeful that this new strategy will one day be able to improve the lives of the millions of people suffering from bone injury due to trauma, cancer, osteoporosis, osteonecrosis and other devastating conditions of the skeletal system.

What are the advantages of utilizing engineered bone grafts in treatment?

Management of segmental bone defects remains an important medical challenge, especially for pediatric patients with a developing skeleton. When people suffer from segmental bone defects a few treatment options exist. The type of treatment depends on the size of the defect, and generally involves the use of bone transplants, alloplastic materials and prosthetic implants. All these treatment options, however, present several disadvantages that can lead to severe health complications.

On the other hand, the ability to use bone grafts grown from patient’s own cells could help overcoming these issues, which include limited bone transplant availability, risk of disease transmission, long recovery time, poor graft integration and remodeling, and biomaterial associated infections.

Can you summarize the SATE process?

In the published study, we have used decellularized bovine bone scaffolds that were manufactured to the exact shape using a 5-axis milling machine. We have used decellularized bovine bone because of its good mechanical properties (which are important for segmental reconstruction in load bearing locations), and because of existing knowledge on its use in bone engineering applications. However, the use of synthetic biomaterials that can be manufactured in a reproducible fashion, rapidly and at an affordable cost is expected to foster translation of tissue-engineered bone grafts to the clinics.

The scaffolds were seeded with mesodermal progenitors cells derived from human induced pluripotent stem cells generated via reprogramming of skin cells. These cells can be derived for any patient and can be manufactured to the numbers (millions to trillions) required for engineering large volume segmental bone grafts.

Following culture in the SATE bioreactor, the tissue-engineered bone segments (modules) could be combined into a single, mechanically stable graft using biocompatible bone adhesives or traditional reconstructive orthopedic devices. Unpublished data have demonstrated that cement-based bone adhesives can be used to piece the different bone segments together. Ongoing studies are now aimed at testing the mechanical stability of segmental grafts engineered using the SATE strategy for future animal studies, and potential clinical applications.

Is a graft made from segments of bone as strong as a graft made in one piece?

I would not say that the two things can be compared at this point. However, partitioning of 3D reconstructions of segmental bone defects transversally to their longitudinal axis maximizes the structural capability of bone grafts engineering using the SATE strategy. Ex vivo and in vivo studies will help assessing the strength and stability of segmental bone grafts engineered using our approach.

What were the challenges in developing SATE?

The real challenge was to put together standard operating procedures that facilitate technology transfer and implementation. For example, one challenge was to come up with a simple universal design for the SATE bioreactor, a configuration suitable for generating segmental bone grafts with a broad range of sizes and geometries. In addition, in order to reduce manufacturing time and allow production at an affordable cost, we had to come up with a design that was suitable for manufacturing the bioreactor using rapid prototyping technologies, in this case 3D printing. Another challenge was to develop a strategy to seed the cells efficiently and uniformly onto the scaffolds. This is very important to ensure reproducibility when growing bone grafts in the laboratory.

In a few words, the real challenge was to make simple something that is technically quite complicated, i.e. growing segmental bone grafts ex vivo. It is only this way that bioengineered bone grafts can make the leap from bench to bedside.

What are the next steps in this research?

The next step will be to test this approach in clinically-relevant models of segmental defects, and work in close collaboration with orthopedic surgeons to develop an effective surgical technique that leads to graft survival and integration. In addition, development of adequate manufacturing and clinical procedures that meet international regulatory requirements, intelligent monitoring of the culture environment during tissue growth in bioreactors, prevention of microbial contamination using environmentally controlled areas (clean rooms), process validation and quality control testing are some other most important challenges that must be addressed before segmental bone grafts engineered using the SATE strategy can be used to treat human patients.

What do you think the future holds for engineered bone grafts?

Someday, the use of bone transplants and alloplastic materials for bone reconstructions might become a thing of the past. We could be able to grow patient-specific bone on-demand, and thus circumvent the complications associated with current treatments. I think I’d like to see more automation and scaling up in tissue engineering. Right now things are still done by hand, and finding ways to automate the process could really change the game. Equally important, development of culture conditions supporting the growth of multicellular bone grafts, which include a vascular system for example, will likely facilitate graft integration and survival, and thus boost the therapeutic potential of tissue-engineered products.

Beside their potential in reconstructive therapies, tissue-engineered bone grafts will be increasingly used as qualified models to study development and disease, and test drugs and biomaterials within a context that better reflects the native bone environment.

Read the paper

Sladkova M, Alawadhi R, Alhaddad RJ, Esmael A et al. Segmental Additive Tissue Engineering. Sci Rep. 8, 10895.

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