Bone & Tissue Engineering Research at NYSCF

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About Tissue Engineering

 

What is tissue engineering?

Tissue engineering is the process of creating custom tissues (including bone) in the laboratory with the aim of treating patients suffering from injury or disease. At the NYSCF Research Institute, we are conducting tissue engineering with human stem cells, allowing us to develop bone grafts that seamlessly integrate into the body, restore function, and relieve pain. This approach could help treat a variety of conditions such as osteonecrosis, cancer, osteoporosis, joint pain, and more. Lab-made tissues can also be used to model diseases and to test new drugs and biomaterials for tissue engineering.

What is the importance of tissue engineering?

Bone defects and injuries are currently treated with bone grafts, taken either from another part of the patient’s body, a donor bone bank, or with synthetic substitutes. However, these treatments carry several complications:

Current treatments may cause immune rejection or fail to integrate with surrounding connective tissues. A patient’s body may register these bone grafts as foreign objects and send the immune system to attack them. And even if the immune system does not attack them, the grafts are not able to create the nerves, connective tissue, and complex vasculature that are needed to completely restore function.

They do not work well for trauma patients. Trauma patients suffering from shrapnel wounds or vehicular injury get little functional or cosmetic improvement from current treatments.

Children outgrow the treatments. Traditional bone grafts are not able to grow along with a child, so these children must undergo periodic surgeries to get them replaced.

Why use stem cells for tissue engineering?

Our scientists use stem cells to create patient-specific bone that has the potential to integrate into the body’s dynamic environment. Bone grafts generated from stem cells are well-positioned to incorporate into a patient’s body because they are generated from a patient’s own cells. These bone grafts can form nerves, connective tissue, and vasculature, grow and change in sync with the recipient’s body, and are less likely to be attacked by the immune system.

 

Tissue Engineering at NYSCF

NYSCF accelerates bone and tissue engineering in many ways:

 

  • We are using our unique, powerful robotic system for creating stem cells. NYSCF scientists have developed an automated robotic system, called the NYSCF Global Stem Cell Array, that does not exist anywhere else in the world. This system can rapidly and reproducibly create stem cells from skin or blood, which can then be turned into bone-forming cells

 

  • We are engineering functional bone. We can take the bone-forming cells, place them in a 3D bone tissue engineering scaffold that is built in the size and shape of the bone that needs to be replaced, and then place the scaffold into a bioreactor. This bioreactor works like the human body, shuttling nutrients in to nurture the growing tissue and removing waste. After a period of time, we have a fully formed piece of customized bone.

 

  • We are scaling up. This method, while effective, can only generate small sections of bone. NYSCF scientists have developed an engineering strategy called Segmental Additive Tissue Engineering (SATE) that allows for bone engineering on a larger scale by combining smaller bone sections grown in the laboratory into large bone grafts.

 

 

Tissue Engineering News

Publications

Below are select publications outlining recent advancements in tissue engineering from NYSCF scientists.

Segmental Additive Tissue Engineering
Sladkova M, Alawadhi R, Alhaddad RJ, Esmael A, Alansari S, Saad M, Yousef JM, Alqaoud L, de Peppo GM.
Scientific Reports. 2018. DOI: 10.1038/s41598-018-29270-4.

In this study, researchers describe a technique for combining segments of bone engineered from stem cells to create large scale, personalized grafts that will enhance treatment for those suffering from bone disease or injury through regenerative medicine.

Comparison of Decellularized Cow and Human Bone for Engineering Bone Grafts with Human Induced Pluripotent Stem Cells
Sladkova M, Cheng J, Palmer M, Chen S, Lin C, Xia W, Yu YE, Zhou B, Engqvist H, de Peppo GM.
Tissue Engineering Part A. 2018. DOI: 10.1089/ten.tea.2018.0149.

In this study, NYSCF Research Institute scientists led by NYSCF – Ralph Lauren Senior Principal Investigator Giuseppe Maria de Peppo, PhD, identified a more effective and cost-efficient method for creating the scaffolds used to generate lab-grown bone using stem cells.

Engineering bone tissue substitutes from human induced pluripotent stem cells
de Peppo GM, Marcos-Campos I, Kahler DJ, Alsalman D, Shang L, Vunjak-Novakovic G, Marolt D.
Proceedings of the National Academy of Sciences of the United States of America. 2013. DOI: 10.1073/pnas.1301190110.

In a step towards personalized bone grafts to treat traumatic injury or congenital defects, this study, led by Darja Marolt, PhD, and Giuseppe Maria de Peppo, PhD, and published in the Proceedings of the National Academy of Sciences, reports the generation of patient-specific bone substitutes from skin cells for repair of large bone defects.

Other Resources

Hear NYSCF’s Dr. Giuseppe Maria de Peppo speak about NYSCF’s tissue engineering projects with NBC News.

NYSCF’s Dr. Giuseppe Maria de Peppo and Dr. Martina Sladkova recently conducted an interview with RegMedNet about SATE, their pioneering method for combining segments of bone engineered from stem cells to create large scale, personalized grafts. Read the interview below.

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 de-cellularized bovine bone scaffolds that were manufactured to the exact shape using a 5-axis milling machine. We have used de-cellularized 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.