As bone graft materials and surgical techniques have evolved, there has been increasing interest in the use of stem cells for bone regeneration. Stem cells are unique cells in our bodies that can morph into a variety of different cells, including bone cells, and can improve the bone healing response.
Stem cells or other tissues used in bone grafting surgery come from two sources:
- Autologous Tissue (autograft) – stem cells or bone harvested from the patient being treated, or
- Allogeneic Tissue (allograft) – stem cells or bone taken from a deceased donor.
In the past 10 years, allograft stem cell products, also known as cellular allografts or allogeneic stem cell grafts, have become a popular bone grafting choice. Due to their source and composition, cellular allografts must adhere to certain protocols, regulations, and processes to ensure the donated tissue is safe to implant into another patient, and that it will be effective. This blog explains how these products are regulated, manufactured, and assessed for safety and efficacy.
For an overview of stem cell use in bone grafting, read more here.
Regulation of Cellular Allograft Bone Grafts
Typical cellular allografts in the bone graft market are classified by the FDA as “Human Cellular and Tissue-Based Products” (HCT/Ps). Due to this classification, they are not required to go through a regulatory clearance process that evaluates the product for safety or efficacy.
The reason behind this FDA classification is historical. When the FDA first began requiring medical devices to undergo a pre-market review for safety and efficacy in the 1970s, allogeneic tissue and organs were exempt because they were primarily processed by hospitals or regional, not-for-profit (NPO) tissue banks. Additionally, these were 100% donated tissue products with no additives and were, therefore, considered to be safe materials. At the time, there were no commercial organizations processing or distributing allografts. The processing was also very limited, primarily consisting of cutting, freeze-drying, or deep freezing the tissue. Even more extensive processes, like bone demineralization, were and still are considered by the FDA to be “minimally manipulated” and outside of its purview.
Today, although the processing of allogeneic tissue grafts for bone reconstruction has become significantly more complex, the FDA still deems it to be within the definition of “minimally manipulated.” Therefore, tissue grafts are referred to as “361 products” which implies no requirement for pre-market review of safety and efficacy. Conversely, any tissue grafts that are not within the guidelines for 361 are termed “351 products” and must receive biologic license application (BLA) approval by the FDA. This regulatory clearance process requires a detailed review of the product and must show clinical efficacy in a clinical trial before it can be distributed. Currently, there are no 351 tissue grafts for bone grafting approved for distribution in the US. A summary of 361 and 351 products is shown in Figure 1.
To qualify for the 361 HCT/P category, the FDA has two main requirements.
- The first requirement, termed “homologous use,” means that the tissue graft must be used in the recipient to regenerate tissue that is identical to the source of the tissue graft. For example, bone can be used as a bone graft while fat derived tissue cannot be used to regenerate bone.
- The second requirement is “minimal manipulation.” This refers to the use of minimal processing to manufacture the tissue product. Typical processes that are allowed include solution rinsing, freezing, freeze-drying, bone demineralization (where bone is soaked in acid to remove the mineral component), and sterilization methods. Specific to cellular allograft products, cells can be isolated from a donor using minimal manipulation techniques, but they cannot be cultured to increase cell number or exposed to solutions that would alter their cell type.
Manufacturing of Cellular Allograft Bone Grafts
Cellular allograft products are manufactured from human bones harvested from deceased donors. In the United States, the recovery of human organs and tissues is performed by tissue banks that, by law, are required to be not-for-profit organizations. These NPOs are responsible for collecting the tissues from hospitals shortly after a donor’s death, performing donor screening, processing the tissue into surgical products, and, in some organizations, distributing products to the hospitals. Aside from NPOs, the processing and distribution of allogeneic tissue can also be performed by a commercial, for-profit entity. Precisely how the cells for each commercial product are obtained is variable and is often associated with either patents or trade secrets. Consequently, it is difficult to know exactly how each commercial live tissue allograft product is manufactured.