Misunderstanding BMA and a Regulatory Framework for Thinking About Combination Cell-Based Therapies – Part Four

Misunderstanding BMA, Minimal Manipulation

In a paper published by Gassman, et al., the authors have made a number of groundless and puzzling statements, which I have been covering over the past few posts.

Misunderstanding BMA and a Regulatory Framework for Thinking About Combination Cell-Based Therapies Series: Part One | Part Two | Part Three

I will provide in this post some context about how the FDA views fat grafts and their uses, so consider the following example offered by the FDA in the Minimal Manipulation and Homologous Use (MM/HU) Guidance the FDA issued last November:  

Example 19-6: The basic functions of adipose tissue include providing cushioning and support for other tissues, including the skin and internal organs, storing energy in the form of lipids, and insulating the body.

a. Adipose tissue is used to fill voids in the face or hands (e.g., for cosmetic reasons). This is homologous use because providing cushioning and support, is a basic function of adipose tissue.

It would seem that the FDA thinks the use of a patient’s fat tissue for filling “…voids in the face or hands…” isn’t a problem. Not sure why the authors in Gassman, et al. think otherwise.

The authors continue with their regulatory assessment by stating:

“…mixing autologous bone marrow, a rich source of many lineages of stem cells, with fat grafts is well beyond minimal manipulation.”

I am not sure what minimal manipulation has to do with it, but they might be literally correct, though the devil is in the details, and will depend on who is doing the mixing. I could envision a situation in which a physician has a fat graft ready to go, and who separately performed a bone marrow aspiration, which subsequently was concentrated. At the physician’s discretion, the fat graft and the BMC are combined and implanted as a lipofilling fat graft. The reason I think this approach (mirrored in the paper by Xing, et al.) doesn’t rise above the standard for minimal manipulation is that working with BMA is a practice of medicine, and concentrating is one form of processing BMA that meets the burden of minimal manipulation. The fat graft isn’t a regulatory problem, since it is used as a structural tissue, and is placed in an appropriate subcutaneous site acceptable to the FDA (see the example above and the issued guidance for more details). And physicians long have had the option to use FDA-compliant materials in whatever combination they choose as a practice of medicine.

On the other hand, there could be an issue of non-homologous use of BMC being injected into subcutaneous tissue. The question is, what basic function of BMC would support it being injected into subcutaneous tissue? I would argue that BMC (or its parent material, BMA) has shown an ability to contribute to the health of both soft and bony tissues. In this case, Xing, et al. showed definite benefits to a lipoaspirate implant when combined with BMA or BMC. So, while the FDA might not be too happy with the combination of BMC and lipoaspirate, I don’t know of an explicit example in which they have shown their disapproval.

The authors move on to a second concern they have involving the “…bony origin of the tissue…”. They continue in the next sentence: “If this commixture were used for fat grafting, the bony component would be in violation.” It would seem that the authors are assigning bone marrow aspirate (or its concentrate) the property of being “bony”. Last time I checked, a bony tissue is one that contains bone, either cancellous or cortical or both. However, bone marrow aspirate is a non-structural tissue, according to the FDA, which is composed of a variety of different types of cells. Some of these cells are associated with creating bone; cells like osteoblasts (or osteoprogenitors), for example. Some of the cells are not associated with making bone in an obvious fashion, like mesenchymal stem cells (MSCs) or hematopoietic stem cells (HSCs). The authors didn’t mention the potential issue of homologous use, but this might be their way of alluding to it.

I will give the authors credit for correctly establishing that the commixture if used to treat a bone disease would be considered a non-homologous use by the FDA. While I contend that a physician could at point-of-care mix a patient’s BMC with their lipoaspirate to treat “voids” for cosmetic purposes, it wouldn’t be compliant to use the BMC/lipoaspirate mixture to treat musculoskeletal conditions. This is because in Example 19-6(b) of the MM/HU Guidance the FDA states the following:

b. An HCT/P from adipose tissue is used to treat musculoskeletal conditions such as arthritis or tendonitis by regenerating or promoting the regeneration of articular cartilage or tendon. This is generally not considered a homologous use because regenerating or promoting the regeneration of cartilage or tendon is not a basic function of adipose tissue.

It is this example that I believe ultimately will prevent health care providers from using lipoaspirate to treat musculoskeletal pathologies like knee OA. The FDA doesn’t mince any words in the example, and provides no wiggle room for intentional mis-interpretation. Anything made from adipose tissue is an HCT/P, regardless of how it is made, which means no adipose-derived HCT/P can be used to treat musculoskeletal pathologies, including enzymatic digested fat tissue (SVF) or mechanically beat up fat tissue (fuzz balls).

If you are interested in considering the possibility of improving survivability of fat grafts, take a look at Xing, et al. You might find it uplifting reading.

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