[sharman]

Part IIIa (turns out I have to shorten this to fit in the post)

Now to compare ADCT and PDN.

My bottom line, Reader's Digest version:

ADCT looks to be very low risk, but my gut is, it probably does not deliver as good a result as PDN, and the good result may fade over time (tho procedure could probably be repeated). PDN, on the other hand, has had a rocky startup period and is inherently fairly invasive, tho this varies with the type of device and surgical method.

Probably the biggest drawback of PDN is how hard it would be, at this point in time, to sort out the available options and make a good choice. I expect we'll know a lot more in the coming year.

Longer version:

MERITS

1) How much improvement can you get, and how good are your odds? (E.g., 70% of patients in a given trial report good or excellent results.)

In the only randomised trial of ADCT, the claim was a reduction in low back pain and disability from 70% to 30%. (The study did not report how many patients had a good result--are they implying all benefited?) Also, whereas the control group that underwent discectomy without ADCT showed progressive decline two years out, discs in the ADCT group stayed healthy, as measured by the water content of the nucleus, as shown on MRI and radiography.

Claims for PDN are similar. Raymedica claims (for its newer generation product) that patients report as much as 70% pain/function improvement, with 80% reporting improvement. I believe there is at least a 2-year follow up available for the Raymedica study.

One advantage of PDN over ADCT may be removal of the degenerated nucleus, if the nucleus material is itself a source of pain (for example, the "interpositional disc tissue in annular tears" and "granulation tissue" Yeung claims to see when he does SED).

2) How long can you expect the improvement to last?

Due to cell senescence, lab studies suggest that the benefits of ADCT may be of limited duration, at least in older patients. "Senescence" is each cell's built-in lifetime--the limit to the number of times the cells can reproduce. In vitro studies (of ACT on non-disc joint tissues) suggest that, due to senescence, cells cultured from the patient's nucleus may have only a limited amount of time that they will reproduce.

So long as the materials do not wear out, one would expect the improvements gained from PDN to be sustained.

Raymedica, the first manufacturer of a PDN device, has 10-year follow up statistics on the first patient population (consisting of 10 patients) successfully implanted. On the ADCT side, while the first procedure was done in 1997, I am only aware of a 1999 pilot study that claims a 5-year follow up. For both devices, so far, the first successes appear to have largely endured.

It may be possible to repeat the ADCT procedure if the benefits fade (I'm hypothesizing here). However, there may be a limit to the number of times you want to harvest cells even from a healthy disc.

2) How credible are the claims? (How many patients, how long has the device been in use? Who's making the claims? Clinical trials in US, Europe?)

ADCT:

For ADCT, there is only one randomized European trial, with 52 patients and three years of reported follow up. There were two previous pilot studies in Europe. The first implantation was in 1996, and there are 5 years of reported follow up from a 1999 pilot study.

Co.don, a cell biology company (they do the culturing of the cells) is the most active marketer, and the source of much of the available information (website and contact info in Part II). The company also claims that (in some patients), there is physical evidence of anatomical improvement, measured by the nuclear water content in the treated versus control (discectomy only) group, as shown on MRIs and radiography. There are some published animal studies that demonstrate successful implantation of viable chondrocytes (as measured by increased expression of the proteins the chondrocytes are meant to produce). There is also a good history of success in chondrocyte implantation to repair other joints tissues, like knee cartilage.

Bertagnoli does this procedure, and mentions it on his website.

I'm unaware of any ongoing or prospective trials. There were two pilot studies, and one small (52 patients) randomised trial.

PDN:

Some PDN devices already have their European CE approvals, and a handful have FDA approved to start pilot studies (IDEs) in the US--these trials are just beginning this year.

There is a long list of medtech companies getting into the PDN business, with competing devices. Much of the information comes from the manufacturers and surgeons involved in the product development.

3) How close does the device get to natural function?

Obviously, ADCT, if it works, restores natural function--working chondrocytes cells in sufficient numbers. The question is, even if you successfully restore to the nucleus the necessary number of functioning chondrocyte cells, churning out proteoglycans and collagen, is that enough? For example, degeneration in the endplates may limit the disc's ability to pump water/nutrients/wastes from the endplates, and so the nucleus still fails to achieve the necessary water content/height/strength. Or a torn, degenerated annulus may just not have the ability to heal itself, or may still be painful on loading, even if the nucleus is restored enough to take its fair share of the load.

The PDNs attempt to mimic nucleus biomechanics and function, with a number of different design and materials. The hydrogels mimic the hydrophilic properties of proteoglycans. All the devices seem to absorb water. For one example of the claims made by a manufacturer, NuCore, an injectable polymer, claims to mimic the "protein and water content of a natural nucleus."

4) How stringent are the patient criteria? (I.e., are you likely to be ruled out because your degeneration has progressed too far?)

Both procedures are indicated only for early stage DDD. My gut is, the ADCT probably requires a healthier patient than PDN.

Due to cell senescence, ADCT may be less effective for older patients, both with respect to the cultured cells' ability to regenerate themselves, and also their ability to produce proteoglycans and other proteins.

5) If this technology is so good, why isn't it all the rage already?

Both procedures have only been around 10 years. Didn't ADR take about that long to gain acceptance too? These procedures are only beneficial to early stage DDD patients, so far fewer good candidates come through a doctor's office. The PDNs do seem to be riding a wave of interest right now, tho, with several companies getting into the development end, and IDE trials underway in the US.

PDNs had a rocky start, with a high rate of implantation failure, which undoubtedly cooled enthusiasm. Much will depend on whether the early problems can be overcome.

My theory for why ADCT has languished (in addition to the smaller appropriate patient population) is, ADCT does not involve any key device or drug that is patentable. Therefore there is no horde of startup medical device companies with the money to expose doctors to the technology, fund trials, etc.