Nucleus Regeneration (ADCT) and Replacement (PDN)

[sharman]

I am very excited about the new technologies for treating DDD by replacing or regenerating the degenerated nucleus. There is a lot to say (and as you've figured out, I talk a lot), so I am splitting this up into four parts: First, in this post, a general discussion of the function and physiology of the nucleus; second, a description of the two competing technologies, ADCT (autologous disc chondrocyte transplantation), a procedure where the patient's cells are harvested, cultured in a lab and re-inserted into the disc, and PDN (prosthetic disc nucleus), where the diseased nucleus is replaced with a prosthethic device; and the third post will compare the risks and benefits of the two procedures. Last (and still a work in progress), a post about complementary therapies/procedures that might be done together with ADCT or PDN, to further enhance the benefits. (Those other therapies were discussed a bit in my post "Can You Heal a Disc?", and the fourth post on ADCT/PDN will follow up on the comments Mark made to "Can You Heal a Disc"?)

Before launching into this, I point out (as discussed on other threads) that these therapies are not going to work with advanced degeneration. The annulus must be relatively intact ("competent"), and there must be decent remaining height (I've seen a minimum of 5 mm cited).

PHYSIOLOGY AND FUNCTION OF THE NUCLEUS

Unlike most organs, the nucleus has very few living cells. Only about 0.25% to 0.5% percent of the nucleus is cells. The rest is water (90% I think?), a substance called proteoglycans, which is the stuff that attracts and holds water in the nucleus, and collagen. The function of the cells is to produce the proteoglycans that attract the water that gives the nucleus its cushioning turgidity. As discs age and degenerate, the amount of water, cells and proteoglycans goes down, the amount of collagen up.

A disc is essentially a ligament: it holds together two bones (vertebrae), in a manner that is strong enough to hold the bones in place, and flexible enough to allow the bones to move properly. The annulus of the disc is virtually the same as other ligaments in the body, composed of the same materials (collagen). But a disc, of course, is a unique ligament, in that it has at its core the jelly-like nucleus. I envision the nucleus as a swollen water balloon, its turgidity giving support and cushion to the adjoining vertebrae. The nucleus decompresses when loaded by expelling water, and re-hydrates at rest.

Besides the mechanical function of support and cushion, the nucleus has a second function, to transmit nutrients and waste to and from the annulus (and itself). This is effected by the 'pumping' action of the nucleus decompressing through the course of the day, and then re-hydrating at night.

So what is going on in a degenerated disc, that causes back pain? The nucleus has no nerve supply, so cannot itself be the source of the pain; IMO, the locus of discogenic low back pain is the innervated outer one-third of the annulus, and specifically the tears in the annulus we see in a degenerated disc.

But we know that a degenerated nucleus is usually associated with DDD--we see the black disc on the MRI. So what role, if any, does a degenerated nucleus play in discogenic low back pain? I see four possibilities:

1) First is the mechanical, the degenerated nucleus can no longer attract and hold water to make the water-balloon-like shock absorber cushion for the spine. This may translate into increasing stress on the annulus--the nucleus no longer absorbs weight and shock, resulting in this burden landing more heavily on the annulus.

2) Second, if the nucleus no longer serves its function of transporting nutrients, water and waste to the annulus, the annulus breaks down, tears, and is less able to heal itself.

3) Third, the degenerated nuclear material may be an irritant to the damaged annulus. Dr Yeung created a procedure he calls Selective Endoscopic Discectomy (SED), in which the endoscope used in the surgery allows him to see the inside of the disc, and to address observed pathologies. Among Dr Yeung's many interesting observations from the SEDs he's performed, two are significant here: First, Dr Yeung stains the nucleus before the operation, and claims that he can tell the difference between healthy nucleus tissue and unhealthy (his SED includes removal of the unhealthy tissue). Second, Dr. Yeung claims to observe "interpositional tissue" in the annular tears--I understand this to mean bits of matter that have become stuck in an annular tear. Possibly then,degenerated nuclear material and/or 'interpositional disc tissue' is an irritant, and/or retards healing of a tear.

4) Fourth, the material of even a healthy nucleus is caustic. If this material leaks onto a nerve root, it can cause sciatica (and maybe also back pain?) If it leaks into an annular tear, this too may be a source of pain. This last may be irrelevant to the ADCT/PDN discussion--if your disc is leaking this badly, the degeneration is probably too far gone to benefit from either of these procedures.

[sharman]

This is Part II, describing the competing technologies of nucleus regeneration (ADCT) and nucleus replacement (PDN).

ADCT

ADCT, autologous disc (or disc-derived) chondrocyte transplantation, is a procedure where cells from the patient's nucleus are removed, cultured in a lab and then inserted into the nucleus of the degenerated disc. It is often done in conjunction with a discectomy, where discectomy is indicated to address a herniation. "Chondrocytes" are cells that produce proteoglycans. Proteoglycans are hydrophilic: they are the substance that sucks water into the nucleus to give it its strength and turgidity, and also to create the pump effect (water expressed from the disc when loaded, sucked back in when rehydrated) that serves to transport nutrients and wastes to and from the vertebral endplates.

Obviously, the theory behind ADCT is that the nucleus has degenerated because of the decline in the number of chondrocytes that produce the essential proteoglycans, and upping their numbers will restore the nucleus to healthier function. This may seem far-fetched, but in fact there's a fairly impressive track record being built with similar therapies to repair/regenerate other joint tissues, such as knee cartilage. (Those tissues are also chondrocytes; this technology goes by the acronym "ACT," for "[generic] autologous chondrocyte transplantation.") And given that the nucleus is mostly water any way, with the living cells comprising only .25 to .5%, nucleus regeneration through transplantation of chondrocytes would seem to have a good chance for success.

The best quick source for information is the website of Co.don, a German company at the forefront of marketing the cell biology technology (they do the cell culturing). Their marketing rep is also very good at responding to email questions. Email address and website are:

info@codon.de
http://www.codon.de/_/

There are two procedures involved in ADCT, one to harvest and one to implant. If done in conjunction with a discectomy, the material removed in the discectomy is used for the culture. Implantation takes places about three months after the discectomy, to give the annulus time to heal. At implantation, the disc is first pressure-tested to make sure the annulus is competent enough to proceed.

If not done in conjunction with a discectomy, the recruited cells are (I believe should be) harvested from healthy discs, to lessen the trauma to the vulnerable disc. The time needed for culturing the cells in the lab is two to four weeks, so that would be the minimum time between procedures. Presumably, you could pressure-test the disc in the first procedure, to determine up front if you are not a candidate.

Improvement comes gradually over a few months.

From what I can tell (and that is what the Co.don representative told me), you'd have to go to Germany for this procedure (two trips or one long stay).

PDN

Prosthetic Disc Nucleus replacement entails removing the nucleus and implanting a prosthetic device intended to mimic the natural function of the nucleus.

There are a mind-numbing array of different PDN devices, in various stages of development, trials and use. You thought it was frustrating trying to decide between a charite and a pro disc? Hanh!

There are two basic kinds of PDN, prefab devices that are inserted (usually in a dehydrated state) into the disc, and fluids that are injected, and then cure in the disc. Among the prefabs, there are design differences such as unconstrained versus constrained (surrounded by a web envelop to hold in shape, and in place); differences in materials used; and differences in shape and size. One device is a spiral coil, which allows the device to exert a mechanical tension on the annulus.

The materials/devices that interest me the most are the hydrogels, a material that has hydrophilic properties, and thus act like the proteoglycans of the natural nucleus. While all the devices strive for a soft, elastic pillow that mimics the cushioning provided by a normal nucleus, and all the devices appear to absorb water, it is not clear to me (at least there is no claim) that all the devices also serve the function of transporting wastes/nutrients through the disc. The hydrogels do make this claim: "The hydrogel's ability to rehydrate itself mimics an important characteristic of an intact nucleus pulposus [namely, pumping up at night, and pumping fluid out during the day]... The "pumping action" of the hydrogel closely mimics the nutrient cycle that is constantly ongoing in a natural disc." "The value of the Neudisc and PDN hydrogel technology is the ability to mimic the intact nuclear material's ability to "uptake" water, continuing the nutrient cycle through the vertebral endplates."

Next, there is an even more bewildering array of options for implantation of the device (both in device design and surgical procedure)--the issue that so far has been the achilles heel of this technology. On the subject of implantation, the injectable prosthetics have the obvious advantage of a less invasive procedure, smaller annulotomy and possibly also maximize fit, and minimize the risk of migration after surgery.

Nucleus replacement has been around for about 10 years. Some devices have their European CE mark. There are at least two investigational trials now underway in the US. One note of caution if you pursue inclusion in a US trial: injectable PDNs (like ADCT) have been most often used in conjunction with discectomies. When used as an adjunt to discectomy, they only inject enough to replace the material removed for the herniation, they don't replace the entire nucleus. Unless I'm reading incorrectly, it appears the injectables will be tried out for total nucleus replacement too. The US trials going on right now, tho, are only for partial replacement as an adjunct to discectomy.

Even with the least invasive, injectable PDN, this is a far more invasive procedure than a simple injection. Among other things, remember, the nucleus has to be removed, which will require endoscopic instrumentation.

[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.

[sharman]

RISKS

1) How much trauma is caused by the implantation procedure (remember, the annulus is left in place).

The ADCT procedure is very minimally invasive. I believe both the harvesting and the implantation can be done through a needle, or small, blunt-tip cannula that causes minimal trauma to the annulus.

PDN, on the other hand. The first generation devices had high failure rates due to migration/extrusion out of the annulotomy, as well as subsidence into the endplates (due to poor fit with the endplates? due to the device being harder than a natural nucleus?) Several new implant designs, as well as redesigned surgical procedures, have been advanced and are still in trial and development phases. Reportedly, the new procedures have brought the implant failure rate down for Raymedica's PDN, but not solved the problem completely.

PDN is inherently more invasive than ADCT. The removal of the nucleus as the necessary first step is not a simple thing, judging from the discussion about techniques and surgical tools to effect this step. As for implantation of the device, it would seem that the injectable PDNs have an advantage, requiring smaller incisions/annulotomies, and possibly resulting in better fit and adherence.

2) Any risks associated with the materials? Toxicity, particulate wear, allergies?

ADCT obviously uses only the patient's cells and so compares favorably to foreign implants in this category.

PDNs appear to use materials well tested for biocompatibility. Unlike ADRs, there is no friction or hard surface that could result in particulate wear over time.

3) Any reported ill effects? How many patients have had the device implanted, and how long have they been walking around with it?

I'm not aware of any reports of ADCT causing complications, side effects, etc. There are the usual risks of the surgery. The first implant group was in 1996. I think I remember reading that about 250 patients total have had the procedure, but I cannot find that reference now, so I may be dreaming it. In the very similar technology of chondrocyte transplantation for other joints (e.g., knee cartilage repair), there is a good history of safety.

With PDNs, the big stumbling block has been implantation of the device. Early generations of the surgery had a high rate of migration of the device outside the annulus, subsidence into the endplates, etc. The latest products and procedures display a wide array of new approaches, which will hopefully eliminate such risks, or reduce them to minimal. But, we still don't know.

It appears that, once you get past the hurdle of implantation, PDNs have a good track record on safety (10 years) for patients who've been walking around with them for many years.

4) Might it wear out and need replacement?

There is a theoretical likelihood that the benefits of ADCT will fade over time, at least for older patients, due to cell senescence. However, unlike a foreign device that, if failed, must be removed or worked around (e.g., if an ADR wears out), ADCT does not create future problems not inherent in normal disc degeneration any way.

There is no clinical evidence either way yet, but it would seem theoretically possible that a PDN could wear out, or degrade over time.

5) Is it revisable if things go wrong?

Obviously, there have been many PDN revisions--but I can't quite figure out from the literature what they've done with those patients who've required "a second surgery" or "revision" if the implantation fails. Do they implant a second PDN? Revise to fusion or ADR? Obviously, they can't unscramble the egg.

6) Is there damage if things go wrong?

It seems like a failed PDN implantation could cause collateral damage--e.g., damage the nerve root if the device migrates outside the annulus. Are endplates damaged when there's subsidence? I could find little info.

7) Does it burn bridges for further surgeries?

Neither ADCT nor PDN would rule out future fusion or ADR at the same or other levels.

[mmglobal]

Wow Sharman... nice post. It's tough to find the time to respond to so much at once. Sorry for the delay.

But a disc, of course, is a unique ligament, in that it has at its core the jelly-like nucleus. I envision the nucleus as a swollen water balloon, its turgidity giving support and cushion to the adjoining vertebrae.

The analogy works, but think of the nucleus as more like crab meat instead of jelly. The last surgery I observed included putting an ADR in where there was a relatively tall and well hydrated disc. (There were structural issues and pathology at this level, but the nuclueus was nearly normal.... very unusual.) When the surgeon removed this big 'puck' of nuclues examined it very closely. I'm used to seeing nucleus tissue as crab meat, but this was so moist and the structure of the tissue seemed so much better. More degenerated discs are very tough and stringy. Discs that have been IDET'ed may have been turned brown by the barbeque that's been done on it. The worse the degeneration, the tougher and stringier the meat. The healthier the tissue, the whiter, moister, more tender, etc.... I swear you could put it in a crab salad and nobody would know the difference, although I don't know what it tastes like.

The discussion about the sources of discogenic pain needs some comment. I honestly don't believe that the pain mechanism is fully understood. All of the items mentioned are completely asymptomatic in some people, while highly symptomatic in others. Left out is the discussion of granulation tissue. With the annular tears, acidic toxins secreted by the disc, etc... an inflammatory response is generated. This may cause inflammatory tissue, normally on the dorsal disc wall that can be highly innervated. This is why careful discectomy is required for ADR. Lack of complete discectomy for ADR or fusion may result in ongoing pain.

ADCT

the recruited cells are (I believe should be) harvested from healthy discs

I'd have a very tough time allowing any procedure that would potentially damage a healthy disc. I've not heard this, but that doesn't mean it's not done. The only presentations I've seen regarding ADCT involve harvesting cells from the disc that requires the discectomy, not from a healthy disc. Again... the scope of my experience is limited... just because I haven't seen it, doesn't mean it's not true.

Injectable nucleus replacements

only inject enough to replace the material removed for the herniation, they don't replace the entire nucleus.

I've seen several presentations about many of the injectables. As I understand it, the slug of polymer that will become the nucleus replacement must be large enough and well shaped to have structural integrity. While it's true that they are not striving to do a complete discectomy, a large amount of nucleus is removed from the disc to provide a decent cavity for the injectant.

ADRs, there is no friction or hard surface that could result in particulate wear over time.

This is an interesting statement. I'm curious how the polymer will hold together over time... what will slough off? will there be wear? I'm reminded of other famous quotes:

• "It worked in the lab!"
  
• In theory, there is not difference between theory and practice. In practice, there is!

I don't buy the assumption that the current crop of nucleus replacements, whether injectible, endoscopically implanted, or more traditional implants like PDN will be easily revisable. What will the state of the endplate be after the failed device is explanted? Will it accomodate and ADR?

There are still a ton of questions and much of this technology is very new. However, this is what people warned me against when I went to Germany for my ADR 4.5 years ago. If I was early enough in the degenerative cascade to consider such treatments, I'd be taking a very good look at them. But, with what I've seen about new technologies, surgeons experience, failed deployments of what seemed to be the best thing since sliced bread (IDET, original PDN and many others), my look will be very skeptical. That doesn't mean don't do it.... it just means don't buy the markenting spin... do more homework... maybe wait for the exprience with the new technology develops.

Just my layperson... I'm not a doctor, yada, yada, yada, opinions based on my limited view of the spine world...

Mark

[sharman]

Amazingly enough, I have one more long part to this already interminable piece. This part will talk about combining ADCT and PDN with other therapies. (May be split up, due to post length limits)

First, three apologies. 1) Sorry to take so much space with this. If you're getting sick of it, imagine how I feel. 2) I apologize for not taking the time and energy to post sources, and figure out how to link on this forum. If there is any info here you would like sourcing for, just ask, and I'll be happy to dig it out and post it. 3) "PDN" is strictly speaking a brand name used by Raymedica for its nucleus replacement products. But I know of no generally used acronym for "nucleus replacement prostheses," so there, that's the term I've glommed on to.

So getting to it:

There are four possible complementary therapies: (i) endplate abrasion, (ii) selective endoscopy, (iii) thermal annuloplasty/ablation of granulation tissue and (iv) biologic agents. These therapies were discussed in the thread "Can you Heal a Disc?"; this post will talk about how and if they can be combined with ADCT or PDN. Finally, there's a small section on further developments and issues with ADCT.

Combining therapies is not entirely wild-eyed speculation on my part. This is from the website of Spinewave, the company that makes NuCore, one of the injectable hydrogel PDNs:

"On going efforts are characterizing the use of the material as a cell-delivery vehicle for disc repair and reconstruction. Related development efforts are exploring methods for repair and regeneration of the cartilage endplate that are implemented to enhance the host-implant interface. Prior to the introduction of the above-mentioned bio-material, our work proposed to utilize a process for the treatment of the vertebral endplates. The goal of this process is to restore the endplates as closely as possible to their natural state prior to disease or degeneration. The nature of the treatment will depend on the type of scaffolding that is intended to be introduced to the nuclear cavity. Endplate therapy is a potential means of enhancing biomaterial integration and cell survival, but remains a long-term and currently untested methodology."

I Endplate abrasion

So let's talk endplates. So-called "Mdic changes" (named after the researcher who first identified them) are often seen in patients with symptomatic DDD. There are three types of Modic change: Type I is inflammation/edema of the endplate; type II is replacement of the bone with fat (indicating that the inflammation has been of long duration: type I morphing into type II) and type III is bone sclerosis, hardening of the bone ("as the body tries to heal the damaged disc, extra bone cells are formed.") Degenerative changes in the endplates may contribute to the pathology of DDD by compromising the nutrient/waste/water exchange between the nucleus and the endplates.

(And/or, the endplates might themselves be pain generators. At this point, my eyes have well and truly rolled back in my head--I don't have the strength to consider another pain generator. If the endplates are the pain generators, you wouldn't think an ADR would fix things, would you? Seems that having a keel chopped in it, or cleats nailed into it, would exacerbate rather than ameliorate such a pain source.)

Hoogland at Munich's Alphaklinik has been doing a procedure he calls endplate abrasion, where he scrapes the endplates to remove calcification:

"The calcified bone of the adjacent vertebrae is refreshed by means of special fraises and sharp spoons, in order to acheive a better blood circulation. The now vital vertebral bone will grow new tissue, eventually restoring the schock-absorbing qualities of the intervertebral disc."

Hoogland has just published results of a 66-patient study, and claims excellent results for patients with Modic 1 changes (80% good or excellent), versus 40% good/excellent in Modic II. Back pain of 5 years or less duration also correlates with better outcomes with this procedure. Hoogland claims to acheive observable re-hydration three months following the procedure.

So, in theory, endplate abrasion would appear to complement both ADCT and PDN (although there is no more living nucleus requiring a healthy endplate, PDN does require the ability to uptake and expel water through the endplates, so abrasion (or other endplate therapy--SpineWave would not divulge much about the "process for the treatment of the vertebral endplates" that they are investigating) might improve this function.

Important caveats with respect to combining abrasion with ADCT: Abrasion is invasive; introducing this into the treatment plan somewhat cancels out one of the biggest advantages of ADCT, the minimal trauma. While it is sorely tempting to find a way to boost the effectiveness of ADCT (my gut feeling, that it is the least likely therapy to work, and will require a very healthy disc to start with), I would have to be very convinced of the benefits of abrasion before accepting the additional risk.

II Selective endoscopic procedures

Yeung speaks of using his visualized endoscopic procedures to see and remove parts of the nucleus that have degenerated, and also "interpositional disc tissue" he finds stuck in annular tears. It is thought that the 'interpositional tissue' prevents the tears from healing, or serves as an irritant. How the presence of degenerated nuclear material contributes to back pain is not clear to me, but perhaps this study suggests the mechanism: "The high levels of proinflammatory mediator found in disc tissue from patients undergoing fusion suggest that production of proinflammatory mediators within the nucleus pulposus may be a major factor in the genesis of a painful lumbar disc." Maybe degenerated (necrotic?) material creates or exacerbates the inflammation.

Hoogland combines these endoscopic procedures with his endplate abrasion.

Again, adding invasive procedures to an ADCT raises the risk level. For PDN, the nucleus is entirely removed, so that's a moot point, but as long as they're in there anyway hauling out the NP, it may make sense to look at the tears and make sure anything stuck there is removed.

[sharman]

III Thermal annuloplasty/ablation of granulation tissue

A normal disc is avascular, has no blood supply and, as previously noted, only the outer third of the annulus is innervated (has nerve endings and therefore, pain sensitivity). There is however blood supply to the innervated outer third of the annulus (or just outside? I'm not certain which). Part of the normal inflammatory healing response is neovascularization, the growth of new blood vessels into a wound. The neovascular tissue is 'granulation tissue.' The granulation tissue grows into the annular tear, and the new blood supply brings new nerves with it. A hallmark of disc degeneration is a more vascularization and innervation deeper into the disc than normal.

Annular tears usually develop from the inside out, from the interface with the nucleus (where there is no blood/nerve tissue) out into the outer third. Is that how back pain progresses? The tear first hits the sensitive outer third of the annulus, then neovascularization brings the growth of nerves to the previously insensitive inner annulus? Perhaps the pain mechanism is contact between these new nerves in the tear and the caustic material of the nucleus (a good reason the inner part of the annulus is nerveless in the first place). Perhaps it is simply the multiplication of nerve endings in a wound (the tear) that does not adequately heal. (IMO, mechanical low back pain, pain that increases with activities that load the disc and are relieved with rest, is more likely due to pressure on the innervated tear than chemical toxicity from nuclear material invading the tear. But it could be some of both.)

The body's normal healing process thus apparently works against it with damaged discs, bringing nerve endings to a space where they're likely to encounter chronic irritation.

Thermal annuloplasty

Thermal annuloplasty is the application of heat to the annular tear. The heat causes the tear to shrink (how collagen reacts to heat). It is also hypothesized that the procedure may depopulate the nerve endings in the tear, tho the claim is usually phrased as "maybe" and "partially." The procedure has been done with IDET and discTRODE (same concept, just different heating methods); Yeung does it in conjunction with his SED, with the advantage of being able to view the tear as it's being treated.

I'm leery of thermal annuloplasty. It seems obviously to carry the danger of further damaging the annulus, even when the procedure is visualized and thus more controlled (the surgeon can see the tear react to the heat--is it shrinking or enlarging?), as in Yeung's SED.

IDET has proven disappointing and new studies from Yeung tell us that even patients who enjoy an initially successful result deteriorate again in a few years. (Consistent, by the way, with the mechanism of pain relief being depopulation of nerve fibers--the same as RF ablation of the facets, which also sees improvement eroding when nerves grow back.)

Ablation of granulation tissue.

Now the granulation tissue. Ablation is again the application of heat. Used on granulation tissue, my understanding is that it is akin to cauterizing a wound. I imagine it stops further progression of capillary formation? I can see maybe where that prevents further, more painful deterioration--how does it relieve pain? Do you cure inflammed tissue by heat-blasting it? Frankly, granulation tissue is where I give up. I would truly welcome any insight or info anyone may have into how this tissue plays a role in back pain, and why it's a good idea to ablate it. I am aware of no one but Yeung doing this. And again, I am leery of using heat to alter disc tissues.

IV The Biologicals

Combining biological enhancements is a variation discussed not infrequently in connection with ADCT (that is, the little you see ADCT discussed) and the SpineWave bit I quoted above suggests that they can be combined with PDN as well: "The material [injectable hydrogel] [can be used] as a cell-delivery vehicle for disc repair and reconstruction." [The company is being coy with information, so I'm speculating here. Is the delivery being made to the cells of the annulus and/or endplates (given the nucleus has been removed)? Or is this only intended to be used when their PDN is used as an adjunct to a discectomy, and much of the nucleus remains?)

The notion here is that biological enhancers like growth factors can be embedded into the hydrogel or matrix on which the ADCT cells are grown (the matrix then to be injected with the cells).

I believe there are now clinical trials underway testing intradiscal injection of growth factors as a DDD therapy (at least one in Los Angeles); if that bears out as a therapy, it certainly makes sense to add it to ADCT and possibly PDN. Mark tells me that Dr Garcia in Florida will be starting a trial for intradiscal injection of BMP.

With an ADCT, of course, it will also always be possible to inject biologics at any time--before, maybe during, and certainly months or years after the procedure. With PDN, I don't know. All or most of the PDNs appear to be porous, or at least wet. Can you inject these manmade nucleuses with therapeutic agents, and get them to the annular or endplate tissues you wish to repair?

(And for that matter, to digress, can you do provocative discography on a PDN'd disc? If problems develop down the road, how can you tell if you need to revise the PDN to an ADR or fusion?)

Another possible biologic enhancement for ADCT (now in animal trials at the Cleveland Clinic?) is gene therapy, where through genetic engineering the cultured cells are amped up, so that they produce more of the proteoglycans that keep the nucleus hydrated, and possibly even reproduce more readily. Among other things, this would hopefully combat the senescence that may make an older patient a less good candidate for ADCT.

The final biologic agent in this category is disc prolo, the dextrose solution that is thought to kickstart a healing cycle in the annular tear (which I've tried with some success and some failure). Disc prolo could be done before or after an ADCT, not sure about a PDN.

[sharman]

V More Stuff on ADCT

Finally, some thoughts and issues and new developments with ADCT.

When you are doing ADCT not in conjunction with a disectomy, the first question is where to harvest the cells from. It seems to me, the harvest should be from very healthy discs, not the damaged one. While mucking around with a healthy disc always introduces a new risk factor (but hey, we do it in provocative discography), it seems foolish to me to further harass the compromised disc by using it as a donor site.

Technologies now under development may soon allow the harvesting of cells from less vulnerable sites. There's a patent application I googled up that talks about using gene therapy to turn chondrocyte cells harvested from other joints/cartilage into proper nucleus chondrocytes. And, at the University of Manchester, trials may be underway this year on a technology to turn mesenchymal stems (adult stem cells) harvested from the patient's marrow into nucleus chondrocytes, which can then be cultured for implantation. (Note, this seems a different procedure from a disappointing 10-patient study undertaken by Microspine (no positive results reported at all), where stem cells were injected directly into the disc.)

(Of course, the U.Manchester surgeon (Richardson) then throws cold water on straight-up ADCT: "Cells from degenerate discs are not suitable for tissue engineering..." Wonder what he thinks about harvesting from healthy cells?)

If you're going to do the ADCT in conjunction with another invasive therapy, optimal timing becomes an interesting decision. Is it best to do the SED/abrasion/whatever first, allow the disc to heal, and then transplant? Or do the SED/abrasion, etc. when you can simultaneously inject the new cells? Right now, I'm leaning toward the latter. First of all, it's one less time you're poking a hole into the disc--presumably, you can do the injection through the same cannula you use for the abrasion, etc. Second, if we're going to be poking around in a traumatic fashion, scraping and removing things, especially if a volume of material might be removed, I like the idea of immediately providing new chondrocytes to start the rebuilding.

(Where ADCT is done in conjunction with a discectomy, three months is allowed between for healing. But there, the invasive discectomy is going to happen any way, that tissue is going to be used for the culture, and there's no way to change the order of the procedures: a discectomy, followed by at least a month for the cells to culture, so may as well make it three for optimal healing. So that practice and experience does not, IMO, have any bearing on the optimal process for ADCT not performed as an adjunct to discectomy.)

One last rambling thought about ADCT. You can probably tell, I really want this thing to work, and I have to try to keep a reality check on my enthusiasm. I've just had a chance to talk at length with Mark. Let me try to distill the pros and cons, the hopeful stuff and the caveats:

1) It is sobering that there is, in Mark's words, no 'buzz' about this procedure--it's been out there 10 years now. I want to believe this is because it is only a small patient population that can benefit, and because there is little patentable technology; hence, there is little money for trials and marketing.

2) It seems too good to be true, that you could heal up a chronic and stubborn condition like low back pain, just by culturing and reinjecting the patient's own cells. Nonetheless, there is a real track record of success building in the closely related field of knee/hip etc cartilage regeneration.

3) Is it an acceptable risk to harvest cells from healthy discs? If not, then it's a couple more years' wait for stem cell or similar technology to culture nucleus chondrocytes from less vulnerable tissue (bone marrow, joint cartilage). I have yet to talk to a surgeon who does this procedure; I may find I cannot find anyone willing to undertake the procedure except in conjunction with a discectomy.

4) And if you want to combine ADCT with other therapies, good luck finding a doctor or clinic who is willing to do, and is proficient in, both techniques.

There! I do believe I've punched myself out. I look forward to any thoughts or info any one else would care to impart!

[Rebecca]

Now I was just at the Cleveland Clinic for 2nd Posterior fusion. The First anterior didn't take; screws fell out. Second anterior fusion lasyed1.5 yrs vs 10 year "supposed". Now my Neuro is THERE and took OUT old post stuff andd implanted new and added c3 thru T1 using what I believe is old technology. I heard nothing of this research. Am I too far gone. Also I have high nickel intolerance and I believe he insterted stainless surgical of which I am also highly allergic. Compositon approx 15-20% nickel. Was on my wristband and it's in all my files. He has yet to inform me of what was implanted as I see total different struction with cage and wired. I suspect one wire loop has disengaged from screw. Pain facet doc gave copy rad and my MASSAGE THERAPIST spotted it on Xray and can feel wire. I am told info on a "if I ask" basis only. I have c8 nerve damage due to surgery as well. Very concerned about instrumentation.....comments. He will be forthcoming about cervial surgical implants. My chart is supposedly in "compilation" still. 3 months later Nov 06. I think trying to dodge and I will go to head of hospital next week. I refuse to be treated as a moron or a guinea pig or did was he just neglectful. His PA says oh, it's not much but I have major reaction to a touch of a paper clip. I am extremely tired of being in the dark and now 4 years of pain/crap and contant stress. Unfortunately litigation becomes a factor. Any comment? Excellent, most informative reading yet!
Becky Belcher
937-885-1122

[Rebecca]

nerve function due to damaged C8 from this past surgery.

bECKY

[sharman]

I surely know nothing about fusion. When you ask if you are 'too far gone' for the newer technologies, obviously you're not talking about the levels that have already been fused, right? I would say, if these new technologies bear out, there's a good chance they will save you from having more fusions, if another level starts to deteriorate and you treat it in time. One rule of thumb for the nucleus regeneration/replacement is, you need at least half of your disc height still.

I'm also no help about the hardware and your metal allergies. One thing does seem worth considering. If I'm correct in this understanding, the hardware is to keep things in place while you fuse. Once you're fused, you don't need it any more. So, given your understandable concern about the metal allergies, perhaps you can plan to have the hardware removed at the earliest opportunity. Of course another surgery is always risk,there's scarring, etc. But it's an option. Wonder what you could do to find out if you are having a bad reaction to the metal. Are you not recovering as expected from the fusion?