P R O C E E D I N G S

(8:03 a.m.)

CHAIRPERSON RAO: Good morning and welcome. My name is Mahendra Rao, and I'm the Acting Chair, I guess the Chair now, the Chair of the Biological Response and Modifiers Committee.

Please note that the name has changed. It's now called the Cellular Tissues and Gene Therapies Advisory Committee. That name change happened just -- I think it's the first time it has been meeting under this new name.

Before I turn the mic over to Gail, I just wanted to explain a few of the ground rules for having this meeting, and I wanted to remind people of a couple of things.

So I want to remind people that this is an Advisory Committee meeting, and it's mainly involved with getting comments from the committee members and the invitees who are going to be ad hoc members of the committee. Everybody else is welcome to participate, but you have to be recognized by the Chair before you can do this, and there will be a special time period where you can be recognized.

If you need to make a special statement, then you should please contact Gail and see whether there's time to be able to make that statement.

As you'll see, you need to use the microphone, and I'm going to ask all the members of the committee to remember that you should switch it off to avoid background noise when you put the microphone off after you finish speaking, and then wait for the Chair to recognize you before you start the conversation.

Thanks.

Gail.

MS. DAPOLITO: Good morning. The following announcement addresses conflict of interest issues associated with this meeting of the Cellular, Tissue and Gene Therapies Advisory Committee on March 3, 2005. Pursuant to the Authority granted under the committee charter, the Director of FDA's Center for Biologics Evaluation and Research appointed the following individuals as temporary voting members for the committee discussion of cellular therapies for repair and regeneration of joint surfaces: Drs. Matthew Allen, Richard Coutts, Wayne McIlwraith, Alan Nixon, Darwin Prockop, Sean Scully, and Rocky Tuan.

Based on the agenda, FDA determined that there are no specific products being considered for approval at this meeting. The committee participants were screened for their financial interests. To determine if any financial conflicts of interest existed, the agency reviewed the agenda and all relevant financial interests reported by the meeting participants.

The Food and Drug Administration prepared general matters waivers for participants who required a waiver under 18 USC 208. Waivers were granted to Drs. Richard Coutts, Mark Hochberg and Alan Nixon.

Because general topics impact on many entities, it is not prudent to recite all potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussions before the committee, these potential conflicts are mitigated.

We wish to note for the record that Ms. Alison Lawton, the non-voting industry representative for this committee, recused herself from the discussions of Topic I related to cellular therapies for repair and regeneration of joint surfaces.

With regard to FDA's invited guest speakers, the agency has determined that their services are essential. For the discussions related to cellular therapies for repair and regeneration of joint surfaces, the following disclosures will assist the public in objectively evaluating presentations and/or comments made by the participants.

Dr. Joseph Buckwalter is employed at the University of Iowa, Iowa City, Department of Orthopedics. He consults with Genzyme.

Dr. Marc Hochberg is employed at the University of Maryland School of Medicine. He receives research support and consults with firms that could be affected by the discussions.

Dr. Frank Luyten is employed by the University of Leuven, Belgium, and Dr. Charles Peterfy is employed by Synarc. He has associations with firms developing non-cellular osteoarthritis and cartilage therapies.

We would like to note for the record that Dr. Matthew Allen is serving as a temporary voting member and a speaker making a presentation for Topic I.

FDA participants are aware of the need to exclude themselves from the discussions involving specific products or firms for which they have not been screened for conflicts of interest. Their exclusion will be noted for the public record.

With respect to all other meeting participants, we ask in the interest of fairness that you state your name, affiliation, and address any current or previous financial involvement with any firm whose products you wish to comment upon. Waivers are available by written request under the Freedom of Information Act.

Thank you.

CHAIRPERSON RAO: So this 38 committee has two new members, and I'm going to ask them to introduce themselves first. Dr. Tomford.

DR. TOMFORD: I'm Dr. William Tomford. I'm a professor of orthopedic surgery, Harvard Medical School. I am an active clinician/orthopedic surgeon at Massachusetts General Hospital in Boston, and I have an interest in bone and cartilage storage transplantation and preservation.

CHAIRPERSON RAO: Thank you, Dr. Tomford. If you would give the mic.

The other new committee member is Sharon Terry.

MS. TERRY: Hi. My name is Sharon Terry, and I'm the President and CEO of the Genetic Alliance, which is a coalition of 600 advocacy groups.

I come to that as a parent of two children with a genetic disease, having founded PXE International to support research on that disease.

CHAIRPERSON RAO: Thank you, Sharon.

I'm going to ask all of the committee members to introduce themselves as well, and we'll start from the left with Dr. Nixon.

DR. NIXON: Hi. I'm Dr. Alan Nixon. I'm working at Cornell University. I'm Professor of Orthopedic Surgery there and the Director of the Comparative Orthopedics Laboratory.

DR. COUTTS: I'm Richard Coutts. I'm an orthopedic surgeon from San Diego, California with the University of California, San Diego. I've had a longstanding interest in cartilage healing and tissue engineering of cartilage.

MR. McILWRAITH: I'm Wayne McIlwraith, Professor of Surgery and Director of Orthopedic Research at Colorado State University.

DR. SCULLY: Sean Scully. I'm a Professor of Orthopedics at the University of Miami with an interest in cellular biology.

DR. TUAN: Rocky Tuan, Chief of the Cartilage Biology and Orthopedics Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH. My interest is cartilage biology and tissue engineering.

DR. ALLEN: Matthew Allen. I'm a veterinarian. I'm Associate Professor of Orthopedic surgery at SUNY-Upstate in Syracuse, and my work really focuses on the validation and development of animal models of orthopedic diseases and conditions.

DR. BLAZAR: Bruce Blazar at University of Minnesota, Professor of Pediatrics, and my interest is in cellular and gene therapies related to inherited disorders and bone marrow transplantation.

CHAIRPERSON RAO: I'm Mahendra Rao. I'm at the National Institute of Aging and I work on stem cells.

MS. DAPOLITO: Gail Dapolito, Executive Secretary for the committee.

I'd also like to introduce the committee management specialist, Rosanna Harvey.

Thank you.

DR. TSIATIS: Hi. I'm Butch Tsiatis. I'm a Professor of Statistics at North Carolina State University.

DR. ALLAN: I'm Jon Allan. I'm a scientist at the Southwest Foundation for Biomedical Research, and I'm a virologist and I study pathogenesis of SIV in non-human primate models.

DR. HIGH: I'm Kathy High. I'm a hematologist at the Children's Hospital of Philadelphia, and my research interests are in cell and gene therapy.

DR. HARLAN: I'm David Harlan. I'm the Chief of the Islet and Autoimmunity Branch of the NIDDK at the NIH. My interests are immunotherapies for Type I diabetes.

MR. STEVENS: I'm Ted Stevens, another at Kaiser who's been delayed. I'm the Chief of the Restorative Devices Branch in FDA's Office of Device Evaluation and the Center for Devices.

DR. McFARLAND: I'm Richard McFarland. I'm a medical officer in the PharmTox Branch of the Office of cell Tissue and Gene Therapy of the Center for Biologics.

DR. LEIBENHAUT: My name is Susan Leibenhaut, and I'm a medical officer in the Office of Cellular Tissue and Gene Therapies, the Clinical Evaluation Branch.

DR. MOOS: I'm Malcolm Moos. I'm a product reviewer in the Division of Cellular and Gene Therapies with interests in cellular therapies for repair and regeneration generally and research interests in the characteristics of cells that can be used for those purposes.

CHAIRPERSON RAO: If we could have people at the FDA introduce themselves very quickly, too.

DR. PURI: Do we have to use the mic? Okay.

I'm Raj Puri, the Division Director of Division of Cellular and Gene Therapy, the Center for Biologics Evaluation Research, FDA.

DR. FREY: Joyce Frey, Deputy Office Director for the Office of Cellular Tissues and Gene Therapy at CBER.

DR. WITTEN: Celia Witten, Division Director of the Division of General Restorative and Neurological Devices in the Center for Devices for two more days, and as of Monday, the Director of the Office of Cellular tissue and gene therapies.

DR. MIDTHUN: I'm Karen Midthun, Deputy Director for Medicine, Center for Biologics.

CHAIRPERSON RAO: So now that you've met all of the big chiefs at the FDA, I'll ask Karen to come and give a few words.

DR. MIDTHUN: Good morning, and welcome. I'd like to take this opportunity to thank Dr. Bruce Blazar, Dr. Katherine High and Ms. Alison Lawton, all of whom are completing their terms on our Advisory Committee.

We very much appreciate the expertise that you have brought to this committee and the time and dedication that you have given to us. We recognize that is a very large contribution and very much appreciated.

You've helped guide the center through many challenging issues in the gene and cell therapy arenas, and we hope that in the future we can also draw upon your expertise.

And as a small token of our appreciation, I have some plaques that I would like to give to each of you. So if you would please come up to the podium.

(Whereupon, plaques were awarded.)

(Applause.)

DR. MIDTHUN: And I just would also like to take the opportunity. Fortunately Dr. Witten was able to introduce herself. She is joining us as Director of the Office of Cellular Tissue and Gene Therapies. We're very excited to have her joining us.

She is coming to us from Center for Devices, where she has been the Director of General Restorative and Neurological Devices, and she brings with her a great background from Center for Devices and also a background in rehabilitation and physical medicine. So we're very, very much looking forward to having her join us, and I'm sure you will have an opportunity to get acquainted with her.

So thank you, and thank you for your contributions, and now we'll get on to some serious business.

CHAIRPERSON RAO: Thank you.

I guess we can get on to the main part of the meeting here, and I'll start with asking Dr. Moos to give us the FDA's perspective of the questions and the issues that they would like us to discuss.

I want to remind everyone that today we have a pretty long day, and so all of the speakers, please try to stay within your allotted time and give us room for a reasonable number of questions.

DR. MOOS: Thanks, everyone, for joining us for this discussion of cellular therapies for the repair and regeneration of joint surfaces. This is an area where the agency recognizes an increasing amount of activity and significant opportunities, but also where we see that there are significant challenges, and in situations like this, we like to try not only to tell you what your problems are, but to take an active role in helping to guide participants in the field past those problems.

One kind of activity that we've been involved with for some time but now has an official name and official sanction so that it's called the critical path initiative. Originally we were going to hear a detailed report on this at this session, but to make room for what on your agendas is listed as Topic II tomorrow afternoon, that was dropped.

However, I'd like to make first the point that information on this topic is available through our Web site, given at the bottom of this slide, and secondly, to call attention to the idea that advisory committees which conventionally have been used to assess specific products or proposals relatively late in the development scheme are also acknowledged as being useful much, much earlier, particularly in the areas of cell and gene therapies, as we've been finding over the past few years, to help us identify what scientific tools are needed to move products from bench to market.

Now, the kinds of questions that arise sort of generically for cell products are several. Initially there is often a focus on what is needed to get into exploratory clinical trials, and this depends on getting enough proof of concept data to justify that there's a rationale for pursuing these sorts of experiments in the first place and also enough supporting safety data from preclinical studies to conclude that the risks are acceptable in light of potential benefits.

In addition, one needs to know enough about the product to have some idea of what it is, whether it is demonstrating reasonable integrity, viability, and so forth; whether it's pure and other specifications, such as enough stability to support the trials and shipping qualification, free stock qualifications and so forth.

But those questions are not exactly the same questions as need to be answered to get the entire product development cycle through marketing approval completed. So after initial trials have begun, it's important to continue to address issues relating to the product: of potency, viability, more studies on how to identify the product, the impurities that might be in it, how best to assess purity, and these other specifications.

So it's very important in view of the difficulty with cellular therapies for several of these not only to keep going and trying to work hard while initial trials are underway, but to start thinking about these issues hard as early as possible in the development cycle.

As confirmatory trials are nearing their completion, it's important to have most of these issues ironed out, and I've listed some of them below so that licensure can be entertained, and perhaps next generation products can begin their development cycles.

Now, these are questions that are generic to lots of types of products, and during the discussion, I am sure that there will be many issues that will make one or another of you think of these broad applications, and we recognize that one area of endeavor can inform another.

I will show you a specific example or two of that tomorrow. However, the Chairman and the organizing committee agree that we want to try as much as possible to stay focused today and tomorrow on those issues that are specific to cells that might be used for the repair of joint surfaces.

And so Dr. Rao has been empowered to use all means fair and foul short of physical violence to steer you back on track as necessary.

Now, the committee has been posed with a number of specific questions which have been set down in print in the packages that most of you have, and I'll just say a few general words about them.

Conventionally the products of this type that have been written about and considered have begun with samples of predominantly autologous cartilage from a non-weight bearing surface of usually the knee, and the knee has been the focus for most efforts to date. We hope that some of what we discussed today might have applications in other joints, but so far that remains for the most part in the future.

Other collection sites have been entertained, the periosteum, the synovium, and there are other things that have been imagined and proposed as well, mesenchymal cells derived from bone marrow stroma or from bone marrow, autologous fat, even allogeneic sources of various types, and the committee will be asked to discuss some of the issues involved in identifying appropriate starting materials for the manufacture of these products.

Once the tissue is collected, it is placed generally in culture for purposes of expansion with or without some other types of manipulation, and there are many questions about what happens outside of the normal in vivo environment that need to be addressed, and some of these are also going to be a focus of our discussion.

Among the possible manipulations are the addition of other types of components, whether these might be substances produced by the cells themselves or artificial matrix components that might introduce specific considerations that will need to be factored into characterization of the products in development of release testing.

A very important part in the development cycle is the use of the appropriate models for various different purposes required to support safety and proof of concept, and also to use them in the appropriate way. Possibly more than one model might be needed to contribute to the overall picture of what might be expected in human studies.

And finally, the products are readministered in some form back into the patient, and there are issues with the design of appropriate scientifically powerful clinical trials.

During the course of the meeting, the organizing committee has considered that there are three main themes. The first is scientifically sound clinical trials. The second, capabilities and limitations of preclinical models, and the third is how to manufacture and test products so that we know that they are safe, effective, and consistent.

As you heard previously, and I think it bears repeating one more time, this is a meeting to address scientific and medical issues and is not intended to address any specific product or proposal.

More than usually, there is interplay between these areas, and we hope to develop how preclinical models, for example, might be used to qualify potential sets of release tests, and how the preclinical testing may also best serve the design of appropriate clinical trials.

I'd also like to acknowledge and to emphasize that the conception of the meeting has been done jointly between the Center for Biologics and the Center for Devices and Radiological Health, and members on this list of the folks who have helped me put this meeting together appear from both of the centers, and we have tried very hard to develop a consistent scientific and medical framework for considering all of these issues, and in all of our written materials have endeavored to avoid language that is associated with one or another specific regulatory mechanism.

And so if you hear us slip and say things like Phase 1, 2, 3 or pivotal feasibility instead of exploratory and confirmatory, I hope we can be forgiven. The underlying concepts really are what are at issue here, and what our focus is intended to be.

And a special thanks, of course, to our Executive Secretary, whom many of you have spoken with, and to Rosanna, who has helped in many of the logistical details.

Now, to serve those goals, just a rough road map, today we're going to hear some invited presentations, and those will begin with an overview of clinical considerations by a Dr. Joseph Buckwalter from the University of Iowa, and an overview of a number of bench to bedside issues by Dr. Frank Luyten from the University of Leuven.

That will be followed by preclinical presentations both from the outside and by the agency and by discussion of preclinical questions, then by a presentation and discussion of clinical issues which we anticipate might go long enough it will have to wind that up tomorrow morning.

Then we will discuss the product questions and wind up this portion of the meeting tomorrow afternoon. The second topic will be addressed under the direction of my colleague Dr. Carolyn Wilson.

And finally, I'd like to repeat a little bit, a few things that Dr. Rao said. A record of this meeting which will contain many, perhaps if we are lucky, all of the slides and a transcript of the proceedings, and to that end, I would like to ask participants to please be sure and use the microphones, and as excited as I'm sure some of you will get from time to time, to take turns when talking so that our transcriptionist is able to keep up with the discussions.

That concludes my introduction. So I'd like to invite Dr. Buckwalter to give us his overview with my thanks for making the trip.

Dr. Buckwalter.

DR. BUCKWALTER: Well, thank you very much.

I really appreciate the invitation to be here. The biologic resurfacing of joints is an absolutely fascinating subject and one that I've been personally interested in for 25 or 30 years, and I also appreciate the invitation to give a surgeon's perspective on how we evaluate the outcomes of biologic resurfacing of joints.

But I stress "a surgeon" because surgeons bring different perspectives to procedures and how they evaluate outcomes, and certainly you see that in a diversity of procedures that are used for biologic resurfacing of joints, decisions about which patients you operate on, which procedure you use for which patient.

And I think in putting that all in perspective, it's important to understand how surgeons evaluate procedures and how they make decisions about which procedure to use on which patient and the factors that influence their perceptions of the outcomes of results.

And I say this because most of the information we have about surgical procedures does not come from randomized control trials or hard evidence. It comes from a series of cases assembled by surgeons, and a number of things influence their perception of the outcome of results, and I don't think these can be underestimated.

Certainly the first is in doing a procedure if a surgeon believes it works, if he or she has considerable skill and experience in doing that procedure, not only does their perception of the outcome improve. I actually suspect the outcome improves.

One of the elements of surgical judgment that is so critical is what patient do you operate on. It's not so simple as looking at an X-ray and saying this patient needs a total knee or a total hip," or they need a cartilage resurfacing procedure. Surgeons factor in patient expectations, life style, their psychological make-up, a whole variety of factors in making a decision about who they operate on, and with time, I believe most surgeons get better at selecting the patients they operate on.

They also get better most of the time at least in their skills, but one of the most important is who do you operate on.

In general, surgeons, particularly in orthopedics because it is such a physical and functional specialty, tend to look at outcomes in terms of the technical success of the operation. When we fix a fracture, we look at how well we restore the anatomy. How close did we come to the way that limb looked before it was injured?

We have a child with scoliosis. We look at how well we corrected the curve, and I would suggest that most of the time in cartilage resurfacing, we've looked at how well we restore the anatomy of the joint.

Fourth, we tend to look at short-term outcomes, and that's obviously essential for many of these procedures, but when we look at many of the things we do at two, ten, and 20 years, we see different results at each decade. It's not uncommon that procedures enter the orthopedic armamentarium, and I suspect in most surgical disciplines without evidence from a control or comparison group, for that procedure, and it's common that there are no validated measures preoperatively and postoperatively. So I think it's important to put that in context when we start looking at biologic resurfacing.

At the present time, surgeons face a wide variety of choices in terms of biologic resurfacing of joints. The classic approach is, including penetrating subchondral bone, soft tissue transplantation are relatively well understood. There are a host of others that are entering clinical practice and some of which you will focus on that surgeons have to choose from in making a decision for an individual patient.

In addition, we do autografts and allografts, and of course, there is the very exciting, emerging area that's sort of a fusion of these two, which is tissue engineering, growing an implant outside the body in the lab and putting it in the patient. In some parts of the world that's already happening, and that's certainly a very exciting technology.

Penetration of subchondral bone, it's a 50 or 60 year old procedure. It's stimulation of the marrow to regenerate the joint surface. Around the world and certainly in the U.S., the most common way of doing that, and certainly I believe the most common procedure by all of the data that I'm familiar with is so-called micro fracture, which is penetrating the articular surface and articular defect in the femoral condyle here with a sharp instrument or awl stimulating bleeding and clot formation and then stimulating repair of an articular surface.

Now, this is a slide from the work of a surgeon named Lanny Johnston who performed a number of these types of procedures. He actually did it by abrasion.

Here's a patient that in 1980 had essentially no medial joint space. He did an abrasion arthroplasty, 83 weight bearing radiograph. They do have some sort of chondral repair.

And Dr. Johnston harvested a number of these specimens over the years, and here's an example of one where you see the kind of regenerate tissue that formed following abrasion arthroplasty in the human knee.

And I should have emphasized my task or my invitation was to talk about the human knee. Soft tissue grafts have been done since the first part of this century, everything from chromic treated bladder to fascia, to periosteum, to perichondrium, and indeed, this is an example of a periosteal graft generating new tissue.

Decreasing articular contact stress. I'd like to point out that this is not just a biologic phenomena. It's a mechanical phenomena, and recreating the right mechanical environment is extremely important, I think most surgeons would agree, and we know from studies of releasing, if you can imagine doing this, actually releasing the muscles that cross an injured joint and stimulating repair of the surface that way, performing osteotomies or, more recently, the concept of actually distracting a joint to stimulate repair.

And this is just a finite element model that we're using to study regeneration of the articular surface in the ankle joint. That's the talus, and this is a fractured tibial surface, and we calculate the forces and their concentration in different parts of the joint and then look at how the tissue regenerates in different parts of the joint depending upon the loading of the joint.

Now, just to give you an example of this kind of phenomena, this is a lady 23 years old, had a distal tibial articular surface fracture; within two years developed severe and disabling osteoarthritis. This is treatment of that by restoring the alignment of the talus under the tibia, distracting the joint, and here her pre-op film. Here she is at six months and at two years that joint surface not only holds up, it actually seems to improve slightly.

And this phenomenon was first described by surgeons in Utrecht in the Netherlands where they've done a number of these procedures, but I show this just to illustrate the influence of the mechanics of the joint on any of these biologic procedures.

There are, of course, a number of artificial matrices that are being popularized and used in different parts of the world for stimulating cell in-growth, cell multiplication, cell production of a new matrix, and regeneration of an articular surface.

Chondrogenesis factors, a variety of them, are certainly already being used in a number of animal studies and in some parts of the world, even in Australia and New Zealand, being used in patients to stimulate repair of an articular cartilage defect.

This is an illustration from some work that I was involved in in Switzerland in the '90s, looking at resurfacing of chondral defects using chondrogenesis factors.

You're most interested in cell transplantation, and a dilemma is surgeons look at this, are a lot of choices, and more choices coming along. Do you use chondrocytes or stem cells? Do you use autografts or allografts? Should it be embryonic, fetal, neonatal allografts? Should it be mature cells? A tremendous amount of information just here at this meeting in Washington last week actually at the ORS and the Academy about all of these strategies.

This is, of course, the basic procedure of debriding the defect, covering it usually with a periosteal flap, although many surgeons and centers are using other materials to do this, and then injecting cells under the defect.

Osteochondral autografts have been used since the 1950s, using patella, proximal fibula, and then more recently the concept of mosaicplasty where grafts are harvested from one part of the joint, transferred to other parts of the joint. A number of papers coming out, actually transferring grafts from the knee joint to the ankle joint, and a variety of other such choices.

Allografts also have a role in resurfacing of joints. This is the shell allograft concept of resurfacing a defect with a small graft or resurfacing a major part of the joint with a large osteochondral graft, often performing an osteotomy.

So how does a surgeon make sense of all of this? And when you see a patient in the clinic that presents with a chondral defect, how do you decide which of this wide variety of biologic procedures makes the most sense for that specific patient?

And obviously that hasn't sorted out, and what I put up here will no doubt be contested by surgeons in different parts of the world, but I've tried to give you a little sense of current practice around the world in terms of how do we handle this.

And I picked four centimeters. Some people pick two centimeters. Some people pick three centimeters. There are obviously a lot of choices, but I tried to put something out there that we could argue about or discuss.

But most people would say if there's a small defect, debridement and micro-fracture or some sort of marrow stimulation technique would be reasonable, particularly in patients that have had no previous treatment. And if they have a larger defect, if they've had previous treatment, if they have significant symptoms, many people would then go to autogenous cells.

Some, however, would use autografts or allografts, and for very large defects most would use either allografts or a very complex combination of periosteal and cell grafts called a sandwich graft or other similar strategies. If there's deformity, many would perform an osteotomy. Not everyone, but certainly if there's malalignment of the knee joint, most would perform an osteotomy.

So what are the results that surgeons are looking at in trying to decide which of these procedures should be performed on their patients?

Well, part of what makes the choice difficult is all of the things I've shown you have been reported using the methodology I showed you in that second slide to restore biologic surface, but how do you decide for an individual patient which procedure is best?

Well, if you look at most of our available literature, there are a whole variety of clinical disorders and patients that are being treated for this. We have surgeons who are expert in every one of these techniques and tend to be strong advocates for that technique and are very skilled in that technique.

There are a variety of outcome measures and how do you decide which is most appropriate? And as you are well aware, there are very few prospective randomized studies.

So what are the issues in evaluating results in the human knee for biologic resurfacing? There are a variety of patient factors that will influence outcome. Certainly defect size and type, severity of symptoms, age of the patient, and then there are a host of confounding variables.

And I have put patient expectations up here because this particular strategy of resurfacing a joint probably is more dependent on what the patient expects in terms of the outcome than many things we do. If somebody has a tibia fracture, we know what they expect. They expect a realigned limb. They expect a functional limb. They expect to be pain free, et cetera.

But what does somebody expect that has a chondral defect? And I'll discuss that a little bit more in a moment, but then there are a variety of other issues, including activity level, body mass, joint alignment, previous surgery, and how well their muscles function.

And then how do you look at outcome? I'll come back to this point, but speaking as a surgeon, I'm most interested in is the patient happy. Is their function what they want? Is their joint function what they want? They and I are perhaps less interested in the structure of their joint and what kind of tissue is replacing the defect.

Now, I want to spend just a very short time on different types of defects because, as I say, I look at the literature, and I see a lot of mixed approaches to exactly what we're talking about, and I'd like to distinguish the traumatic chondral defects and the osteochondritis dissecans defect from the degenerative defect both in terms of pathogenesis, age of the patient, and the tissues that are involved.

And this is a very crude, over-simplified analysis of a lot of data on human knee arthroscopy and cataloging what defects we're seeing mostly by a surgeon named Dandy.

But what it shows you is in terms of the percent of total articular surface defects in the human knee -- and as I said, grossly simplified, if you will -- the so-called osteochondritis dissecans or osteochondral defects are most common in adolescent and young adults. These chondral defects that I'll show you in a moment tend to be most common in mid-aged and young adults and then degenerative defects increase in frequency with increasing age.

And this is an example of the typical osteochondral defect in the young adolescent or young adult. This is an example of a pretty typical femoral condyle condylar defect in a young adult where there's a segment of the -- this is the articular surface. This is the subchondral bone, and so you see the defect.

This is, of course, a defect that involves both cartilage and bone, and then, of course, with age, cartilage changes. It becomes less stiff, more friable. There are alterations in the matrix, in the cell behavior, all of which change the biology of the joint, and it's for that reason perhaps more than any other that with increasing age we see increasing evidence of joint degeneration, osteoarthritis, and joint dysfunction.

Now, why does that have any relationship to the issues of cartilage repair? Well, let me just briefly summarize a lot that's in the literature comparing the two most common biologic approaches for small defects, as I showed you, micro fracture and chondrocyte transplantation.

Here's a study for all of its imperfections, but it's similar to the data from the a lot of studies, and to be brief, I'm just going to show you one or two that are representative of a lot that's published.

Looking at marrow stimulation, drilling the articular surface, trying to stimulate a new articular surface, a small series admittedly, but looking at osteochondral lesions in the ankle joint, the patients were under 30, 92 percent good results. If they're over 50, 20 percent, similar studies on radiographic. So a dramatic difference in terms of penetrating subchondral bone with age.

An older study on perichondral arthroplasty showing that although it may work relatively well in people under 30 and perhaps up to 30s or 40s, in people over 40 it just doesn't work very well.

Chondrocyte transplantation, this is just some data on cell function versus age, chondrocyte function versus age. You can see there's a slow decay with age, and this is a study presented at the ICRS, and it's in press right now, looking at the baseline synthetic pattern of human chondrocytes with age, but then looking at how they respond to anabolic stimuli, and as you can see, there's a decay with age.

So those are the issues. Those are the patient issues. Now, how do we as a surgeon want to look at the outcome of attempts to biologically resurface joints?

And as I said, from our perspective, the most important -- my perspective, and I say most surgeons -- is patient function, joint function, joint structure, and chondral tissue, and I'll look briefly at those.

I think it's worth thinking a little bit about what we mean by patient function. Certainly if somebody is confined to a wheelchair and we restore to them the ability to walk, however limited, that is a spectacular result for that patient.

But many of the patients I see coming into our sports clinic don't want to be restored to walking. They want to go from doing 5K races to doing marathons, and they tell us that they have a little medial knee pain if they train too hard, and so forth. So there's a range of perspectives in patients who have joint disease in terms of what they expect out of a procedure and what they are going to accept as a good result.

Joint function. Many of the studies do relatively little in terms of looking at joint function, although obviously they look at pain, but in terms of range of motion, how well the joint moves, its stability, these things are hard to measure objectively, but certainly once again from the patient's perspective and the surgeon's perspective, they're very important, and I think it