Stem Muschler

EXHIBIT E

TO MEMORANDUM IN SUPPORT OF PLAINTIFF’S MOTION FOR

SUMMARY JUDGMENT

MUSCHLER DECLARATION

REDACTED [Pending Motion to Seal]

United States v. Regenerative Sciences, LLC, Civil Action No. 1:10-cv-01327-RMC

IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

UNITED STATES OF AMERICA, ) Civil Action No. 1:10-CV-01327-RMC ) ) Plaintiff, ) ) v. ) ) REGENERATIVE SCIENCES, LLC, et al., ) ) Defendants. )

DECLARATION OF GEORGE F. MUSCHLER, M.D.

George F. Muschler, M.D. hereby declares as follows:

Introduction and Qualifications 1. I am a Doctor of Medicine and am board certified in Orthopaedic Surgery. I

received a Bachelor of Science degree from the University of Illinois in Champaign Urbana,

Illinois in 1977. I received my medical degree from Northwestern University in Chicago, Illinois

in 1981. I am licensed to practice medicine in Ohio. I have been a practicing board certified

orthopaedic surgeon for 20 years, working in the area of reconstructive orthopaedic surgery and

arthritis surgery.

2. I hold appointments as Professor of Surgery at Case Western Reserve University,

in Cleveland, Ohio, and as Professor of Molecular Medicine at the Cleveland Clinic Lerner

College of Medicine at Case Western Reserve University.

3. I also hold several appointments within the Cleveland Clinic in Cleveland, Ohio. In particular, I hold appointments in the Department of Orthopaedic Surgery, the Department of Biomedical Engineering, the Tausig Cancer Center, and the Transplantation Center. I also serve

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in several administrative capacities within the Cleveland Clinic. I am Vice Chairman of the

Orthopaedic and Rheumatologic Institute and Vice Chairman of the Department of Biomedical

Engineering.

4. Since 2004, I have served as Director of the Orthopaedic and Rheumatologic

Research Center (ORRC), an interdisciplinary center of over 50 clinical and basic investigators

drawn from 13 departments within the Cleveland Clinic, involved in research related to the

musculoskeletal system. In aggregate, ORRC members execute research programs with a total

annual budget of over $10 million.

5. Since 2004, I also have served as Director of the Clinical Tissue Engineering

Center (CTEC), a center funded by the Ohio Department of Development’s Third Frontier

Program. The CTEC selects and integrates laboratories and technologies across Ohio to

accelerate the rate of innovation and the development of new therapies and products in the area

of musculoskeletal medicine and in the treatment of skin and wound healing problems. Since its

inception, CTEC has attracted over $9 million in funding that is directly targeted to bring

forward new safe and effective products and clinical strategies.

6. Since 2007, I have served as a Co-Director of the Armed Forces Institute of

Regenerative Medicine (AFIRM). AFIRM is a large interdisciplinary consortia of over 35

laboratories and investigators at 28 institutions, which is charged with rapidly and effectively

developing new therapies to address the challenges of limb salvage and regeneration,

craniofacial reconstruction, burn injury, and scar prevention and remediation. AFIRM is funded

by the Department of Defense through the Medical Research and Material Command (MRMC).

I also serve as the AFIRM Liaison to the Major Extremity Trauma Research Consortium

(METRC), which is a network of over 20 major civilian trauma centers and four military

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treatment facilities, charged with development and execution of prospective clinical research

programs that address urgent questions related to the care of major extremity injuries.

7. I have served as a consultant or research collaborator to several companies during

my medical career related to the design and evaluation of biomedical products and devices,

including Stryker, Stryker Biotech, Orthovita, Thereics, Depuy, Zimmer, Genetics Institute,

Wyeth, and Medtronic.

8. I have served as a frequent reviewer for National Institutes of Health (NIH) grant

applications since 1996, most recently as a member of the Tissue Engineering Study Section

through 2009. In this capacity, I have been intimately involved in the basic and preclinical

assessment of a large spectrum of research strategies and technologies related to biomaterials and

cell therapy.

9. In October 2008, I was appointed to be a consultant to the Orthopaedic and

Rehabilitation Devices Panel of the Medical Devices Advisory Committee for the United States

Food and Drug Administration’s (FDA) Center For Devices and Radiological Health. The

Orthopaedic and Rehabilitation Devices Panel reviews and evaluates data concerning the safety

and effectiveness of marketed and investigational orthopaedic and rehabilitation devices and

makes appropriate recommendations to the Commissioner of Food and Drugs.

10. I have also had experience in hosting forums related to the design, development,

and assessment of new technologies for medical therapeutic applications. In this regard, in 2004,

I founded the Cleveland Clinical Musculoskeletal Innovation Summit Series, which has held

three-day international summits almost yearly focusing particularly in the area of tissue

engineering and regenerative medicine therapies for bone and cartilage.

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11. I also have been an active clinical and basic investigator in the area of tissue

engineering, regenerative medicine, and cell therapy strategies, and I have been the recipient of a

series of R01 grant awards from the NIH. (R01 grants are awards made to support a discrete,

specified, circumscribed project to be performed by the named investigator(s) in an area

representing the investigator’s specific interest and competencies, based on the mission of the

NIH.) As noted above, I have also received grants from the Department of Defense (TATRC

and AFIRM).

12. I have served as an investigator in several clinical studies, including the first

prospective randomized trial of an implanted growth factor for musculoskeletal applications:

Osteogenic protein – 1 (OP-1 – aka BMP-7) for the treatment of established tibial non-union

(Friedlaender GE. Perry CR. Cole JD. Cook SD. Cierny G. Muschler GF. Zych GA. Calhoun

JH. LaForte AJ. Yin, Treatment of Established tibial non-unions using human recombinant

osteogenic Protein-1 (OP-1). Journal of Bone & Joint Surgery - American Volume. 83-A Suppl

1(Pt2):S151-8, 2001.), and most recently an ongoing trial of an injectable formulation of BMP-2

for prevention of osteopenic fractures of the femoral neck (i.e., hip).

13. Since 2007, I also have served as member of the Executive Committee of the

Alliance for Regenerative Medicine (ARM). ARM is a Washington, DC-based non-profit

organization whose mission is to educate key policy makers about the potential of regenerative

medicine and to advocate for favorable public policies—funding, regulatory, reimbursement and

others—to facilitate advances in the field.

14. I am a member of numerous medical societies and organizations related to my

field, including the American Academy of Orthopaedic Surgeons, American Orthopaedic

Association, Orthopaedic Research Society, American Society for Bone and Mineral Research,

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International Society for Fracture Repair, Association of Bone and Joint Surgeons, American

Association for the Advancement of Science, American Society for Testing and Materials,

International Society for Stem Cell Research, Tissue Engineering and Regenerative Medicine

International Society, and the International Bone Research Association.

15. I have authored or co-authored 53 peer-reviewed publications and 12 book

chapters, primarily in the fields of orthopaedic surgery and musculoskeletal medicine. This

includes several articles on the specific topic of stem cell and progenitor cell biology and the

potential therapeutic role of stem cells or progenitor cells in musculoskeletal conditions. A copy

of my Curriculum Vitae, which includes a list of my publications as well as additional

information regarding my qualifications, is attached to this declaration.

16. As a practicing board certified orthopaedic surgeon and as a result of the positions

and appointments I hold (which are discussed above and in my CV), I am required to be

familiar with the drugs, devices, and biological and cellular products that are generally

recognized by experts as safe and effective for human use, that are used to treat orthopaedic

injuries and conditions. Moreover, by virtue of my training and extensive experience in

academic medicine, as an investigator in clinical trials, and in my role in CTEC and AFIRM, I

am familiar with the quantity and quality of evidence that is needed to establish the safety and

effectiveness of drugs. I am likewise familiar with FDA's regulations that define the criteria for

adequate and well-controlled clinical investigations, which are set forth at 21 C.F.R § 314.126.

In my view, these regulations accurately express many of the scientific principles that underlie

adequate and well-controlled clinical investigations.

17. I have been asked by the FDA to provide my professional opinion on several

issues related to a cultured cell product manufactured by Regenerative Sciences, LLC (“RS”),

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including whether the cultured cell product falls within the Federal Food, Drug, and Cosmetic

Act’s (“FD&C Act”) definition of a “prescription drug”; whether there are any published

adequate and well-controlled studies of RS’s cultured cell product; whether there have been any

published adequate and well-controlled studies of any mesenchymal stem cell (MSC) product to

be used for the same conditions and in the same manner as the RS cultured cell product; whether

the RS cultured cell product is generally recognized as safe and effective by qualified experts;

and, finally, whether the labeling for the RS cultured cell product bears “adequate directions for

use.” After briefly describing RS’s cultured cell product, I will address each of these questions.

RS’s Cultured Cell Product

18. In preparing this declaration, I have reviewed, among other things, RS’s website,

www.regenexx.com; publications by RS’s medical director, Christopher Centeno, M.D. and his

co-authors, regarding RS’s cultured cell product; unpublished descriptions of research on RS’s

cultured cell product; copies of treatment records for several patients who were treated with RS’s

cultured cell product; and an RS pamphlet regarding the Regenexx procedure. I understand that

the FDA conducted inspections of RS between February 23 and April 15, 2009, and June 2 and

16, 2010, and I have reviewed the investigators’ summaries of those inspections, which were

documented in Establishment Inspection Reports (EIRs).

19. Dr. Centeno and his co-authors described the manufacture of the RS cultured cell

product in a recent publication (Centeno CJ et al., Safety and Complications Reporting on the

Re-implantation of Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate

Technique, Current Stem Cell Research & Therapy, 2010;5:81-93 (2010 EIR Exhibit MRD 95

(Kreuzer Dec. Exhibit 30))) (hereafter, “Centeno 2010 article”). A similar, but not identical,

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process is described in the firm’s current manufacturing standard operating procedures (“SOPs”).

The process includes the following steps, among others:

Bone marrow is harvested from the patient’s iliac crest (hip) or synovial fluid is

taken from the patient’s knee. Blood is drawn to be used to prepare platelet

lysate. The marrow or synovial fluid is aspirated into syringes.

The marrow or synovial fluid and blood are transferred to RS’s laboratory. The

marrow or synovial fluid is centrifuged to separate nucleated cells from the red

blood cells. The nucleated cells are placed in a separate 50ml conical centrifuge

tube and pelleted. After the cells are counted, they are resuspended in Dulbecco’s

modified eagle medium (DMEM) with doxycycline (an antibiotic), heparin, and

platelet lysate.

Nucleated cells are then seeded in a tissue culture flask, and incubated (at 37°C,

5% CO2 Culture medium is changed

after 48-72 hours, removing the majority of the non-adherent cell population.

Colonies formed by proliferating adherent colony founding cells develop by

days in culture. The resulting mixture of adherent and culture expanded cells are

harvested using trypsin, an enzyme.

The adherent culture expanded cells are then re-plated at a density of 6,000-

12,000 cells/cm2 in α-MEM, platelet lysate, doxycycline, and heparin, and grown

to near confluence.

Once the cells appear to be confluent they are passaged. The

cells are treated with trypsin to dislodge the cells from the flask, rinsed,

resuspended, and reseeded into new culture flasks. After cells are grown for

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in culture, they are harvested using

trypsin, washed in phosphate buffered saline, and loaded into a syringe with

“other additives.”

The cell population that results from this method of cell processing based on

adherence to tissue culture plastic and in vitro expansion is designated by the

authors and RS to be a mesenchymal stem cell (“MSC”) population.

20. According to SOP 119.3, titled “Preparing Mesenchymal Stem Cells for

Injection” (2010 EIR Exhibit MRD 126 (Kreuzer Dec. Exhibit 45)), when the manufacturing

process has been completed, the cultured cell product is placed in a syringe in a sterile bag. The

bag is labeled with the patient’s name, date of birth, laboratory notebook number, cell passage

number, day in culture, cell number, number of cells cryo-preserved, and condition of cell

suspension. No other labeling information appears to be provided with the product to the

treating physician or patient. According to the Centeno 2010 article (2010 EIR Exhibit MRD 95

at 83 (Kreuzer Dec. Exhibit 30)), after the cells are shipped by RS to the clinic, using a

fluoroscope to guide the needle, the physician inserts the MSCs percutaneously (i.e., through the

skin) into either a peripheral joint or an intervertebral disc. See also e.g., 2010 EIR Exhibit

KDM 9 at 5 (Kreuzer Dec. Exhibit 61) (noting use of lateral fluoroscope in procedure implanting

MSCs into patient’s knee). In addition, the article states that, prior to MSC injection, contrast

agent diluted with phosphate buffered saline is injected with the cells into the tissue to allow

visualization of the distribution of the injection. This apparently is used in targeting of the

injectate and documentation of the flow of material after injection.

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21. The RS website makes both broad and specific statements regarding the

conditions that can be treated using the cultured cell product, including (but not limited to) the

following:

“The Regenexx Stem Cell Expansion Procedure has been studied extensively for

several years and continues to prove to be safe and reliable.”

http://www.regenexx.com/about-regenexx/researched-and-effective-stem-cell-

procedure/ (November 22, 2010)

“What types of problems can be treated? Fractures that have failed to heal, joint

cartilage problems, partial tears of tendons, muscles, or ligaments, chronic

bursitis, avascular necrosis of the bone, and lumbar disc bulges.”

http://www.regenexx.com/common-questions/

22. In addition, the “Regenexx” pamphlet states, “Who is a candidate [for the

Regenexx procedure]? Patients with non-healing bone fractures[;] Osteoarthritis of the knee,

hip, ankle, shoulder, hands[;] Chronic bulging lumbar disc[;] Injuries to the meniscus, rotator

cuff[;] Avascular necrosis of the shoulder, hip[; and] Chronic bursitis.” 2010 EIR Exhibit MRD

13 (Kreuzer Dec. Exhibit 13). The pamphlet also says that “The Regenexx procedure is safe and

can often prevent the need for surgery.” Id.

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The Regenexx Cultured Cell Product is a Prescription Drug

23. I have been informed that, under the FD&C Act, a drug “intended for use by

man” is a prescription drug if “because of its toxicity or other potentiality for harmful effect, or

the method of its use, or the collateral measures necessary to its use, is not safe for use except

under the supervision of a practitioner licensed by law to administer such drug ….” See

21 U.S.C. § 353(b)(1)(A).

24. In my opinion, the RS cultured cell product is a prescription drug for the

following reasons:

a. The method of using the cultured cell product and the collateral measures

necessary for its use must be performed by a skilled clinician and cannot be safely performed by

a lay person. The cultured cell product is injected into the patient with the aid of a fluoroscope in

an effort to ensure proper placement of the cells. See paragraph 20 above. Even assuming a lay

person would have access to a fluoroscope or MRI - which seems highly unlikely - these

methods of administration demand an understanding of anatomy and pathophysiology that is

beyond the knowledge of a lay person. Moreover, the direct administration of the product

involves the use of skills and procedures that can only be acquired through experience and

training as a physician or health service worker. These include:

Sterile technique to avoid introduction of bacteria or other infectious or toxic

agents to the tissues.

Placement and direction of the needle being used to administer the product to

avoid injury to important anatomic structures.

Caution to ensure that the needle is not placed in a manner that will result in direct

injection of the product into the lumen of an artery or vein. Most commonly, this is

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accomplished by “drawing back on the needle.” If blood flows readily into the syringe,

then the needle is likely to be placed inside a blood vessel and should be repositioned

(assuming that an intravascular (IV) injection was not the intended mode of

administration).

Caution during injection to insure that an appropriate level of mechanical

resistance is encountered, indicating that the product is being delivered into an

appropriate tissue site. For example, when intending to inject into a joint space, a low

level of resistance is encountered. Similarly, when intending to injecting into an area of

dense scar, tendon or ligament, a relatively higher level of resistance is expected. The

feel of resistance that is inappropriate to the setting of injection should alert the physician

or health professional administering the injection that the procedure may not be

delivering the product into an appropriate or intended site.

In summary, because the mode of administration is injection into a specific anatomic site

(i.e., a joint space, tendon sheath, facial plane or muscle compartment), and the safe

administration of the RS cultured cell product requires the avoidance of trauma or inadvertent

injection into nerves or major blood vessels, the RS cultured cell product can only be

administered by a skilled clinician, who is knowledgeable in accurate diagnosis of

musculoskeletal medical conditions, human anatomy, and experienced in the safe and sterile

administration of injection agents into the appropriate musculoskeletal sites.

b. The indications that the cultured cell product is intended to treat, in almost

all cases, are not conditions that a layperson can be expected to accurately “self-diagnose.”

Specifically, these include: osteoarthritis of the knee, hip, shoulder, hands, and ankle; non-

healing bone fractures; chronic bulging lumbar disc; injuries to the meniscus, rotator cuff;

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avascular necrosis of the hip, shoulder; and chronic bursitis. Moreover, even if a layperson were

correct about the diagnosis, a lay person would not have the training or judgment to evaluate the

available treatments and to determine which course of treatment to follow. A lay person would

not have the knowledge, training or judgment to determine and weigh the risk and benefit of the

RS’s cultured cell product as an injection therapy.

Studies and Articles Regarding RS’s Cultured Cell Product

25. I have been asked to give an opinion regarding whether there are any adequate

and well controlled studies of RS’s cultured cell product for any of the conditions for which it is

being promoted and used (see paragraphs 21-22 above). In answering this question, I have

reviewed publications by Centeno et al. regarding RS’s cultured cell product, an unpublished

summary of RS’s research program, and two unpublished case series. In my opinion, RS’s

cultured cell product has not been tested in a single adequate and well-controlled clinical study

for any of the indications described in paragraphs 21-22. The materials reviewed are:

#1 Centeno CJ et al., Partial Regeneration of the Human Hip Via Autologous Bone

Marrow Nucleated Cell Transfer: A Case Study, Pain Physician 2006;9:253-256.

#2 Centeno CJ et al., Increased Knee Cartilage Volume in Degenerative Joint Disease

using Percutaneously Implanted Autologous Mesenchymal Stem Cells, Platelet Lysate

and Dexamathasone, The American Journal of Case Reports, 2008;9:201-206 (2009 EIR

Attachment 14 (Kreuzer Dec. Exhibit 23)).

#3 Centeno CJ et al., Increased Knee Cartilage Volume in Degenerative Joint Disease

Using Percutaneously Implanted, Autologous Mesenchymal Stem Cells, Pain Physician,

2008;11(3):343-353 (2009 EIR Attachment 12 (Kreuzer Dec. Exhibit 21)).

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#4 Centeno CJ et al., Regeneration of Meniscus Cartilage in a Knee Treated with

Percutaneously Implanted Autologous Mesenchymal Stem Cells, Medical Hypotheses,

2008;71:900-908 (2009 EIR Attachment 13 (Kreuzer Dec. Exhibit 22)).

#5 “Summary of Adult MSC Research to Date: Regenerative Sciences, Inc.” (2009 EIR

Exhibit 97 (Kreuzer Dec. Exhibit 11)).

#6

#7

#8 Centeno CJ et al., Safety and Complications Reporting on the Re-implantation of

Culture-Expanded Mesenchymal Stem Cells using Autologous Platelet Lysate Technique,

Current Stem Cell Research & Therapy, 2010;5:81-93 (2010 EIR Exhibit MRD 95

(Kreuzer Dec. Exhibit 30)).

26. Performing a well controlled study in the evaluation of a new therapy is critically

important in order to detect and/or demonstrate any tangible benefit that is provided by the new

therapy. These materials and the “studies” described in the preceding paragraph do not meet

criteria for adequate and well controlled trials, in the following ways:

a. The method for product preparation and delivery is not standardized

across all subjects, and varies across each of the “studies” reported.

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b. No effective historical or concurrent control group is defined. A control

group is a group of patients with similar or identical characteristics who differ from patients who

have received a treatment (in this case, RS cell therapy injection) only in the fact that they have

not received the therapy. In this way, comparison between the two groups can be used to infer

whether or not the treatment has an effect. If so, patients who received treatment would be

predicted to have statistically significant improvement over any change in the untreated control

group.

c. No method is defined to control for the potential of a placebo effect. A

“placebo effect” is a sense of subjective improvement that is attributed to a treatment benefit, but

which is mediated not by the direct action of the agent but rather by psychological factors that

attribute benefit to a perceived treatment event where there is none.

d. No method is defined to control for selection bias, reporting bias, or

observer bias. Selection bias is bias induced by choosing to compare patients who differ in

important ways that influence outcome, but are unrelated to a treatment effect. Reporting bias

refers to selectively reporting favorable results, but not unfavorable results. Observer bias is the

tendency for an observer who would like to find, or expects to find, a certain result to

preferentially see or interpret data to be supportive of his/her views. In well-controlled studies,

these issues are often addressed by methods such as randomization (assigning patients to

treatment groups using a numerical system that is independent of the personal influence of a

clinical decision maker), blinding (keeping the observer and even the patient unaware of which

treatment a patient received), and independent assessment (assigning tasks of objective

assessment to an observer who is free of personal interest, preference, or the expectation of

finding a given result).

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e. The studies do not define objectively quantifiable methods to measure

disease severity prior to treatment or outcome following intervention.

f. The studies do not define statistical methods to measure treatment effect

(i.e., using a standardized unit of measurement to assess the change in status, e.g., before

treatment and a fixed period after treatment), quantify variation in outcome, nor to define the size

of the patient sample (number of patients) needed to have the statistical power necessary to

demonstrate that the magnitude of change associated with therapeutic intervention had clinical

relevance.

Case Reports

27. At the outset, it is critical to note that no amount of individual case reports can

establish the safety or effectiveness of a treatment regimen. Scientists call such information

“anecdotal evidence.” Only well-controlled clinical studies can scientifically demonstrate that a

product is safe and effective for a particular use. As I show below, the case reports discussed in

this section are independently deficient for a variety of reasons.

28. Between 2006 and 2008, Dr. Centeno and several co-authors published four case

reports, each involving a single patient. (Items #1-#4 in paragraph 25). The first involved use of

marrow-derived nucleated cells that were not expanded in culture prior to injection. The three

later articles involved marrow-derived cells that were expanded in culture. Each report is

described briefly below with an explanation of why it is not possible to draw scientifically-based

conclusions on the safety or efficacy of the RS cultured cell product based on these case reports.

a. Centeno CJ et al., Partial Regeneration of the Human Hip Via Autologous

Bone Marrow Nucleated Cell Transfer: A Case Study, Pain Physician, 2006;9:253-256. This

article is a case report regarding a single patient with unilateral hip pain who received two

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“nucleated cell transfer procedures” one month apart. A nucleated cell pellet was prepared from

an aspiration of the patient’s bone marrow and processed by density separation using a centrifuge

(as described on page 254 of the article). This pellet was mixed with an injectable medium for

each procedure − 2 mL hyaluronic acid for the first procedure and thrombin-activated platelet

rich plasma in the second procedure. The preparations were injected into the hip joint “with a 25

gauge 4-inch quinkie needle,” and the authors state that they confirmed the success of

intraarticular delivery by the statement that the “majority of the spread being intra-articular at the

femoral head.” Id. at 254. The authors estimated that fewer than 100,000 MSCs were

transferred in the first procedure and that 300,000-400,000 MSCs were transferred in the second.

The increase in the second procedure was attributed to a larger marrow aspirate. The authors

report that, at 4 weeks after the first procedure, no changes on MRI were seen but the patient

reported “some clinical improvements.” With regard to the second procedure, the authors

reported that a 4-week post procedure MRI after the second procedure “demonstrates a clearly

identifiable joint space” and an area “demonstrating apparent neocortex.” Of note, the evidence

supporting this observation were two MRI images from similar but not identical transaxial views

of the tissue site. These images lack a detailed description of the imaging methods used. No

independent expert in MRI imaging is identified as an observer to support the authors’

interpretation of these images. In addition, the authors report a 15 degree range of motion

change and the patient reported a one-level improvement in travel, recreation, and standing

tolerance and a two-level improvement in sitting tolerance, using a self-reporting functional

rating Feise index (Spine 2001). The authors concluded:

“This case report describes apparent partial articular surface neocortex regeneration in a severely degenerated hip 8 weeks after autologous intraarticular bone marrow transfer. To date, we are unaware of any

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published report of regeneration of any portion of a human hip through adult autologous stem cell therapy. More research with more subjects is needed to determine if this technique has clinical merit, including case series and randomized controlled trials as well as, improved imaging protocols (including micro-CT). ….” (emphasis added)

b. Centeno CJ et al., Increased Knee Cartilage Volume in

Degenerative Joint Disease using Percutaneously Implanted Autologous Mesenchymal

Stem Cells, Platelet Lysate and Dexamathasone, The American Journal of Case Reports,

2008;9:201-206 (2009 EIR Attachment 14 (Kreuzer Dec. Exhibit 23)). This single

patient case report involved injection of culture expanded adherent cells (5.6 x. 106),

which the authors refer to as “MSCs,” into the joint space in the patient’s right knee using

a 25 gauge 2-inch needle. The injection of culture expanded cells was followed by “10cc

of whole [bone] marrow and 1 cc of 10% platelet lysate.” Id. at 203. The patient was

also given intraarticular knee injections of 10% platelet lysate one week and two weeks

after the “MSC” injection, and the second of these post-procedure injections was

supplemented with 1 ml of 10 ng/ml dexamethasone, a corticosteroid. The authors

reported that a comparison of pre- and post-procedure MRIs “demonstrated a decrease in

the volume of the cartilage defect on the medial femoral condyle,” and that at 3-month

follow up, the patient’s pain score was 0/10, and “pain with knee extension decreased

from … 3/10 to 2/10.” Id. at 204. The authors concluded that this case report “shows

MRI evidence of femoral chondral healing in this middle aged patient” that they believe

is the “first case report in a human subject” of cartilage regeneration using “MSCs.” Id.

at 204.

Again, these images lack a detailed description of the imaging methods used. No

independent expert in MRI imaging is identified. Tracings performed on the pre-

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treatment and post treatment MRI scans using software for performing volumetric

analysis are described as being performed by an “independent observer,” whose

qualifications and identity are not defined. No change in cartilage or meniscus volume

were described. Measurements from a single observer, not surprisingly, are highly

reproducible (SD<5%). Moreover, the volume of the defect that is described is very

small. The starting volume is 20.7 mm3, and ending volume is 14.7 mm3. This small

change in a very small lesion is likely well within the range of inter-observer error or

variation between individual MRI images, were this to have been tested using more than

one observer and more than one MRI image. Finally, a large area of fluid contrast (white

regions representing water signal within a fluid collection) is seen on the post injection

image that is not seen on the first image, suggesting either the presence of an effusion or

of contrast material in the joint at the time of the second image. This observation is

neither mentioned nor explained in the text.

The authors acknowledge that the “effects could have been due to the platelet

lysate” and that patient’s “clinical response could have been due to the Dexamethasone

injection provided post transplant procedure,” although they did not believe that was

likely based on the dose. The authors note that “without biopsy, there is no way to

determine if the change was fibrocartilage or true hyaline cartilage” and that “[a]nother

issue with the clinical result is that the chondral defect was only repaired by

approximately 1/3.” Id. at 204. In addition, they acknowledged, “the generalizability of

this technique to the larger population of patients with symptomatic osteoarthritis

and traumatic knee injury is unknown.” Id. at 205 (emphasis added).

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c. Centeno CJ et al., Increased Knee Cartilage Volume in

Degenerative Joint Disease Using Percutaneously Implanted, Autologous Mesenchymal

Stem Cells, Pain Physician, 2008;11(3):343-353 (2009 EIR Attachment 12 (Kreuzer

Dec. Exhibit 21)). Very similar to the previous case report described in b. above, this

single patient case report involved injection of 22.4 million culture expanded cells into

the joint space in the patient’s knee using a 25 gauge 2-inch needle. The procedure also

included first documenting that the infusion needled was in the knee joint using Isovue

contrast agent diluted 50% with PBS. Injection was then performed using 1 mL of

nucleated cells suspended in phosphate buffered saline and 1 mL of 10% platelet lysate.

As with the previous case report, the patient received 2 additional 10% intraarticular knee

1 mL platelet lysate injections one week and two weeks after the MSC procedure, and the

second post transplant procedure was supplemented with 1 mL of 10 ng/mL

dexamathasone. Id. at 350. MRI images were collected using a “GE 3.0T magnet” and

“Proton Density Fast Spin Sequences”; however, details of the imaging equipment and

methods are not provided. The authors report that “pre-and post-procedure MRI analysis

demonstrated an increase in meniscus and cartilage volume . . . .” Id. at 351.

In contrast to the prior case report, which found no effect on cartilage volume, in

this case the magnitude of this increase in both tissues was is in the range of 15-20%.

These data implied that by 1 month approximately 0.9 cm3 of cartilage and 1.6 cm3 of

meniscal tissue had been regenerated. Again, one observer is used, but the observer’s

identity and qualifications are not described. The authors also report that “[a]t 3-month

follow-up, modified VAS pain scores [range 0-10] decreased from 4 to 0.38” and

“[r]ange of motion in extension increased from -2 degrees to +3 degrees . . . .” Id. at 351.

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The authors stated similar caveats as before: the clinical response could have

been due to the dexamethasone injection (although they felt this was unlikely); there is

“no way to determine if the change was … true hyaline cartilage”; and the

“generalizability of this technique to the larger population of patients ... is unknown.” Id.

In addition, they acknowledged that “no conclusion can be made from one case report”

but asserted that “if similar findings are published from pilot studies and then larger

well-designed trials, the results may have implications for interventional pain

management.” Id. (emphasis added).

d. Centeno CJ et al., Regeneration of Meniscus Cartilage in a Knee

Treated with Percutaneously Implanted Autologous Mesenchymal Stem Cells, Medical

Hypotheses, 2008;71:900-908 (2009 EIR Attachment 13 (Kreuzer Dec. Exhibit 22)).

The patient in this case report was treated in the same manner as the patients in the

above-described case reports, with the following exceptions: (a) At the time of the

injection of culture expanded marrow-derived cells, the patient was injected with the 2 cc

hyaluronate sodium (Hyalgan), 45.6 million MSCs, and 10 cc of fresh whole marrow;

and (b) that patient was given a pulsed ultrasound device to be worn over the medial

aspect of his right knee for 20 minutes a day for three weeks. Id. at 905. The authors

reported that a comparison of pre- and post-procedure MRIs “demonstrated an increase in

meniscus volume of approximately 1.1 cm3; however, no change was found in cartilage

volume and the presence or absence of cartilage defects are described. As with each of

the prior case reports, the identity and qualifications of the observer performing MRI

measurements of tissue volume is not cited. At 3-month follow up, modified VAS scores

decreased from 3.33 to 0.13.

21

As before, the authors acknowledged that this magnitude of improvement could

be attributed to the use of Hyalgan (a viscous solution of sodium hyaluronate that is

injected into the joint to improve symptoms based on presumed lubrication and anti-

inflammatory properties) and not the injected cells. They also acknowledge that the

“generalizability of this technique to the larger population of patients with

symptomatic osteoarthritis and traumatic knee injury is unknown.” Id. at 906

(emphasis added).

29. Overall, and individually, these four case reports provide no value in

advancing evidence of safety or efficacy of the injection of culture expanded cells, for the

following reasons:

a. The culture expanded cell population that is being utilized in these

studies is not adequately characterized. No data is provided with respect to the physical

or biological characteristics of these cell populations nor their heterogeneity. In

particular, no assessment is made to characterize their in vitro performance, biological

potential (capacity to differentiate into one or more phenotypes (i.e., mature cell and

tissue types)), expression of surface markers, or state of differentiation (gene expression)

during processing or at the time of transportation for injection. In the absence of this

information, the content of the product (nature and quality of the cells) that results from

the in vitro processing that is proposed may vary significantly from one patient and one

sample to another. The output of the production methods may vary randomly or it may

drift over time (with either positive or negative effects on the outcome) without the

knowledge of RS or its patients.

22

b. The composition of the materials injected is not adequately

characterized. The protocol for each patient differed in some respect: the number of

cells, passage number, the composition of carrier materials (e.g., phosphate buffered

saline vs. hyaluronic acid), the use of a contrast agent to confirm appropriate delivery into

the desired location, and the addition of other bioactive agents (e.g., dexamethasone or

platelet lysate). The effect of these differences in protocol (positive or negative) on

outcome has not been systematically assessed in a statistically appropriate way.

Therefore, no one protocol has been shown statistically to be more effective than any

other.

c. The purpose of conducting clinical investigations of a drug is to

distinguish the effect of a drug from other influences, such as spontaneous change in the

course of the disease, placebo effect, or biased observation, see 21 C.F.R. 314.126;

however, RS’s “study” design does not isolate culture expanded cells as the likely cause

of any positive treatment effect. The therapy in each patient is confounded by the fact

that in each case additional agents or modalities were used that themselves could be

independently responsible for symptomatic improvement − specifically, the use of

dexamethasone, hyaluronan, plasma lysate, and/or pulsed ultrasound. As a result, the

positive benefit of the injection of the culture expanded cells provided by RS has not

been demonstrated in a statistically viable way. We do not have evidence that the

addition of these cells improves the outcome over the injection of dexamethasone,

hyaluronan, or the use of other adjuvants without the use of cells. Nor is evidence

provided that the administration of cells is superior to an appropriate placebo (e.g., sham

injection, injection of a carrier medium without cells, or other possible controls).

23

d. Claims made related to changes in tissue volume of cartilage,

meniscus or cartilage defects following injection are not supported by sufficient evidence

that rigorous methods of imaging or image analysis were applied by individuals who

have appropriate training and experience in this area. The studies, as described, are not

designed to control for potential bias in interpretation by clinician observers who have a

personal or professional interests in seeing a positive result.

e. The population of patients contained in these reports is not

uniform. They vary with respect to site of treatment (hip and knee) and diagnosis

(osteoarthritis and avascular necrosis) and are not well characterized with respect to the

severity of disease at the time of presentation and treatment. As a result the number of

patients treated for any one indication is insufficient to draw any generalizeable

conclusions regarding the likely outcome in any one patient group were they exposed to

the proposed cell injection therapy.

f. Insufficient information is provided regarding the characteristics of

the Institutional Review Board (IRB) approved study under which these patients are

being treated. The IRB reference number is not used in any of these reports. It is

therefore not clear if these patients were treated under the same or separate IRB approved

protocols. The fact that Dr. Centeno and Dr. Schultz sit as members of the IRB that is

approving and monitoring the studies performed on their patients creates the potential

risk of compromising the independence, objectivity and rigor of the IRB oversight of

these studies. This concern is elevated by the fact that: 1) protocol changes (entrance

criteria and treatment methods and modalities) have been made very frequently, 2) there

does not appear to have been an independent monitor to adjudicate complaints, and 3) the

24

investigators apparently have not been pressed to move beyond limited case reports

lacking adequate prospective study design (patient characterization and quantitative

outcome assessment) and appropriate controls for sources of bias.

RS’s Unpublished Research Summary

30. I have also reviewed a copy of an internal RS memorandum titled,

“Summary of Adult MSC Research to Date: Regenerative Sciences, Inc.” 2009 EIR

Exhibit 97 (Kreuzer Dec. Exhibit 11) (hereafter, “Research Summary”). The Research

Summary explains that

a.

lt

25

.

b.

26

c.

27

d.

28

e.

29

31.

30

Based on these observations, while I have no reason to question the motive of Dr.

Centeno et al. to provide service to patients, I am concerned at this point that continued progress

along the direction that has currently been established may be degenerating into an undisciplined

and unfocused and even groping and wishful fishing expedition. The process that has been

established does not appear to be subject to adequate oversight at the level of the IRB. From the

personal level, this has the risk of exposing hopeful patients to a broad range of unnecessary and

unproductive clinical therapy attempts under the banner of a “research investigation” that is, in

fact, incapable, by design, of detecting the very treatment effect that RS purportedly hopes to

demonstrate. On the medical level, I am concerned that the studies, as proposed, are being

conducted using a culture expanded cell product that has not yet been adequately characterized.

Furthermore, product specifications for quality assessment have not been defined, specific

release criteria are not articulated, and the product has not been subjected to a rigorous

assessment of safety that satisfies contemporary practice standards.

31

Unpublished Case Series

32.

a.

32

33

b.

34

2010 Published Safety Study

33. As noted above, earlier this year, Centeno et al. published the results of “a

prospective study aimed at examining the safety profile of culture-expanded MSCs in

human orthopaedic applications.” (Centeno CJet al., Safety and Complications

Reporting on the Re-implantation of Culture-Expanded Mesenchymal Stem Cells using

Autologous Platelet Lysate Technique, Current Stem Cell Research & Therapy,

2010;5:81-93) (2010 EIR Exhibit MRD 95 (Kreuzer Dec. Exhibit 30)). There were two

groups of patients in the study: “Group 1 (2006-2007) patients (n=45) were followed.

Once a general safety profile for implantation was established, [the authors] then

followed a second, larger patient cohort (Group 2, 2007-2009) (n=182) with the use of a

formal disease and complications surveillance program.” Id. at 81. The authors noted

that “a non-profit, IRB (Spinal Injury Foundation-IRB00002637)” approved the MSC

transplant protocols and therapy for the Group 1 patients. Id. However, no IRB approval

was cited related to the treatment of the Group 2 patients. Id.

34. A total of 227 patients were treated (Groups 1 and 2), with 14 lost to

follow-up. Inclusion criteria in both Group 1 and 2 were the same: a) Age 18-65; b)

Chronic or degenerative disc disease causing significant functional disability; c) Failure

of conservative treatment; and d) Unwillingness to pursue surgical options. Both Groups

were to undergo a pre-injection MRI and then follow-up MRI scans to detect any

abnormal growth or tumor formation. Patient complaints prior to April 15, 2009 were

logged and adjudicated to determine whether they were likely to be an adverse event

related to treatment and also to rate the severity using a conventional HHS Adverse Event

Reporting system. In addition, several side studies were performed using patient samples

35

from this cohort to assess the toxicity of Omnipaque (radiographic contrast material used

during injections), the effect of dosing for autogenous platelet lysate, and to characterize

the CD antigen profile of the culture expanded cells.

The authors reported that, “Some patients underwent more than one procedure”

and that “Mean follow-up time from procedure was 10.6 +/- 7.3 months, with 235

procedure follow-up contacts occurring at 3 months or more, 180 at 6 months or more, 96

contacts at 12 months or more, and 19 contacts at more than 24 months.” Id. at 84.

Patients underwent 118 knee procedures, 78 hip procedures, 13 disc procedures, 10

ankle/foot procedures, 10 shoulder procedures, 6 hand/wrist procedures; 9 received

various other site treatments. Id. The authors stated:

No MRI evidence of tumorigenesis, or of significant complications, was observed at the re-implant sites. The adjudicated complaints identified 7 cases of probable procedure-related complications, all of which were either self-limited or were remedied with simple therapeutic measures. In addition, based on the same criteria, three possible stem cell complications were also reported. These were again either self-limited or were remedied with simple therapeutic measures.” Id. at 89.

The authors reported “no evidence of neoplastic complications in any re-implant

site in 227 patients, who were monitored with high field MRI tracking or via general

surveillance”; however, they acknowledged, “Our study does not address the question of

tumor formation beyond our surveillance period. Another limitation of this study is that

the sample size is not large enough to detect a very low prevalence of tumor formation.”

Id. at 92.

35. There are several critical weaknesses or unconventional abnormalities in

this study:

a. The inclusion criteria do not appear to have been followed. The

36

criteria described would appear to limit recruiting of patients to those with spinal

problems and specifically disc disease. Only 13 of the 227 patients had spinal

procedures. The vast majority of the patients were treated for conditions of the hip or

knee, but ankle, shoulder, hand, wrist and “other sites” are also listed.

b. As described above, the paper appears to imply that no IRB

approval was obtained for the evaluation and follow-up protocol in which patients in

Group 2 were enrolled.

c. The period of follow-up that was used in this report is far too short

to represent a meaningful screening test for tumor formation. Less than 50% of subjects

were followed for 12 months and less than 10% for 24 months. Moreover, details of the

timing of MRI follow-up is provided for Group 1 (page 84 of the article). This is

surprisingly not provided for subjects in Group 2. The authors state:

While it is possible that tumors may still form at some time beyond the average follow-up period represented in our data, this possibility likely decreases at a geometric rate. MSCs replicate every 2-4 days in culture and if that growth were to continue at a similar pace following implantation, a small tumor would be discernable on high field MRI within just a few weeks to months. Our study does not address the question of tumor formation beyond our surveillance period.

Id. at 92.

I disagree with the authors’ implication that any tumors caused by the MSCs

would likely be found within the time period covered by their study. Although the MSCs

replicate quickly in culture, a culture dish is not representative of the conditions the cells

experience once injected into the body. The conditions in a culture dish are optimized for

cell growth. Once injected in the body, local conditions in the tissues vary widely. Cells

take cues from both the tissue matrix that they come in contact with and signals from

37

surrounding cells. Even in the clinical setting of highly malignant and invasive tumors

(e.g., sarcomas, malignant tumors of the musculoskeletal system) cells that are spilled or

left behind during surgical procedures may take years to become evident. After what

may appear to be a complete surgical removal of a tumor, local recurrence (regrowth of

the tumor due to retained cells) will be evident by 2-3 years in only 90% of the time. As

many as 10% of all local recurrences may not become evident until after 3 years and can

recur as long as 20 years after surgery. Moreover, if a culture expanded cell did acquire a

premalignant mutation during the period of in vitro culture expansion, it is very unlikely

that this one mutation would result in the formation of a highly malignant tumor.

Progression toward malignancy would likely require a series of mutations (often referred

to as second and third “hits”) among the progeny of any transplanted cell. As a result,

were tumors to be formed by the progeny of culture expanded cells, they would likely to

only become manifest many years after implantation.

d. According to the paper, four of the six authors (Centeno, Schultz,

Cheever, and Robinson) have equity ownership in RS. Centeno 2010 article at 81.

Another author (Marasco) has equity ownership in NeoStem, a company to which RS has

reportedly licensed the Regenexx procedure in Asia.

http://www.regenexx.com/2009/05/regenexx-in-china/ (November 22, 2010). Thus, all

but one of the authors in this report have direct financial conflicts. Of particular note, Dr.

Centeno and Dr. Schultz served as the only two reviewers charged with screening follow-

up MRI scans for evidence of abnormal growth or tumor formation. Centeno 2010 article

at 82. They also served as the only two adjudicators of patient complaints. Id. at 83.

e. The protocols described for cell preparation provide an exceptional

38

range of variability. Subculture between 2 and 7 passages was allowed and preparation

using either platelet lysate 20% or “Conditioned Serum” (prepared from platelet rich

plasma exposed to CaCl2 and thrombin to degranulate platelets) was incubated at 370C

5% CO but could be used any time between 1 hour and 6 days after preparation.

f. The testing of potential toxicity of Omnipaque solution was

inadequate, limited only to live/dead assay (detection of the presence or absence of cell

death) after relatively short exposure. No assessment was made of the potential toxic

effect of Omnipaque on the functional performance of the culture expanded cells (i.e.,

their subsequent proliferation and differentiation in vitro or their capacity for survival

after injection, which would require an in vivo assessment). Moreover, statistical

characterization of the number of subjects assessed and measures of variation (e.g.,

standard deviation), power, and statistical significance are lacking.

g. Assessment of platelet lysate (PL) effects on the proliferation of

cells (increasing the number of cells present after each passage) are more convincing, but

nevertheless deficient. The methods state that 10 patients were recruited for this

assessment, but data from only 9 patients are presented. Raw trends appear to show clear

benefit of increasing PL dose on proliferation. However, statistical analysis details are

not provided, and no comparison is provided to the “conditioned serum” method.

36. Overall, the 2010 publication by Centeno et al. represents a substantial

advance over the quality of data presented in the first four case reports. However, this

“safety” study does not have the benefit of any useful control group, does not provide

any evidence of efficacy, and does not present convincing evidence of safety. As a

result, in my opinion, it does not present evidence of safety that would be accepted by

39

most knowledgeable clinicians. Moreover, given the composition of the investigators

and particularly the observers and adjudicators in this study (i.e., equity holders in RS

without independent review or oversight), the study remains highly subject to, and does

not control for, potential bias in both observation and interpretation of data. As a result, I

do not believe that any conclusions regarding safety or efficacy of the RS cultured cell

product can be based on this study.

37. Although bearing more on the ethical context of these studies than their scientific

context, the IRB overview of these studies warrants brief discussion. The IRB that took

responsibility for review, approval, and oversight of the studies authored by Dr. Centeno is

identified as the Spinal Injury Foundation IRB. In the case of the Centeno 2010 article, the paper

states that treatment of the “Group 1” patients was approved by the Spinal Injury Foundation

IRB. Centeno 2010 article at 81. No mention is made of any IRB approval of treatment of the

Group 2 patients discussed in that study.

From records provided to me, it appears that Dr. Centeno has an unusually close

relationship to the Spinal Injury Foundation IRB: Dr. Centeno was the registered agent and

Medical Director of the Spinal Injury Foundation. See 2009 EIR Attachments 6-7 (Kreuzer Dec.

Exhibits 19-20). It should be noted that Dr. Centeno apparently recused himself from voting on

the IRB’s approval of the studies. It is not clear if he was also excluded from the review and

discussion of these protocols and/or if the voting records of IRB members were secret, so as to

minimize potentially biased influence of a professionally and financially conflicted member. It

should also be noted that John Schultz, M.D., and Michael Freeman, Ph.D., who are listed as co-

authors on some of Dr. Centeno’s publications regarding the RS cultured cell product, were also

members of the SIF Board of Directors.

40

38. It is of potential significance that, according to the current (November 22,

2010) Spinal Injury Foundation website (http://www.spinalinjuryfoundation.org/), the

Spinal Injury Foundation is now operating under a different name, International Cellular

Medicine Society, which is located in Oregon. Among the nine points in the ICMS

mission statement is the goal: “To establish that when A-ASCs are minimally culture

expanded, are not biologic drugs but rather human tissue.”

http://www.cellmedicinesociety.org/physicians/join (accessed November 22, 2010). Dr.

Centeno also serves in a leadership role in ICMS, specifically as the Medical Director.

http://www.cellmedicinesociety.org/home/boards-and-councils/board-of-directors

(accessed November 22, 2010).

Published Articles Reporting Studies of MSCs for Orthopaedic Indications

39. I have also caused a search to be made for any published adequate and

well-controlled studies of any other MSC product used for the same conditions (see

paragraphs 21-22) and in the same manner as the RS cultured cell product (percutaneous

injection, without other surgical intervention). The purpose of this search is to determine

whether any formulation of a cell product with the general features attributed to “MSCs”

has been shown, through published adequate and well controlled studies, to be safe and

effective for the treatment of any of the orthopaedic indications for which RS’s cultured

cell product is being promoted and used. As discussed in greater detail below, there are

no published adequate and well controlled clinical investigations in the peer

reviewed literature upon which one could conclude that the RS cultured cell product

is safe and will reliably have the effect it purports to have in any clinical setting of

musculoskeletal care.

41

40. As an initial matter, there are two areas of published literature that I do not

consider to be relevant to the discussion of the RS cultured cell product:

a. Substantial literature has developed in the area of cartilage repair

using culture expanded cartilage derived cells that are placed into the knee so that they

are retained in a specific site. This is accomplished by implanting cells within a 3-

dimensional matrix or gel, or by infusing them beneath a layer of autogenous periosteum

(i.e., the surface layer of a patient’s own bone, known to contain progenitor cells that are

capable for forming bone and cartilage) or under other synthetic membranes that are

affixed over the site of a cartilage defect. However, this literature related to the culture

expansion of cartilage derived cells is not relevant to the RS approach of transplantation

of culture expanded marrow-derived cells by injection, and is not included in this

discussion for two reasons: 1) the origin of cells used in this application is from a

different source (i.e., cartilage and not bone marrow), which represent distinctly different

cell types with different biological potential, and 2) the cells used for cartilage repair are

not injected percutaneously, which would allow them to migrate throughout the joint

space. Instead, they are implanted under direct view of the surgeon in or under a matrix

that closes over the cartilage defect preventing migration of the transplanted cells out of

the cartilage defect and into other parts of the joint. As such, cells used in this

application represent a different cell type and also a different clinical application than

those manufactured by RS.

b. Starting with a paper by Lazarus et al. Bone Marrow Transplant

16:557-564, 1995, a substantial volume of clinical data has been generated from clinical

trials involving the peripheral infusion of culture expanded marrow derived cells (i.e.,

42

(infusion of cells into a vein so that they be distributed within the blood stream). These

cell populations are generally referred to as MSCs (an acronym indicating mesenchymal

stem cell). However, culture expanded cells derived from bone marrow and intended for

peripheral infusion are also referred to by a variety of other proprietary names. These

trials include evaluation of the effects of culture expanded cells primarily in the setting of

life-threatening conditions, including: bone marrow transplantation for hematological

malignancies, treatment of immunomodulation disorders (graft vs host disease (GVHD)),

lupus, and treatment in the setting of acute myocardial infarction. This literature also

includes evidence of engraftment of culture expanded cells delivered by peripheral

intravenous (IV) infusion of culture expanded engineered cells. Some of these studies

have provided evidence of clinical efficacy of culture expanded cells in the setting of the

systemic bone disease, osteogenesis imperfecta (Horwitz et al. Proc Natl Acad Sci

99:8932–7, 2002).

This literature related to the transplantation of culture expanded cells by

peripheral infusion is not relevant to the RS approach for two reasons: 1) there is no

evidence that the biological phenotype and biological potential of the cell population

prepared by RS and the cells used in these studies are identical, and 2) the route of

delivery via peripheral intravenous injection results in a dramatically different pattern and

volume of distribution of the cells, when compared to injection into an intraarticular

space (a joint) or into periarticular soft tissues (muscle, tendon, ligament, meniscus).

41. Some preclinical studies (i.e., studies performed in animal models to

evaluate the likely efficacy of a clinical product) have been published which suggest a

possible role for injection or topical application of culture expanded marrow derived cells

43

in the treatment of: degenerative cartilage or disc disease; ligament or meniscal injury or

degeneration; and/or open wounds. However, these studies are limited to relatively

preliminary observations in small animals and occasionally in large animals. These

studies do not provide a base of evidence that enables clinical translation at this point.

:

a. There is evidence that culture expanded cells can be injected into a

knee joint of a rat and found to be retained in some number within the joint, including

sites of injury (e.g., anterior cruciate ligament (ACL)). Arung et al., Knee Surg Sports

Traumatol Arthrosc 14:1307-14, 2006. However, the efficiency of this transfer and the

long term fate and durable contribution of cells that are transplanted in this way to new

tissue formation has not been documented in any animal study, to my knowledge.

b. There is evidence that culture expanded marrow-derived cells

expressing a set of markers consistent with the “MSC” phenotype can be delivered in a

fibrin spray into cutaneous wounds in a murine (i.e., mouse) model and contribute to

acceleration of wound closure. Falanga et al., Tissue Engineering 13:1299-1312, 2007.

. Similarly, Wu et al. (Stem Cells Oct

2007;25(10):2648-59, 2007) have reported, also in a murine model, that culture expanded

marrow-derived cells will engraft in an open wound and accelerate wound closure and

appear to produce proangiogenic factors (Vascular Endothelial Growth Factor (VEGF)

and angiopoietin-1 (stimulants of new blood vessel formation)). However, these findings

in mice do not definitively predict that these mechanisms will be activated in the same

44

way in humans, much less that human wounds treated in the same manner will

necessarily demonstrate clinical success.

c. There is evidence that culture expanded marrow-derived cells can

be transplanted into a cartilage defect in the rat using a fibrin matrix to retain them in the

site, and that these transplanted cells will produce extracellular matrix (contribute to new

tissue formation (perhaps scar and perhaps meniscus)) for up to 8 weeks after

transplantation. (Izuta et al., Knee 12:217-223, 2005). However, this does not support

the approach taken by RS, .

d. Murphy et al. (Arthritis Rheum 48:3464-3474, 2003) have reported

possible positive effects of injection of culture expanded bone marrow in a caprine (i.e.,

goat) model of osteoarthritis (OA). Ten million cells were injected in a dilute solution of

hyaluronan 6 weeks after menisectomy and ACL resection. The authors reported

apparent regeneration of meniscal tissue and reduced degeneration of cartilage. Follow-

up of these observations by the original authors or other investigators with longer term

studies and more quantitative measurement of cartilage and meniscus preservation or

regeneration are lacking, however. RS does not appear to have attempted to reproduce

this work in an appropriate preclinical model before attempting many alternative methods

in their series of uncontrolled Stage I through III studies.

e. There is evidence in a rat model that following an acute partial

ACL injury that culture expanded cells can be delivered by intraarticular injection and

that this delivery is associated with improved ACL repair and mechanical performance.

Transplanted cells were found to represent a minor population in the ACL wound defect,

but could be detected within the defect site. Kanaya et al., Arthrhoscopy: 23:610-617,

45

2007. These findings are provocative. However, rat and human culture expanded cells

have substantial differences in their morphological features and biological performance.

The failure of rat models to predict human clinical performance has been well

documented in many clinical settings. Further assessment in small and large animal

models is needed and likely to be ongoing. No substantiating studies have yet been

published, to my knowledge, to demonstrate that these findings can be reproduced in a

large animal model (e.g., dog, goat, sheep). Also, I am aware of no ongoing prospective

clinical trials in which this question is being addressed.

f. The capacity of culture expanded cells to migrate into sites of

cartilage defects has been called into question by Xu-hong Jing et al. (Joint Bone Spine

75:432-438, 2008) who, using a rabbit model, labeled culture expanded cells before

injection using iron particles and found little evidence of homing into the site of a

cartilage defect.

g. Sakai et al. have published a series of papers supporting a possible

role for injection of culture expanded marrow-derived cells in the setting of degenerative

disc disease using a rabbit model. They reported a positive effect of intradiscal injection

of marrow derived cells in a rabbit model of degenerative disc disease, manifested by

increased disc height. Biomaterials 27:335-345, 2006. This paper followed on previous

studies demonstrating the survival of transplanted cells in the disc space and expression

of some disc appropriate marker genes (Spine 30:2379-2387, 2005) and one suggesting,

based on histology observation alone, that injection may decelerate the rate of

degeneration (Biomaterials 24:3531-3541, 2003). While encouraging, confirmation of

46

these preliminary findings in a large animal model (dog, sheep, goat) has not been

reported, to my knowledge, by the Sakai group, by RS investigators, or others.

42. In addition to the preclinical studies discussed in the preceding paragraph,

there are a limited number of clinical (i.e., use in humans) reports available in the English

literature that lend support to the concept that local or topical delivery of a culture

expanded progenitor population might offer clinical benefit:

a. Phillipe Hernigou and colleagues have published an uncontrolled

clinical series since 2002 suggesting a positive effect of injection of marrow derived cells

into sites of osteonecrosis, fracture repair, and fracture non-union. Hernigou has also

suggested that outcome is positively associated with the number of colony forming cells

that are transferred. CORR 405:14-23, 2002, JBJS Br 87:896-902, 2005, JBJS Am

87:1430-1437, 2005, JBJS Am 88 Suppl 1 Pt 2: 322-327, 2006. These studies support the

concept that marrow processing may be of value and that the concentration of progenitors

in native bone marrow may be suboptimal for clinical efficacy without processing. There

have been no substantive adverse events reported in the Hernigou papers, suggesting a

low risk safety profile for this approach. However, the processing of these marrow

derived cells has been performed through density separation (centrifuge) and not using in

vitro culture expansion as proposed by RS. Density separation yields a highly

heterogeneous population of nucleated cells from bone marrow that represents all cell

types in marrow and provides a low prevalence of progenitor cells that would give rise to

MSCs. In contrast, the RS product begins with this heterogeneous density separated

mixture and subjects this population of cells to an environment that results in depletion of

over 99.9% of the starting population and a phase of preferential expansion of the most

47

rapidly dividing cells. The composition of these two cell samples differ so greatly that

the outcome of these studies is not relevant to supporting claims of safety or efficacy for

the RS cultured cell product.

b. A small clinical trial using culture expanded marrow-derived cells

for treatment of articular defects in three patients was described by Wakitani et al. (J.

Tissue. Eng. & Reg. Med 1:74-79, 2007). This involved short term expansion of cells in

a GMP facility, characterization of cells as positive for CD29, CD44 and CD105 while

negative for CD34 and CD14, followed by local implantation on a porcine collagen sheet.

Symptoms reportedly improved in all patients and MRI and/or arthroscopy provided

evidence of defect filling, but this could not be characterized as hyaline cartilage. This

study followed upon two prior papers. In one prior clinical trial (Osteoarthritis and

Cartilage 10:199–206, 2002), 24 patients were randomized to undergo tibial osteotomy

for medial compartment osteoarthritis, and 12 were treated with cell transplantation under

a sutured periosteal flap. Clinical symptoms improved and trended better in the cell

treated group, but were not statistically significant. In a second prior paper (Cell

Transplantation 13:595-600, 2004), two patents were treated using culture expanded

marrow derived cells in a collagen gel placed under a flap of periosteum to treat chondral

defects in the patella. Fibrocartilaginous tissue was restored and documented at 1 or 2

years using arthroscopy. Symptomatic improvement persisted at 4 and almost 6 years,

respectively.

The methods in these three papers are similar to the RS approach only in that that

the starting source for culture expanded cells is autologous bone marrow. Methods of in

vitro expansion and transplantation differ so substantially that no obvious correlation can

48

be made between these two approaches with respect to prediction of clinical efficacy or

safety.

c. Another small feasibility trial was reported by Kitoh et al. (Bone

35:892-898, 2004) in which culture expanded cells were injected with platelet rich

plasma (PRP) into the site of distraction osteogenesis during lengthening of long bones in

two patients with achondroplasia and one patient with congenital pseudoarthrosis. No

obvious benefit was derived. However, no complications occurred. Follow-up period

was as short as 4 months. Culture expansion methods included autologous serum.

Release criteria included only negative cultures and testing for pathological viruses. This

paper is perhaps the most similar to the approach being taken by RS. However, the data

provided add little to the scant available evidence for efficacy and long term-safety of this

approach.

d. A prospective trial of injection of culture expanded cells in the

treatment of long bone fracture was reported by Seok-Jung Kim et al. (BMC

Musculoskeletal Disorders 10:20, 2009). This study included 64 patients with closed

long bone fractures, primarily of the femur and tibia (51/64). Marrow was aspirated at

the time of initial fracture fixation surgery in all patients. Autogenous marrow-derived

cells were expanded in vitro over 4 weeks and directly injected into the fracture site. If,

at 6 weeks, the overall fracture score was lower than 3 points out of a possible 8 points (2

for each cortex), patients were recruited and randomized. At 8 weeks, the 31 patients

randomized to the treatment group were injected with 12 million cells in 0.4 ml of fibrin

gel using fluoroscopy guidance. No sham injection was used in the 33 controls, so the

potential for needle trauma treatment effects are not controlled for. Flow cytometry was

49

used to characterize some patient samples with respect to expression of two bone markers

(collagen I and alkaline phosphatase), but no other CD antigens were characterized.

Overall union rate was not reported to be different. Callus formation was slightly higher

in the treatment group at 1 and 2 months post injection, but not statistically different.

Methods used to blind the readers of radiographs with respect to treatment group were,

unfortunately, not defined. No unusual adverse events were noted; however, one patient

in the injection group required treatment for a Methicillin-resistant staphylococcus aureus

(MRSA) infection.

These data suggest a possible role for injection of culture expanded cells in the

setting of delayed union of fresh fractures, but did not demonstrate statistically significant

radiographic improvement nor evidence of clinical value. The study offers little guidance

with respect to characterization of the culture expanded cell population used, nor

recommendations for quality control parameters or release criteria.

e. The feasibility of treating osteonecrosis of the femoral head using

culture expanded autogenous marrow-derived cells has also been reported by Miller et al.

(Leukemia 22, 2054–2061, 2008) in a series of five pediatric patients with symptomatic

osteonecrosis lesions at the time of percutaneous drilling (decompression). This method

involves using a drill to core out an open path between regions of vascular and non-

50

vascular bone. This has been shown in prior studies to result in a reduction in the

intraosseous pressure, which is thought to contribute to reduced blood flow and bone

death.

The methods used in the study are cited as conforming to GMP requirements, and

utilized platelet lysate, rather than animal derived serum products during the period of

cell expansion in culture. No complications were reported. Most relevant to the issues

faced by RS is that this paper defined specific release criteria (viability >90% and

expression of CD73 and CD105 by more than 90% of cells as assessed by flow

cytometry). Cultures were performed on initial samples and on last passage samples –

one week before implantation. In addition, they assessed chromosomal stability of the

culture expanded cells using high-resolution matrix-based comparative genomic

hybridization (CGH). They found no chromosomal alterations up to 12 weeks in culture

using human platelet lysate and plasma, but limited the in vitro expansion period to 4

weeks as a precaution.

These standards represent a level of characterization of product at a level that has not yet

been demonstrated by RS. The release criteria selected by the Miller group to define an MSC

population are consistent with, but not identical to, criteria that have been proposed by the

Mesenchymal and Tissue Stem Cell committee of the International Society for Cellular Therapy

(Horwitz et al., The International Society for Cellular Therapy position statement. Cytotherapy.

7:393-395, 2005 and Dominici et al., Minimal criteria for defining multipotent mesenchymal

51

stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy.

8:315–7, 2006). This body has proposed three criteria:

1. Plastic adherence of isolated cells in culture.

2. The expression of CD105, CD73 and CD90 in >95% of the cultured cells,

and lack of expression of markers including: CD43, CD45, CD14, CD11b,

CD79α, CD19, and HLD-DR in >95% of the cultured cells.

3. The differentiation of the “MSCs” into osteoblasts, adipocytes and

chondroblasts in vitro.

These criteria ignore other potentially important markers that have been cited by

other authors including: NGF-R, PDGF-R, EGF-R, IGF-R, CD49a/CD29, STRO-1,

STRO-3, CD146 and CD106. While it is clear that there is no one way to define the

identity of potentially valuable cell populations in this domain, the importance of

establishing a consistent standard for characterization is widely recognized. Useful

reviews of the literature and history around characterization of the identifying features

and biological potential of “MSCs” are provided by Arthur et al. (J. Cell Physiology

218:237-245, 2009), Spitkovsky et al. (Minimally Invasive Therapy 17:2; 79–90, 2008)

and Brooke et al. (Seminars in Cell & Developmental Biology 18:846–858, 2007).

f. Tumorigenicity of culture expanded marrow derived cells has been

documented by Serakinci et al. (Oncogene 23:5095-5098, 2004), Wang et al.

(Cytotherapy 7:509-519, 2005), and Rubio et al. (Cancer Res. 65:3035-9, 2005) and

chromosomal abnormalities are well known after prolonged periods of in vitro culture

expansion. These reports present a sobering potential failure mode when considering

culture expanded cell therapies for non-life threatening disease.

52

RS’s Cultured Cell Product Is Not Generally Recognized by Qualified Experts as Safe and Effective for Any Orthopaedic Indication

43. As noted above, I have been a practicing board certified orthopaedic surgeon for

20 years, and I belong to many medical organizations comprising leading clinicians and

scientists devoted to the challenge of advancing medical care through stem cell biology, tissue

engineering, and regenerative medicine. I keep abreast of the scientific literature in my field of

expertise. I am familiar with the treatments that orthopaedic surgeons use to treat the

orthopaedic injuries and conditions described in paragraphs 21 and 22 above. I do not currently

use any cultured cell product − manufactured by RS or any other company − in my practice. As

indicated here and in other parts of this declaration, I am independently aware of no other

orthopaedic surgeons using the RS cultured cell product to treat orthopaedic (or other)

conditions. Moreover, in my opinion there is not general recognition among physicians that

RS’s cultured cell product is safe and effective for any use.

44. Furthermore, it is my opinion that no marrow-derived MSC product has, as yet,

been shown to be a safe and effective in the treatment of any of the indications for which the RS

cultured cell product is being promoted and used. There is currently only one culture expanded

cell product that is widely available and not infrequently used to treat a musculoskeletal

condition in the United States: Carticel™, marketed by Genzyme. The cell source for Carticel is

autologous cartilage-derived cells, not marrow-derived stem cells or synovial fluid-derived stem

cells like the RS product. The Carticel product does not fit the general definition of MSCs, nor

does it make claims related to the criteria proposed as a definition of MSCs: adherence

characteristics, surface marker expression, and multipotentiality. While the cells used in

Carticel™ are culture expanded, they represent a different population of cells to that which is

53

generated using the RS processes. As a result, the existence of the Carticel product and any

history of safety and efficacy associated with it cannot be legitimately proposed as a predictor of

the safety and efficacy of a culture expanded population of marrow-derived cells.

45. As evidenced by the review provided above of available clinical reports

describing the clinical use of marrow-derived cells, the reports available to date represent only

scattered experiences using cell populations with widely varying metrics of quality control and

characterization. There are currently no well-controlled clinical trials that provide objective

quantitative evidence of efficacy for culture expanded bone marrow derived cells or culture

expanded synovial fluid derived cells. There are also only rudimentary standards of

characterization of cell surface markers, morphology or in vitro biological performance that can

be used as reproducible release criteria (quality control) or as objective metrics that predict

clinical performance.

46. There are no adequate and well-controlled clinical trials of the RS cultured cell

product. Although there are scattered pre-clinical and clinical reports of potential safety and

efficacy of therapies based on the injection or infusion of culture expanded autogenous cells,

none of these reports is an adequate and well controlled clinical investigation that would enable a

qualified expert to conclude that the RS cultured cell product can be used safely and will reliably

have the effect it purports to have in any clinical setting of musculoskeletal care.

Adequate Directions for Use

47. I have been informed that, under the FD&C Act, a drug is “misbranded” if its

labeling does not bear adequate directions for use and that that term has been defined by

regulation (21 C.F.R. § 201.5) to mean “directions under which the layman can use a drug safely

and for the purposes for which it is intended.” The regulation also states that directions for use

54

may be inadequate because, among other reasons, of omission, in whole or in part, or incorrect

specification of certain types of information, including:

(a) Statements of all conditions, purposes, or uses for which such drug is intended, including conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral, written, printed, or graphic advertising, and conditions, purposes, or uses for which the drug is commonly used; except that such statements shall not refer to conditions, uses, or purposes for which the drug can be safely used only under the supervision of a practitioner licensed by law and for which it is advertised solely to such practitioner.

(b) Quantity of dose, including usual quantities for each of the uses for

which it is intended and usual quantities for persons of different ages and different physical conditions.

(c) Frequency of administration or application. (d) Duration of administration or application. (e) Time of administration or application (in relation to time of meals,

time of onset of symptoms, or other time factors). (f) Route or method of administration or application. (g) Preparation for use, i.e., shaking, dilution, adjustment of temperature,

or, other manipulation or process. 48. I have been further informed that the “label” is the written, printed, or graphic

matter upon the immediate container of the drug and the “labeling” includes all labels and other

written, printed, or graphic matters (a) upon the drug or any of its containers or wrappers, or (b)

accompanying the drug.

49. As noted above (paragraph 20), RS’s SOP 119.3 (2010 EIR Exhibit MRD 126

(Kreuzer Dec. Exhibit 45)) provides that, when the manufacturing process has been completed,

the cultured cell product is placed in a syringe in a sterile bag that is labeled with the patient’s

name, date of birth, cell passage number, laboratory notebook number, day in culture, cell

number, number of cells cryo-preserved, and condition of cell suspension.

55

50. The labeling for RS’s cultured cell product in this manner does not bear adequate

directions for use that would enable a layperson to use the product safely and for the purposes for

which it is intended. Not only does it lack the information specified in the FDA regulation (21

C.F.R. § 201.5), but also, in my opinion, it is not possible to write directions for use so that a

layperson could use the RS cultured cell product safely. Even if one were to assume that the

product itself is safe (non-toxic, non-immunogenic, and free of short term or long-tern sequelae),

the safe use of the RS cultured cell product would nevertheless require a skilled and highly

trained professional to place the needle under sterile conditions into a specific anatomic location

(e.g., the knee joint) while also avoiding anatomic structures (e.g., arteries, veins, and nerves)

that could be injured by the needle or by inadvertent direct injection of the cell product. The safe

targeting and delivery of the product therefore requires, at a minimum, a detailed knowledge of

human anatomy, which a layman cannot be expected to have.

51. Safe targeting and delivery also requires experience. The standard method of

training for physicians and other health care providers (e.g., nurses and physician assistants) in

procedures for safe injection therapy involves a combination of verbal or written instruction and

anatomic diagrams. It also generally involves the opportunity to first observe the procedure

being performed by a skilled practitioner, followed by a period to practice the procedure under

the supervision of a skilled practitioner. In this way proficiency in the procedure and a sufficient

opportunity for education in the “feel” of the procedure when performed under a normal range of

anatomic variation is achieved. Only in this way is a new practitioner competent to know how a

procedure should be performed correctly and with appropriate effect. The description of the

techniques used by RS in delivering injections, which involve the use of a fluoroscopic

confirmation of needle placement within the joint using a radioopaque contrast agent,

56

demonstrates clearly that, the responsible use of these agents falls beyond the skill set of a lay

person.

52. I have been informed that FDA has, by regulation, exempted prescription drugs

for human use from the “adequate directions for use” requirement if certain conditions are met.

21 C.F.R. § 201.100. One of these conditions is that the “labeling on or within the package from

which the drug is to be dispensed bears “adequate information for its use, including

indications, effects, dosages, routes, methods, and frequency and duration of

administration, and any relevant hazards, contraindications, side effects, and precautions

under which practitioners licensed by law to administer the drug can use the drug safely

and for the purposes for which it is intended, including all purposes for which it is

advertised or represented.” (emphasis added) I have been asked both whether the labeling on

or within the RS cultured cell product bears that information and, if not, whether it would be

possible to write such information, based on the information currently available about the

product.

53. As noted above, when the manufacturing process has been completed, the

cultured cell product is placed in a syringe in a sterile bag that is labeled with the patient’s name,

date of birth, cell passage number, laboratory notebook number, day in culture, cell number,

number of cells cryo-preserved, and condition of cell suspension. RS SOP 119.3. No other

labeling information appears to be provided with the product to the treating physician or patient.

If this is true, then it is self evident that the labeling for RS’s cultured cell product does not meet

the requirements for exception outlined above (i.e., that labeling on or within the package from

which the drug is to be dispensed must bear “adequate information for its use, including

indications, effects, dosages, routes, methods, and frequency and duration of administration, and

57

any relevant hazards, contraindications, side effects, and precautions under which practitioners

licensed by law to administer the drug can use the drug safely and for the purposes for which it is

intended, including all purposes for which it is advertised or represented.”).

54. With respect to the second question − whether it would be possible to write such

information, based on the information currently available about the product − the answer is

clearly “no.” Although it is clearly possible to write directions for use that a trained physician

could understand, the directions must have a firm scientific foundation. It is my opinion that

directions for use that are not based on scientific evidence of safety and efficacy based on widely

accepted standards of study conduct and documentation are not “adequate.” As discussed in the

review of available data from RS, as well as the data available from pre-clinical and clinical

studies of related use of “MSCs” for injection, RS has not, in my opinion, provided adequate

research evidence that the product is safe (free of short term or long-term adverse effects) and

effective (consistently beneficial to the patient), above and beyond the placebo (i.e., effect of

caring attention, reassurance, the ceremony of injection, and subsequent care and rehabilitation

involved in the current therapy) for any of the indications for which it is promoted. Therefore, I

must answer “no” to this question, based on the evidence that I find available related to the RS

cultured cell product, regardless of whether the intended user is a layperson or a physician.

GEORGE FREDERICK MUSCHLER, M.D.

The Cleveland Clinic Foundation 9500 Euclid Avenue

Cleveland, OH 44195

Dept. of Orthopaedic Surgery (A-41) Dept. of Biomedical Engineering (ND2) Section of Adult Reconstructive Surgery Orthopaedic & Rheumatologic Research Center

Clinical Tissue Engineering Center Phone: 216-444-5338 Phone: 216-445-7195 Fax: 216-445-6574 Fax: 216-444-9198 e-mail: [email protected] e-mail: [email protected]

Birth date:

Place of Birth:

Home Address:

Spouse:

Children:

EDUCATION

University of Illinois, Champaign-Urbana, IL 1974 -1977 Bachelor of Science (Chemistry)

Northwestern University School of Medicine, Chicago, IL 1977-1981 Doctor of Medicine

POST GRADUATE EDUCATION

Internship in General Surgery 1981 -1982 University of Texas Southwestern Medical School and Affiliated Hospitals, Dallas, Texas

Residency in Orthopaedic Surgery 1982 -1986 University of Texas Southwestern Medical School and Affiliated Hospitals, Dallas, Texas

Fellowship in Musculoskeletal Oncology 1986 - 1988 Memorial Sloan-Kettering Cancer Center, New York, NY

Fellowship in Bone Research and Metabolic Bone Disease 1986 -1988 The Hospital for Special Surgery, New York, NY

PROFESSIONAL APPOINTMENTS

Surgeon (Orthopaedic Surgery) The New York Hospital- Cornell Medical Center 1986 - 1988

George F. Muschler, M.D. Curriculum Vitae

Full Staff Section of Musculoskeletal Oncology Department of Orthopaedic Surgery The Cleveland Clinic Foundation

Full Staff Section of Adult Reconstruction Department of Orthopaedic Surgery The Cleveland Clinic Foundation

Full Staff Section of Musculoskeletal Biology (Connective Tissue Biology) Department of Biomedical Engineering The Cleveland Clinic Foundation

(Joint Appointment) Acting Head, Section of Musculoskeletal Biology

Full Staff The Cleveland Clinic Cancer Center (Joint Appointment)

Associate Researcher The Cleveland Clinic I.H. Page Center for Outcomes Research

Director Orthopaedic Clinical Research Center (OCRC) Department of Orthopaedic Surgery

Adjunct Professor Department of Biomedical Engineering Case Western Reserve University

Professor Department of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Professor of Biomedical Engineering Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Vice Chairman Department of Biomedical Engineering The Cleveland Clinic Foundation

Page 2.

1988 - 2001

2001 ­

1991 ­

1991 -1994

1995 ­

1999 ­

2001 - 2005

2004 ­

2004 ­

2004 ­

2004 ­

George F. Muschler, M.D. Curriculum Vitae

Director Orthopaedic Research Center (ORC) Departments of Orthopaedic Surgery and Biomedical Engineering The Cleveland Clinic Foundation

Director Clinical Tissue Engineering Center (CTEC) The Cleveland Clinic Foundation Case Western Reserve University University Hospitals of Cleveland

Co-Director Alliance for Regenerative Medicine (ARM) Cleveland Clinic Rutgers and partnering institutions

Vice Chairman for Research Orthopaedic and Rheumatologic Institute Cleveland Clinic

Co-Director Armed Forces Institute for Regenerative Medicine (AFJRM) Rutgers Partnering Institution

Page 3.

2005 ­

2005 ­

2007 ­

2007 ­

2008

George F. Muschler, M.D. Curriculum Vitae

INSTITUTIONAL ADMINISTRATIVE ACTIVITIES

Orthopaedic Research Committee Orthopaedic Computer Committee, Chairman Orthopaedic Quality Assurance Committee Orthopaedic Education Committee Cancer Center Task Force Biomedical Engineering and Transplantation Study Section of the Research Programs Committee

Reviewer Chairman

Cleveland Clinic Research Programs Committee Executive Committee, Dept. Biomedical Engineering Orthopaedic Electronic Medical Record Taskforce

Chairman Orthopaedic Web Site Work Group

Chairman Orthopaedic Total Joint Outcomes Project, Project Leader Orthopaedic Taskforce on Outcomes Infrastructure

Chairman Orthopaedic Research Center (ORC)

Founding Member Musculoskeletal Advisory Committee (MAC)

Member Chairman

Director Orthopaedic Clinical Research Center (OCRe)

Director Clinical Outcomes Research Center (CORC)

Member Steering Committee

Multidisciplinary Bone Cluster Group Chairman

Multidisciplinary Cartilage Cluster Group Member Co-Chairman

General Clinical Research Center (GCRC) Mentor Academy Committee

BRU (Animal Care Core) Advisory Committee Search Committees

Department of Biomedical Engineering (Biomechanics) Department of Neurosciences (Stem Cell Biology) Department of Stem Cell and Regenerative Medicine (Chair) Department of Orthopaedics (Outcome Research) Department of Biomedical Engineering (Tendon Mechanobiology} Department of Biomedical Engineering (Tissue Engineering)

Department of Biomedical Engineering (Imaging) Transplantation Center

Member Cleveland Clinic Lerner College of Medicine

Clinical Experience Oversight Committee

Page 4.

1988 - 2002 1989 -1991 1989 -1998 1989 -1992 1990 -1991

1989 -1998 1992 -1998 1992 - 1998 1991 ­

1996 - 1998

1998 - 2000 1998 - 2001

2000 - 2001

2000 ­

2000 ­2005 ­2005 ­

2001 - 2005

2005 ­2005 ­

2002 ­

2002 ­2002 - 2007

2003 - 2007 2003 - 2007

2001 - 2003 2002 - 2004 2003 ­2004 - 2005 2004 - 2005 2004 - 2006 2007 ­

2004­

Aug 2009 - Feb 2010

LICENSES

Texas 1982 New York 1986 Ohio 1987

George F. Muschler, M.D. Curriculum Vitae

ADMINISTRATIVE EDUCATION

Case Western Reserve University Weatherhead School of Business Cleveland Clinic Executive Program in Practice Management Physician Management Seminars

Kellogg School of Management, Northwestern University AOA Leadership Course - Module II AOA Leadership Course - Module III . AOA Leadership Course - Module IV

PROFESSIONAL CERTIFICATION

American Board of Orthopaedic Surgery Certified - July 13, 1990 Re-Certification - Valid January 1, 2001 - December 31, 2010

PROFESSIONAL SOCIETIES

American Academy of Orthopaedic Surgeons American Orthopaedic Association Musculoskeletal Tumor Society Connective Tissue Oncology Society Orthopaedic Research Society American Society for Bone and Mineral Research International Society for Fracture Repair - Charter Member Association of Bone and Joint Surgeons Mid-American Orthopaedic Association Ohio Orthopaedic Association Cleveland Orthopaedic Society The New York Academy of Sciences American Association for the Advancement of Science American Society for Testing and Materials International Society for Stem Cell Research Academy of Medicine of Cleveland Tissue Engineering Society Tissue Engineering and Regenerative Medicine International Society (TERMIS) International Bone Research Association (IBRA)

SOCIETY ACTIVITIES

American Academy of Orthopaedic Surgeons Committee on Orthopaedic Basic Science Quality Improvement Initiatives Task Force Research Committee - Tissue Engineering Panel

Page 5.

1992 -1993 1996 -1997

2004 2006 2007

1990 ­2002 ­1992 - 2002 1990 - 2001 1986 ­1988 ­1988 ­2000 ­1994 -1998 1990 ­1988 ­1988 - 2002 1988 ­2003 ­2004 ­2004 ­2004 - 2005

2005 ­2006 ­

1995 - 2004 2000 - 2001 2000 - 2002

George F. Muschler, M.D. Curriculum Vitae

Chairman Biological Implants Committee Council on Research, Quality Assessment, and Technology Extremity War Injuries Research Symposia

Planning Committee Planning Committee for Evidence-Based Medicine Summit

Orthopaedic Research and Education Foundation Local Campaign Chairman Resident Research Grants Peer Review Committee

Orthopaedic Research Society Board of Directors Treasurer-Elect Treasurer Executive Committee

Radiation Therapy Oncology Group Working Group in Bone and Soft Tissue Sarcoma

Musculoskeletal Tumor Society Research Committee

Association of Bone and Joint Surgeons AV Committee

Alliance for Regenerative Medicine Board Member Executive Committee Government Relations Committee

BOARDS

Center for Stem Cell and Regenerative Medicine (CSCRM) Scientific Advisory Board

Clinical Tissue Engineering Center (CTEC) Director, PI and Chairman, Internal Advisory Board

National Center for Regenerative Medicine (NCRM) Executive Committee

Orthopaedic Research Society Alliance for Regenerative Medicine Armed Forces Institute for Regenerative Medicine InMotion Musculoskeletal Institute

Scientific Advisory Committee

OTHER PROFESSIONAL ACTIVITIES

Cleveland Center for Medical Technology Subcommittee on Orthopaedic Products and Devices

Ohio Edison BioTechnology Center (EBTC) Commercialization Cabinet (Charter Member)

Page 6.

2002 2002 - 2008 2008 - 2011

2008 2009 ­

1991 - 2003 2005 -2009

2006 ­2006 - 2007 2007 - 2010 2007 ­

1996 - 1997

2000 - 2002

2002 ­2002 - 2003

2009 ­2009 ­2009 ­

2005 ­

2005 ­

2005 ­2006 ­2007 ­2008 ­

2009 ­

1995 -1996

1997 -1999

George F. MU5chler, M.D. Curriculum Vitae

Page 7.

Food & Drug Administration (FDA) Medical Devices Advisory Committee, Center for Devices and Radiological Health (CDRH) Orthopaedic and Rehabilitation Devices Panel, Consultant 10/08 - 10/12

US Army Medical Research and Materiel Command (USAMRMC) Scientific Steering Committee for Regenerative Medicine 2009

2009 Stakeholders Meeting of the Peer Reviewed Orthopaedic Research Program (PRORP) March 26-27, 2009

PROFESSIONAL HONORS AND AWARDS

American Orthopaedic Association North American Traveling Fellow 1989

Orthopaedic Research and Education Foundation Career Development Award 1990 -1992

J.P Ranney Award (Cleveland Clinic Innovations) 2006

Best Doctors Listing - Orthopaedic Surgery Northern Ohio Live Magazine 2007

REVIEW ACTIVITIES

Journals Journal of Biological Chemistry Calcified Tissue International Clinical Orthopaedics and Related Research

Guest Editor Symposium (w Tom Bauer, M.D. Ph.D.) Bioactive Materials in Orthopaedic Surgery

Journal of Bone and Joint Surgery (American) Journal of Orthopaedic Research Journal of Applied Biomechanics Tissue Engineering Stem Cell

1994 - 2006 1994 1996 ­

2001 1997 ­1997 ­1997 2005 ­2005­

Societies Orthopaedic Research Society (Meeting Abstracts) 2004 - 2006

Organizations Department of Veterans Affairs

Merit Award Review Committee Orthopaedic Research and Education Foundation

Howmedica Bone Growth Research Grants Career Development Awards Resident Research Grants Peer Review Committee

NIH - Center for Scientific Review Ad Hoc Reviews (multiple)

Muscular, Skeletal & Dental Initial Review Group

1995

1997 2003 2005-2009

George F. Muschler, M.D. Curriculum Vitae

Div. of Physiological Systems SBIRISTTR Proposals Tissue Engineering Study Section (SSS-M) Regenerative Medicine

Member (ad hoc) Skeletal Biology Structure & Regeneration Study Section Musculoskeletal Tissue Eng. Study Section (MOSS G)

Member Musculoskeletal Tissue Engineering Study Section

Member Special Emphasis MTE Panel/(ZRG1 MOSS-A (05)

EDITORIAL BOARDS

TEACHING

University of Texas Health Science Center at Dallas Department of Physical Therapy Instructor in Orthopaedics

Texas Women's University School of Physical Therapy Aqjunct Professor of Orthopaedic Surgery School of Occupational Therapy Adjunct Professor of Orthopaedic Surgery

Cleveland Clinic Foundation Attending Surgeon - Teaching Service Orthopaedic Research Committee Orthopaedic Journal Club Director Orthopaedic Science Series Director Basic Science Core Curriculum Mentor

Stem Cell Biology Fracture Repair Bone Graft Substitute Materials Tissue Engineering

Basic Science Disease Curriculum Mentor Arthritis, Cartilage, Cartilage Repair - Co-Director

Resident Research and Education Committee Orthopaedic Resident OREF Mock Review Panel- Director

COURSES AND MEETINGS ORGANIZED

MOS Meeting Symposium Cell-Therapy in your Operating Room Today Director

MOS Meeting Symposium Cell-Based Therapy for Bone and Cartilage Repair Director

MOS Meeting Instructional Course Lecture Cell-Based Therapy for Bone and Cartilage Repair Director

Page 8.

1998 - 2002 1999 - 2000 2001 - 2003

2004 - 2005 2004 - 2005

2005 - 2009

2006

1983 - 1985

1983 - 1985

1983 - 1985

1988 ­1990 - 2003 1991 -1992 1991 - 1993 2001 ­

2003 2003 - 2004 2005 ­

2003

2004

2004