EXHIBIT E TO MEMORANDUM IN SUPPORT OF PLAINTIFFS 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

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 Developments 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 2

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 Administrations (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.

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 investigators 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 policiesfunding, regulatory, reimbursement and othersto 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, 4

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), 5

including whether the cultured cell product falls within the Federal Food, Drug, and Cosmetic Acts (FD&C Act) definition of a prescription drug; whether there are any published adequate and well-controlled studies of RSs 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 RSs cultured cell product, I will address each of these questions. RSs Cultured Cell Product 18. In preparing this declaration, I have reviewed, among other things, RSs website,

www.regenexx.com; publications by RSs medical director, Christopher Centeno, M.D. and his co-authors, regarding RSs cultured cell product; unpublished descriptions of research on RSs cultured cell product; copies of treatment records for several patients who were treated with RSs 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,

process is described in the firms current manufacturing standard operating procedures (SOPs). The process includes the following steps, among others: Bone marrow is harvested from the patients iliac crest (hip) or synovial fluid is taken from the patients 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 RSs 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 Dulbeccos 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 37C, 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 6,00012,000 cells/cm2 in -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 7

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 patients 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 patients 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.

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-cellprocedure/ (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.

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 10

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; nonhealing bone fractures; chronic bulging lumbar disc; injuries to the meniscus, rotator cuff; 11

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 RSs cultured cell product as an injection therapy. Studies and Articles Regarding RSs Cultured Cell Product 25. I have been asked to give an opinion regarding whether there are any adequate

and well controlled studies of RSs 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 RSs cultured cell product, an unpublished summary of RSs research program, and two unpublished case series. In my opinion, RSs 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)).

12

#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). 14

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 15

nucleated cell transfer procedures one month apart. A nucleated cell pellet was prepared from an aspiration of the patients 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 16

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 patients 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 patients 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 pre17

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 patients 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 patients 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 observers 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. 19

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. 20

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 antiinflammatory 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.

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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, RSs 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). 22

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 23

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. RSs 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 24

. b.

25

c.

26

d.

27

e.

28

31.

29

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. 30

Unpublished Case Series 32.

a.

31

32

b.

33

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 34

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. this study: a. The inclusion criteria do not appear to have been followed. The 35 There are several critical weaknesses or unconventional abnormalities in

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 36

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 followup 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 37

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 38

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 IRBs 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 coauthors on some of Dr. Centenos publications regarding the RS cultured cell product, were also members of the SIF Board of Directors. 39

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 RSs 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. 40

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 3dimensional matrix or gel, or by infusing them beneath a layer of autogenous periosteum (i.e., the surface layer of a patients 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., 41

(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 99:89327, 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 42

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 43

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. Followup 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, 44

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

45

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 46

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 10:199206, 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 47

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 48

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, 20542061, 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 non49

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

50

stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:3157, 2006). This body has proposed three criteria: 1. 2. Plastic adherence of isolated cells in culture. The expression of CD105, CD73 and CD90 in >95% of the cultured cells, and lack of expression of markers including: CD43, CD45, CD14, CD11b, CD79, 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; 7990, 2008) and Brooke et al. (Seminars in Cell & Developmental Biology 18:846858, 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. 51

RSs 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 RSs 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 52

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 53

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), RSs 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 patients 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. 54

50.

The labeling for RSs 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, 55

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 patients 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 RSs 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 56

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.

57

GEORGE FREDERICK MUSCHLER, M.D.

The Cleveland Clinic Foundation
9500 Euclid Avenue Cleveland, OH 44195 Dept. of Orthopaedic Surgery (A-41) Section of Adult Reconstructive Surgery Phone: 216-444-5338 Fax: 216-445-6574 e-mail: muschlg@ccf.org Birth date: Place of Birth: Home Address: Dept. of Biomedical Engineering (ND2) Orthopaedic & Rheumatologic Research Center Clinical Tissue Engineering Center Phone: 216-445-7195 Fax: 216-444-9198 e-mail: muschlg@ccf.org

Spouse:

Children:

EDUCATION University of Illinois, Champaign-Urbana, IL Bachelor of Science (Chemistry) Northwestern University School of Medicine, Chicago, IL Doctor of Medicine POST GRADUATE EDUCATION Internship in General Surgery University of Texas Southwestern Medical School and Affiliated Hospitals, Dallas, Texas Residency in Orthopaedic Surgery University of Texas Southwestern Medical School and Affiliated Hospitals, Dallas, Texas Fellowship in Musculoskeletal Oncology Memorial Sloan-Kettering Cancer Center, New York, NY Fellowship in Bone Research and Metabolic Bone Disease The Hospital for Special Surgery, New York, NY PROFESSIONAL APPOINTMENTS Surgeon (Orthopaedic Surgery) The New York Hospital- Cornell Medical Center 1981 -1982 1974 -1977

1977-1981

1982 -1986

1986 - 1988

1986 -1988

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 2005 2005

Page 3.

2007

2007

2008

George F. Muschler, M.D. Curriculum Vitae

INSTITUTIONAL ADMINISTRATIVE ACTIVITIES

Page 4.

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

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

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 LICENSES Texas New York Ohio 1982 1986 1987

Page 5.

1992 -1993
1996 -1997

2004 2006 2007

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 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

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

OTHER PROFESSIONAL ACTIVITIES Cleveland Center for Medical Technology Subcommittee on Orthopaedic Products and Devices Ohio Edison BioTechnology Center (EBTC) Commercialization Cabinet (Charter Member)

1995 -1996 1997 -1999

George F. MU5chler, M.D. Curriculum Vitae

Food & Drug Administration (FDA) Medical Devices Advisory Committee, Center for Devices and Radiological Health (CDRH) Orthopaedic and Rehabilitation Devices Panel, Consultant US Army Medical Research and Materiel Command (USAMRMC) Scientific Steering Committee for Regenerative Medicine 2009 Stakeholders Meeting of the Peer Reviewed Orthopaedic Research Program (PRORP)

Page 7.

10/08 - 10/12

2009

March 26-27, 2009

PROFESSIONAL HONORS AND AWARDS

American Orthopaedic Association North American Traveling

Fellow

1989

Orthopaedic Research and Education Foundation Career Development Award J.P Ranney Award (Cleveland Clinic Innovations)

1990 -1992 2006

Best Doctors Listing - Orthopaedic Surgery Northern Ohio Live Magazine

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 Societies Orthopaedic Research Society (Meeting Abstracts) 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

2007

1994 - 2006 1994 1996 2001 1997 1997 1997 2005 2005

2004 - 2006

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

Page 8.
1998 - 2002 1999 - 2000 2001 - 2003 2004 - 2005 2004 - 2005 2005 - 2009 2006

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

1983 - 1985

1983 - 1985 1983 - 1985

1988 1990 - 2003 1991 -1992 1991 - 1993 2001

2003 2003 - 2004 2005

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

2003

2004

2004