Frequently Asked Questions

Is BioDfactor a stem cell product? NO. BioDfactor is a viable human tissue product. Specifically, BioDfactor is derived from placental tissue that has been cryopreserved to maintain the biologic structure of the collagen that forms the extracellular matrix inherent in the tissue and the viability of the cells naturally present in the placenta. The extracellular matrix provides a natural scaffold for cellular attachment in the body. It is the natural scaffold or micro-scaffold created by the morselized tissue matrix that facilitates the cell migration and proliferation of the patients own cells to achieve the primary function of the product as an in vivo wound covering. The microscaffold is derived from those components essential for fetal growth and development and includes the residual proteins, carbohydrates, hyaluronic acid, growth factors, and other chemical compounds and cells naturally present in the placental tissues and fluid.

Distributing BioD the rules

I have heard the term Section 361, what does it refer to? The FDA has issued specific rules governing the manufacture and distribution of human cells, tissues, and cellular and tissue-based products (HCT/Ps). These rules also establish donor eligibility, current good tissue practice, and other procedures to prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps. Section 361 of the Public Health Service Act is the governing statute that requires applicable manufacturers to comply with the regulations set forth in 21 CFR Part 1271. The rules governing Section 361 HCT/Ps are different than the rules governing drugs, devices and biologic products. What are the principal criteria to be classified as a Section 361 HCT/P? The principal criteria for an HCT/P to be regulated solely under section 361 of the PHS Act and the regulations of Part 1271 are as follows: (1) The HCT/P is minimally manipulated; (2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent; (3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent; and (4) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; If all of the foregoing criteria are met, then the product can be marketed as a Section 361 HCT/P and does not require pre-market review or approval as a drug, medical device or biologic. Given the unique regulatory requirements for a Section 361 HCT/P, how do I promote BioDfence and BioDfactor? As Section 361 HCT/Ps, neither BioDfence nor BioDfactor requires FDA pre-market review or approval to market the products. The regulatory requirement is that any claims made or authorized by the manufacturer of a HCT/P must be fair and balanced based on the relevant scientific literature, studies and other data that is available. As such,

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BioDfence should be promoted as an adhesion barrier to reduce surgical complications associated with scar tissue formation around the dura, nerve endings or surgical hardware. BioDfence is sterile and is resorbed in the body during the healing process. BioDfactor should be promoted as a viable human tissue product. The extracellular matrix formed by the placental collagen provides a natural scaffold for cellular attachment in the body. It is the micro-scaffold created by the morselized tissue matrix that provides the primary function of the product as it covers and protects the wound. In addition to the structural properties of amnion, scientific studies have shown that amniotic fluid contains proteins, hyaluronic acids, cytokines and various growth factors, all of which aid in fetal growth and development. These studies have also shown that amniotic fluid contains multipotent cells that are not only osteogenic, but capable of differentiating into all three germ layers of the human body. While the primary function of BioDfactor is to provide a tissue matrix to cover and protect the wound, the presence of these cells may provide ancillary clinical benefits to the patient. Help me understand the term homologous use in the context of filling bone voids in a spine fusion procedure. One of the four criteria for assessing whether a product qualifies as a Section 361 tissue is whether it is intended for homologous use. Specially, under 21 CFR Part 1271, the term homologous use means the repair, reconstruction, replacement, or supplementation of a recipients cells or tissue with an HCT/P that performs the same basic function or functions in the recipient as in the donor. In the donor, amniotic tissue, fluid and cells function as a biologic system that covers and protects the fetus and aids in fetal growth and development, including the growth and development of bone tissue and the musculoskeletal system of the fetus. In fact, it is the hyaluronic acid, growth factors, proteins, and cells in the amniotic fluid that provides the osteogenic environment that is essential for bone tissue growth in vivo. BioDlogics promotes BioDfactor as a cryopreserved human tissue product. We believe this approach is consistent with other FDA guidance issued in connection with their review of other Section 361 HCT/Ps and supported by the extensive literature assessing the therapeutic application of amniotic fluid and tissue generally. As an example of the broader context in which the FDA has historically interpreted homologous use, in 2001 the FDA acknowledged that amniotic tissue could be marketed for ocular surface wound healing and repair as a Section 361 tissue. We believe the FDA would use a similar approach to the interpretation of the term in any review of BioDfactor. Do I need to be a registered Tissue Bank to distribute BioD products? You do not need to register as a tissue bank if you never take physical possession of the products and, therefore, you are not in the chain-of-custody of the tissue. The intention is to have the products sent directly to the hospital where the clinical procedure is to be performed. If, however, you are in the chain-ofcustody, even to transport the product to the health care facility, then the distributor would be required to also be registered as a tissue bank with the FDA. Remember you do not sell human tissue as that is against the law. You are given a commission for your distribution services. Be sensitive to understanding this especially around the hospital environment. I know a doctor that wants to use BioDlogics products in tendon repair and I have heard of both products being used in different areas of the body. Can I sell it for other clinical applications that meet the homologous use requirement? A physician may use these allografts in
any manner that he sees fit based on his professional judgment and the needs of his patient. You may not promote the products beyond the claims that have been approved by BioDlogics, but you can sell it to him. Officially the agreement between BioDlogics and Amedica is for the spine market.

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BioDfence & BioDfence - DryFlex

What is the difference between BioDfence and BioDfence - DryFlex? Both products are sterile, resorbable adhesion barriers, but BioDfence is packaged in sterile saline and, therefore, hydrated when opened while BioDfence DryFlex, as the name implies, is dehydrated during processing and dry to the touch. BioDlogics uses its proprietary DryFlex tissue technology in processing this graft to improve the handling characteristics of the product for those surgeons that found the hydrated graft difficult to work with in the OR. Where EXACTLY does the amniotic tissue come from, placenta membrane or amniotic membrane? It is amniotic membrane, the inner most layer of the placental sac that surrounds the fetus in the womb. Is there an orientation that is required for BioDfence or BioDfence - DryFlex, a right side vs. wrong side to go towards the dura? No. BioDfence did not previously distinguish between the fetal and maternal side during its manufacturing process so, as originally released, there was no way to distinguish the sides of the tissue for purposes of determining orientation. BioDlogics does not believe that the orientation of the tissue is relevant to clinical efficacy. That said, some competitors started to reflect orientation and recommending placement with the maternal side down next to the dura. To avoid any competitive disadvantage, BioDlogics decided to indicate orientation as well so that the physicians can, if they prefer, elect to implant the allograft with a specific orientation toward the dura. The preparation instructions in the product insert describe how you determine orientation if requested by the surgeon. BE SURE THAT NO MESH IS LEFT IN THE PATIENT FOLLOWING PLACEMENT OF THE ALLOGRAFT. Explain Amnion and Chorion in regards to the sides of the tissue? BioDfence is processed using only amnion (the inner layer of the placental sac); BioDlogics separates the chorion (the outer layer) in the processing phase after recovering the placental organ during the C-section. In the clinical paper Tao H, Fan H. Implantation of amniotic membrane to reduce postlaminectomy epidural adhesions Eur Spine Journal 2009 (Canine Study). The paper talks about CAM (Cross-linked Amniotic Membrane), is BioDfence considered cross-linked? The sterilization of the tissue during the manufacturing process has the ancillary effect of crosslinking the tissue. How long does it take BioDfence to resorb in the body? The time will vary between patients and the size of the graft used, but we believe that it generally takes 12 to 16 weeks for the graft to be completely resorbed. The data points we know are as follows: 1. In the proof-of-concept pig study using our graft, the membrane was still visible at 8 weeks when the animals were euthanized. 2. In a larger sheep study using the BioDfence grafts, the grafts were visible at 8 weeks post-op. 3. In the Tao 29 dog canine study, cross-linked amnion was still visible at 12 weeks. 4. In Dr. Ploskas clinical abstract, BioDfence was implanted in September 2009 (we do not know the exact date) and was fully resorbed at the time of the revision procedure in January 2010. Based on the foregoing, we believe resorption generally occurs within 16 weeks.

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Can BioDfence-DryFlex be placed down a tube in an MIS surgery? Yes. The product was specifically designed to allow placement using minimally invasive techniques. The handling characteristics of the dry graft allow it to be pushed down the tube then manipulated by the surgeon for appropriate placement in vivo.

BioDfactor
Why does the brochure say structural matrix when its a liquid? Amniotic tissue is an abundant source of collagen that provides an extracellular matrix to act as a natural scaffold for cellular attachment in the body. Collagen provides a structural tissue matrix that facilitates, among other things, cell migration and proliferation in vivo. BioDfactor was developed using a proprietary technique that morselizes the amnion in an effort to preserve its structural properties in an injectable form. This micro-scaffold created by the morselized tissue matrix is combined with the proteins, carbohydrates, lipids, hyaluronic acid, growth factors, and other chemical compounds naturally present in amniotic fluid and tissue to provide an in vivo wound covering that is derived from those components essential for fetal growth and development. BioDlogics believes that this micro-scaffold provides some structural properties as it covers and protects the wound. Can you explain the antigenic properties of amnion? Immune rejection in the human body occurs when there is a conflict between self and non-self cells that results is immunological conflict. Given the unique function of the placental membrane in the human body, it is believed to produce various immunosuppressive and anti-inflammatory molecules which makes the membrane less susceptible to immunological rejection and, therefore, suitable for use as an in vivo wound covering. The clinical studies and literature often refer to the immunological paradox of pregnancy as the immune privilege of the placental organ due to the low risk of immune rejection. The origin of the immunological conflict is generally known as the Major Histocompatibility Complex (MHC). The MHC is a set of molecules designated as Class I and Class II that are expressed on cell surfaces that trigger immune system defenses, such as an increase in white blood counts or lymphocyte activity. Class I molecules are found on virtually every cell in the human body while Class II molecules are found only on antigenic cells such as B-cells and macrophages. The MHC molecules control the immune response through recognition of self and non-self with those cells identified as non-self targeted for immunologic rejection. Studies have shown that the placental membrane cells do not express MHC Class II antigens which are responsible for the immunologic rejection of allografts in humans. In addition to the absence of MHC Class II molecules, recent scientific research suggests that the placental membrane secretes compounds that may actively cloak the placenta, and the fetus that resides in it, from immunological detection by the maternal cells. To better understand the immune privilege generally associated with amniotic tissue, take a look at the article Immunogenicity of Human Epithelial Cells and Transplantation into Volunteers that can be found on the BioDlogics website. We are not aware of any adverse clinical reactions to products derived from amniotic tissue or fluid that have been processed in a manner similar to BioDfence or BioDfactor. However, as with the implantation of any human tissue there is always some risk of an adverse reaction or immunological response. See the product insert for additional details.

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What studies have been done to confirm that the cells contained in amniotic fluid generally and BioDfactor specifically are not tumorigenic when implanted in vivo? Dr. Anthony Atala and his team at Wake Forest University School of Medicine and the Wake Forest Institute for Regenerative Medicine have published a number of scientific studies and abstracts related to their research of amniotic fluid stem cell lines. In the article, Isolation of amniotic stem cell lines with potential for therapy, the authors found that the surface marker profile of amniotic fluid-derived stem (AFS) cells and their expression of the transcription factor Oct4 suggests that they represent an intermediate stage between pluripotent embryonic stem cells and lineage-restricted adult stem cells. Unlike embryonic stem cells, they found that AFS cells do not form tumors in vivo. Specifically, they found that none of the four human AFS cell lines tested, including late-passage cells, formed tumors in severe combined immunodeficient mice. In addition to the work at Wake Forest on AFS cells generally, prior to the initial release of BioDfactor, a tumorigenicity study was completed using the product. The study involved 40 nude mice with 20 mice injected subcutaneously with BioDfactor. After 12 weeks, none of the animals developed tumors. The study concluded that BioDfactor is considered non-tumorigenic under the conditions of the assay. Does BioDfactor have Induced Pluripotent Cells? No. Induced means artificially derived. All cells in BioDfactor are naturally present in the placental organ and BioDlogics does not culture, expand, induce or otherwise manipulate any of the cell lines. Why cant we mix BioDfactor with a DBM with glycerol, is it dangerous? No, it is not dangerous, it is NOT a contraindication, but glycerol, depending on the concentration, may be harmful to viable cells. Accordingly, BioDlogics does not recommend use of the product with glycerol. In the end, it is the doctors choice.

AmnioExCel
What is AmnioExCel and how is it used? Unlike BioDfence which acts as an adhesion barrier, AmnioExCel has been developed as an extracellular wound covering that will resorb and incorporate more quickly into the surrounding soft tissue. As such, we believe that AmnioExCel is the ideal choice for filling soft tissue defects. It combines the unique biologic structure of amniotic tissue with the enhanced handling characteristics associated with the DryFlex processing technology. Like BioDfence, AmnioExCel is processed from human amnion.

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