LQ SCIENTIFIC & CLINICAL MONOGRAPH

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1 LQ SCIENTIFIC & CLINICAL MONOGRAPH

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3 OrthoFlo Lyophilized Product Description OrthoFlo is a purified human amniotic fluid allograft that is intended for homologous use to protect and cushion, provide lubrication and modulate inflammation. Among other things, amniotic fluid provides mechanical cushioning and supports the mobility of the fetus and modulates inflammation. 1 Through MiMedx s proprietary LyoPur Process, amniotic fluid is filtered and dialyzed to retain the components of the amniotic fluid that are essential to these functions, while removing cells and gestational by-products. The resultant fluid is lyophilized, stabilizing the bioactive components, and enabling storage at ambient conditions for five years. Additionally, OrthoFlo is terminally sterilized using gamma irradiation for added prevention of disease transmission and enhanced assurance of patient safety. Terminally sterilized for enhanced patient safety Stores at ambient conditions with a 5 year shelf life Eighty-three growth factors, cytokines, and regulatory molecules that promote healing and modulate inflammation have been identified in OrthoFlo to date Contains hyaluronic acid to protect, cushion, and provide lubrication for enhanced mobility The multitude of factors preserved in all MiMedx products, their inherent benefits, and the Company s rigorous safety standards provide the critical advantage and differentiation of the MiMedx products. Since 2006, as the premier leader in regenerative medicine, MiMedx has been dedicated to advancing healing through innovative biomaterial products and bioimplants. LQ OrthoFlo Scientific & Clinical Monograph MiMedx 3

4 Amniotic Fluid Overview Amniotic fluid is a dynamic source of nutrients and evolves throughout gestation to aid in the development and protection of the fetus (Figure 1). Growth factors, cytokines and hyaluronic acid are produced and secreted to support specific developmental milestones. For instance, high levels of epidermal growth factor are detected in the amniotic fluid towards the end of pregnancy to promote fetal lung development. 1 FIGURE 1 During Caesarean section procedures, the amniotic fluid is collected from the mother. Amniotic Fluid Chorion Amnion Chorionic Plate Umbilical Cord Placenta To summarize, functions of the amniotic fluid in utero include: 1 An extension of the fetal extracellular compartment A connection between the intracoelemic and extracoelemic components of the developing fetus A physiologic buffer for various extra-fetal compounds Modulation of fluid and electrolyte transport between the mother and fetus across fetal and placental membranes Nutritional support of the fetus Provision of a supportive fluid cushion to the developing fetus, allowing fetal movement and growth Protective functions provided by the inclusion of multiple growth factors and biological molecules Provide antimicrobial effectors that protect the fetus Modulation of inflammation At full-term, amniotic fluid is rich in growth factors, cytokines and hyaluronic acid to support the maturation of the fetus. Because of these functional properties, amniotic fluid has been used clinically since the 20th century. The first applications were in wound healing, followed by a large variety of other applications, including use in musculoskeletal conditions. The use of amniotic fluid as a treatment for orthopedic conditions was recorded as early as 1938; Shimberg reported on a series of sixty-eight cases in which amniotic fluid was used in the treatment of patients with joint disease for various orthopedic conditions. 5 4 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

5 His paper concluded the following: In sixty-eight cases in which amniotic fluid concentrate has been employed in the treatment of various pathological conditions of joints, the use of the fluid concentrate has not been attended by a single unfavorable reaction. Its action is probably both biological and mechanical. It speeds up a defense-repair mechanism within the joints. The results obtained have been impressive in intra-articular fractures, and encouraging in selected cases of atrophic arthritis, as well as in persistent joint effusions. It successfully prevents the formation of new adhesions after closed manipulation of joints. It is a valuable prophylactic after arthrotomy of any type. Its use both in soft tissues and in other serous cavities is suggested. MiMedx LyoPur Process Amniotic fluid is recovered from full-term Caesarean section deliveries. Upon donation, serological and microbial tests are conducted to ensure that it is safe for transplantation. The fluid is subjected to a series of proprietary filtration and dehydration steps, which constitute the LyoPur Process. The LyoPur Process preferentially removes the particulate and by-products naturally produced through gestation including vernix, lanugo hair, urea and uric acid, while retaining the critical biological components. The purified fluid is dispensed into individual vials and lyophilized to preserve the bioactive components and allow for storage at ambient conditions. The product is then terminally sterilized using gamma irradiation. The LyoPur Process provides amniotic fluid for injection without any additives; therefore, OrthoFlo delivers a product that is amniotic fluid in its most pure and natural state. At the time of use, the lyophilized fluid requires a simple reconstitution step using sterile saline. To demonstrate the equivalence between natural amniotic fluid and OrthoFlo, the protein composition was visualized through Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis FIGURE Molecular Weight Protein composition of OrthoFlo compared to fresh amniotic fluid Lyophilized OrthoFlo Unprocessed Amniotic Fluid (SDS-PAGE). This technique separates the individual proteins within each sample based upon molecular weight. OrthoFlo maintains its amniotic fluid profile, as illustrated by the SDS-PAGE gel below (Figure 2). The protein composition of OrthoFlo appears very similar to fresh amniotic fluid with a nearly identical pattern of protein bands. It should be noted that the banding pattern is identical between multiple OrthoFlo donors and with similar band intensity, indicating consistent processing across donors and resulting in a uniform final product. LQ OrthoFlo Scientific & Clinical Monograph MiMedx 5

6 Source of Amniotic Fluid Eligible amniotic fluid donors are living mothers that have delivered a full-term live birth by scheduled Caesarean section. All tissues are recovered under full informed consent of the donor (mothers of the newborn children). All tissues recovered meet stringent specifications during donor screening and laboratory testing to reduce the risk of transmitting infectious disease. OrthoFlo allografts are procured and processed in the United States according to standards and/or regulations established by the American Association of Tissue Banks (AATB) and the United States Food & Drug Administration (FDA). A thorough medical and social history of the donor is also obtained, and all screening tests are reviewed by the MiMedx Medical Director prior to release of the tissues. Only tissues from donors with acceptable test results, according to the standards of MiMedx Tissue Services, LLC, as well as the standards and/or regulations of all state and federal regulatory bodies, are released. The listed communicable disease testing is performed by a laboratory registered with the FDA to perform donor testing and certified to perform such testing on human specimens in accordance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and 42 CFR part 493, or that has met equivalent requirements as determined by the Centers for Medicare and Medicaid Services (CMS). The donor is screened for: HIV-1&2 Plus 0 Antibody HTLV-1&2 Antibody Hepatitis B Core Antibody Hepatitis C Antibody Hepatitis B Virus (Nucleic Acid Test (NAT)) HIV Type 1 (Nucleic Acid Test (NAT)) Syphilis (Serologic Test) Hepatitis B Surface Antigen Hepatitis C Virus (Nucleic Acid Test (NAT)) West Nile Virus (Nucleic Acid Test (NAT))* *WNV NAT screening conducted on donors recovered beginning February 1, No Immune Response As a fetally-derived tissue, amniotic fluid cells lack specific co-stimulatory cell surface markers including CD40, CD80, and CD86 and have low immunogenicity. 6 The amniotic fluid also protects the fetus as an anatomical barrier and is a key regulator of the innate immune system with a composition similar to fetal plasma. 1 Amniotic fluid has been transplanted allogeneically without reports of immune rejection. 5 The immunologically privileged properties of amniotic fluid enable LyoPur Processed OrthoFlo to be transplanted without the need to match blood types or other indicators that would cause rejection. Packaging All LyoPur Processed amniotic fluid allografts are lyophilized and packaged using aseptic controls into an inner peel pouch and sealed with an outer peel pouch system within a clean manufacturing environment. Based upon strict validations, each graft has been effectively sterilized using irradiation. The outer peel pouch is NOT considered sterile. The inner pouch, which contains the allograft, is considered sterile unless the pouches are damaged or compromised, in which case the product should be returned to MiMedx. 6 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

7 Terminal Sterilization MiMedx amniotic fluid allografts, processed using the Company s proprietary LyoPur Process, utilize terminal sterilization as an essential part of the process to further enhance patient safety. This proprietary processing technology provides the MiMedx amniotic fluid allografts with their unique capabilities to retain the factors that are critical for clinical efficacy, provide ease of use by the physician, and offer the capacity to be stored at ambient conditions with a five year shelf life. The terminal sterilization conducted by MiMedx is a validated process in conformance with the International Organization of Standardization (ISO) standard ISO Sterilization of Healthcare Products. Conformance with this ISO standard requires a demanding Sterility Assurance Level (SAL) of 10-6, which is the probability of 1 in 1,000,000 units being non-sterile. To further enhance the safety of its amniotic products, the MiMedx proprietary processing methodology employs aseptic processing techniques in addition to terminal sterilization. MiMedx processes its amniotic and placental products based on the regulations and guidance issued by both the FDA and the American Association of Tissue Banks (AATB) standards and guidance on donor eligibility and screening to reduce the risk of disease transmission via human tissues. OrthoFlo Configuration OrthoFlo is available in four size configurations to accommodate a variety of applications for the intended homologous uses. Item Number LQ-0050 LQ-0100 LQ-0200 LQ-0400 Size 0.5 ml 1 ml 2 ml 4 ml LQ OrthoFlo Scientific & Clinical Monograph MiMedx 7

8 SCIENTIFIC EVIDENCE OrthoFlo contains an array of well-known regulatory proteins, growth factors, cytokines, and chemokines that are naturally occurring in amniotic fluid and the fluid surrounding many joints. The following list of bioactive factors are known to be present within OrthoFlo including: Platelet-Derived Growth Factor AA (PDGF-AA), Bone Morphogenetic Proteins (BMP-5 and BMP-7), and Tissue Inhibitors of Metalloproteinases (TIMPs). The growth factors have been quantified and converted to a (+) rating system to provide relative amounts present in the fluid. REGULATORS OF TISSUE GROWTH IN ORTHOFLO Acronym Cytokine Function Content AR Amphiregulin Promotes growth of epithelial cells, as well as astrocytes, Schwann cells, and fibroblasts ++ BDNF Brain-derived neurotrophic factor Supports the growth, differentiation, and survival of neurons ++ bfgf Basic fibroblast growth factor Heparin-binding protein with broad mitogenic activity; Potent stimulator of angiogenesis ++++ BMP-5 Bone morphogenetic protein 5 Plays a role in bone and cartilage development ++++ BMP-7 Bone morphogenetic protein 7 Plays a role in bone and cartilage development +++ EGF Epidermal growth factor Stimulates proliferation, differentiation, and survival in numerous cell types, including epithelial cells +++ EGF-VEGF Endocrine gland-derived vascular endothelial growth factor Stimulates endothelial cell migration, proliferation, and survival; Potent stimulator of angiogenesis +++ FGF-4 Fibroblast growth factor 4 Broad mitogenic and cell survival activity +++ KGF; FGF-7 Keratinocyte growth factor Promotes proliferation and migration of epithelial cells and keratinocytes ++ GDNF Glial cell line-derived neurotrophic factor Promotes survival and differentiation of neurons +++ HGF Hepatocyte growth factor Regulates cell growth, cell motility, and morphogenesis in epithelial cells; Important in angiogenesis ++++ IGFBP-1 Insulin-like growth factor binding protein 1 Binds and stabilizes IGF-1 as a carrier protein; Alters interactions with surface receptors ++++ IGFBP-2 Insulin-like growth factor binding protein 2 Binds and stabilizes IGF-1 as a carrier protein; Alters interactions with surface receptors IGFBP-3 Insulin-like growth factor binding protein 3 Binds and stabilizes IGF-1 as a carrier protein; Alters interactions with surface receptors IGFBP-4 Insulin-like growth factor binding protein 4 Binds and stabilizes IGF-1 as a carrier protein; Alters interactions with surface receptors ++++ IGFBP-6 Insulin-like growth factor binding protein 6 Binds and stabilizes IGF-1 as a carrier protein; Alters interactions with surface receptors Insulin Insulin Controls glucose absorption, production, and metabolism +++ NT-3 Neurotrophin 3 Supports survival and differentiation of neurons +++ NT-4 Neurotrophin 4 Supports survival and differentiation of neurons ++ PDGF-AA Platelet-derived growth factor AA Stimulates proliferation, migration, and angiogenesis +++ SCF Stem cell factor Regulates maintenance of hematopoietic stem cells ++ TGF-α Transforming growth factor alpha Stimulates proliferation and migration of keratinocytes; Potent stimulator of angiogenesis ++ TGF-β1 Transforming growth factor beta 1 Controls proliferation, differentiation, and apoptosis of numerous cell types ++++ TIMP-1 Tissue inhibitor of metalloproteinase 1 Binds and inactivates a number of matrix metalloproteinases (MMPs) ++++ TIMP-2 Tissue inhibitor of metalloproteinase 2 Binds and inactivates a number of matrix metalloproteinases (MMPs) ++++ VEGF Vascular endothelial growth factor Stimulates endothelial cell migration and activation; Potent stimulator of angiogenesis +++ VEGF-D Vascular endothelial growth factor D Promotes angiogenesis and endothelial cell growth +++ Cytokines and Chemokines Found in OrthoFlo OrthoFlo contains a variety of cytokines and chemokines known to regulate inflammation. Some of the specialized cytokines and chemokines found in OrthoFlo that contribute to the immunomodulatory properties of amniotic fluid include: Interleukin 1 Receptor Antagonist (IL-1ra), Growth Differentiation Factor 15 (GDF-15), and various CCL and CXCL chemokines. 8 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

9 REGULATORS OF INFLAMMATION IN ORTHOFLO Acronym Cytokine Function Content G-CSF Granulocyte colony-stimulating factor Stimulates the proliferation, differentiation, survival, and activation of neutrophils +++ GDF-15 Growth differentiation factor 15 Regulates inflammatory and apoptotic pathways in injured tissues ++++ GM-CSF Granulocyte macrophage colony-stimulating factor Stimulates production of granulocytes and monocytes ++ IL-12p40 Interleukin 12 p40 Subunit of IL-12p70 which stimulates growth and differentiation of T cells and natural killer cells; Can act as IL-12 antagonist ++ IL-13 Interleukin 13 Involved in B cell maturation and differentiation; Inhibits macrophage activity + IL-1α Interleukin 1 alpha Activates lymphocyte proliferation; Induces fibroblast proliferation +++ IL-1β Interleukin 1 beta Involved in lymphocyte proliferation, differentiation, and apoptosis ++ IL-1ra Interleukin 1 receptor antagonist Antagonist of IL-1 signaling +++ IL-6 Interleukin 6 Stimulates production of neutrophils and growth of B cells +++ MCSF Macrophage colony-stimulating factor Involved in proliferation, differentiation, and survival of monocytes and macrophages +++ OPG Osteoprotegerin Soluble decoy receptor that inhibits osteoclast activation ++ TNF-α Tumor necrosis factor alpha Multifunctional regulator of inflammation including cell proliferation, differentiation, and apoptosis ++ Acronym Chemokine Function Content 6Ckine 6Ckine (CCL21) Chemotactic for activated T cells ++++ Axl Tyrosine-protein kinase receptor UFO Involved in growth, migration, and anti-inflammation in multiple cell types ++++ BLC B lymphocyte chemoattractant (CXCL13) Selectively chemotactic for B lymphocytes ++ CXCL16 Chemokine (C-X-C motif) ligand 16 Promotes migration of B lymphocytes ++++ ENA-78 Epithelial-derived neutrophil-activating protein 78 (CXCL5) Recruits neutrophil migration; Promotes angiogenesis and connective tissue remodeling ++++ Eotaxin-2 Eotaxin 2 Induces chemotaxis in eosinophils and T lymphocytes ++ Eotaxin-3 Eotaxin 3 (CCL26) Chemotactic for eosinophils and basophils ++ GCP-2 Granulocyte chemotactic protein 2 (CXCL6) Chemotactic toward neutrophils ++ GRO Growth-regulated protein (CXCL1) Chemotactic toward neutrophils; involved in angiogenesis +++ HCC-1 Hemofiltrate C-C motif chemokine 1 (CCL14) Induces changes in intracellular calcium concentration and calcium release in monocytes +++ HCC-4 Hemofiltrate C-C motif chemokine 4 (CCL16) Chemotactic toward lymphocytes and monocytes ++ IL-16 Interleukin 16 Chemoattractant for CD4+ cells, including T cells, monocytes, eosinophils, and dendritic cells +++ IL-8 Interleukin 8 Induces chemotaxis in neutrophils and other granulocytes ++ IP-10 Interferon gamma-induced protein 10 (CXCL10) Chemotactic toward monocytes, natural killer cells, and T cells +++ LIGHT Tumor necrosis factor ligand superfamily member 14 Stimulates proliferation of T cells +++ MCP-1 Monocyte chemotactic protein 1 (CCL2) Recruits monocytes, memory T cells, and dendritic cells +++ MCP-2 Monocyte chemotactic protein 2 (CCL8) Chemotactic toward monocytes, lymphocytes, basophils, and eosinophils +++ MDC Macrophage-derived chemokine (CCL22) Chemotactic toward monocytes, dendritic cells, natural killer cells, and activated T lymphocytes ++++ MIF Macrophage inhibitory factor Chemotactic toward resting T lymphocytes, monocytes, and neutrophils ++++ MIG Monokine induced by gamma interferon (CXCL9) Chemoattractant for lymphocytes ++++ MIP-1α Macrophage inflammatory protein 1 alpha (CCL3) Chemotactic for neutrophils and monocytes ++ MIP-1β Macrophage inflammatory protein 1 beta (CCL4) Chemoattractant for natural killer cells and monocytes ++ MIP-1δ Macrophage inflammatory protein 1 delta (CCL15) Chemoattractant for neutrophils, monocytes, and lymphocytes ++++ MPIF-1 Myeloid progenitor inhibitory factor 1 (CCL23) Chemotactic toward resting T lymphocytes, monocytes, and neutrophils ++ MSP-α Macrophage stimulating protein alpha Stimulates migration and activation of macrophages ++++ NAP-2 Neutrophil-activating protein 2 (CXCL7) Potent chemoattractant and activator or neutrophils; Stimulates proliferation, prostaglandin E2 secretion, and hyaluronic acid secretion ++ OPN Osteopontin Regulates osteoclast adhesion to bone mineral ++++ PARC Pulmonary and activation-regulated chemokine (CCL18) Chemotactic toward naïve T cells and nonactivated lymphocytes +++ PF4 Platelet factor 4 (CXCL4) Involved in platelet aggregation; Chemotactic for numerous cell types; Regulates hematopoietic stem cells, angiogenesis, and T cell function +++ TARC Thymus and activation-regulated chemokine (CCL17) Chemotactic toward T lymphocytes ++ LQ OrthoFlo Scientific & Clinical Monograph MiMedx 9

10 Protein Composition of OrthoFlo The protein composition of amniotic fluid, OrthoFlo and synovial fluid were compared by gel electrophoresis (Figure 3). Amniotic fluid and resuspended OrthoFlo samples were loaded with equal volumes, while synovial fluid was diluted 6-fold to prevent oversaturation of the bands. For each sample group, three unique donors were compared. OrthoFlo appeared largely unchanged from the amniotic fluid donors, indicating that OrthoFlo processing does not alter the natural protein composition of amniotic fluid. Proteins of similar molecular weight and intensity patterns were also observed in both amniotic fluid and healthy synovial fluid, suggesting that both fluids, which are derived from ultrafiltrates of plasma, possess similar protein contents. FIGURE 3 SDS-PAGE analysis of human amniotic fluid, OrthoFlo lyophilized amniotic fluid allograft, and human knee synovial fluid Protein Ladder Amniotic Fluid OrthoFlo Synovial Fluid 10 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

11 BIOLOGICAL ACTIVITY OF ORTHOFLO The regenerative capacity of OrthoFlo has been demonstrated through in vitro assays where OrthoFlo promotes migration of human fibroblasts, proliferation of human synoviocytes, and production of hyaluronic acid by human synoviocytes. Cell Migration Assay Cell migration is a critical pathway in regenerative medicine as it is often necessary to recruit cells to a particular site to repair injured tissue. The chemotactic nature of various treatments can be modeled using in vitro cell migration assays where directional cell movement in response to a stimulus is quantified. Scratch wound models are considered a subset of cell migration assays where a scratch or acellular zone is created by mechanically removing cells from a defined area and monitoring the closure of that zone in response to treatment. Time course images can be obtained to measure the extent of closure over a period of time (Figure 4). FIGURE 4: Scratch wound migration assay In a scratch wound migration assay, cells migrate inward over time to fill an initially cell-free zone and rate of closure is measured. Scratch Wound Time LQ OrthoFlo Scientific & Clinical Monograph MiMedx 11

12 For OrthoFlo, cell migration into an acellular space was determined using a well-established Incucyte Scratch Wound Cell Migration Assay (Essen Bioscience). Normal human dermal fibroblasts were cultured in the presence of OrthoFlo, either at 0.01, 0.04, 0.2, or 0.8 mg/ml. Basal medium in the absence of serum and complete medium supplemented with 10% serum acted as negative and positive controls, respectively. Over the course of 4 days of treatment with OrthoFlo, percent confluence of cells in the initially acellular space was determined using the Incucyte ZOOM Live Cell Analysis System (Essen Bioscience). OrthoFlo significantly increased cell confluence over the course of 4 days in a concentration dependent manner compared to basal medium, as shown below in Figure 5, indicating that OrthoFlo promoted migration of human fibroblasts into the initially acellular space. FIGURE 5: Migration of human dermal fibroblasts in response to OrthoFlo (L) over 4 days Fibroblasts were treated with 0.01, 0.04, 0.2, or 0.8 mg/ml of OrthoFlo (L). Basal and complete medium acted as negative and positive controls, respectively. Migration of Fibroblasts % Closure of Cell-Free zone Time (hr) 12 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

13 Cell Proliferation Assay Synoviocytes make up the synovial membrane of joint capsules. Synoviocytes are responsible for maintaining the composition of the synovial fluid in the joint, which is critical to facilitate cushioning and movement of the joint and to provide nutrients to the surrounding cartilage. Synoviocytes produce hyaluronic acid, cytokines, and modulators of inflammation as major components of the synovial fluid. Therefore, these are important targets for modulating the disease progression or injury to the joint space. Cell proliferation assays are basic experiments that lead to more detailed experiments. A known number of cells are exposed to various treatments and after a set period, the cell number is quantified and compared to the starting value. This assay provides insight into how a given treatment, with varying concentration of mitogenic factors, affects the rate at which a cell population divides. Normal human fibroblast-like synoviocytes were cultured in the presence OrthoFlo, either at 0.2 or 0.8 mg/ml. Basal medium in the absence of serum and complete medium supplemented with 10% serum acted as negative and positive controls, respectively. After 3 days of treatment with OrthoFlo, cell number was determined by CyQUANT Cell Proliferation Assay (ThermoFisher Scientific). OrthoFlo significantly increased cell number after 3 days compared to basal medium (p 0.05), as shown below in Figure 6, indicating that OrthoFlo promoted proliferation of human synoviocytes. Therefore, OrthoFlo delivers an array of growth factors and cytokines that support growth of human synoviocytes, which is indicative of healthy, dividing cells. FIGURE 6: Proliferation of human knee synoviocytes in response to OrthoFlo (L) after 3 days Synoviocytes were treated with 0.2 or 0.8 mg/ml of OrthoFlo (L). Basal and complete medium acted as negative and positive controls, respectively Proliferation of Synoviocytes * * * Cell Number mg/ml 0.2 mg/ml Basal Complete OrthoFlo (L) * indicates significantly greater than basal medium (p 0.05) LQ OrthoFlo Scientific & Clinical Monograph MiMedx 13

14 Hyaluronic Acid Production Assay The conditioned media from the synoviocytes treated with OrthoFlo was collected after the three-day incubation and analyzed for hyaluronic acid production in response to the various treatments. OrthoFlo significantly increased hyaluronic acid concentration after 3 days compared to basal medium (p 0.05), as shown below in Figure 7, indicating that OrthoFlo promoted production of hyaluronic acid by human synoviocytes. FIGURE 7: Production of hyaluronic acid by human synoviocytes in response to OrthoFlo (L) after 3 days Synoviocytes were treated with 0.2 or 0.8 mg/ml of OrthoFlo (L). Basal and complete medium acted as negative and positive controls, respectively. HA Production (ng/ml per cell) Hyaluronic Acid Production by Synoviocytes * 0.8 mg/ml 0.2 mg/ml Basal Complete OrthoFlo (L) * * indicates significantly greater than basal medium (p 0.05) 14 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

15 COMPETITIVE COMPARISONS The protein composition of OrthoFlo was compared to a variety of flowable placental tissue products currently on the market claiming to be composed of amniotic fluid. OrthoFlo Comparison to FloGraft Freedom FloGraft FREEDOM bioactive amniotic suspension is processed by Crown Peak Industries, LLC (Scottsdale, AZ) and distributed by Applied Biologics, LLC (Scottsdale, AZ). FloGraft FREEDOM is described as a human allograft comprised of chorion-free amnion and amniotic fluid. The SDS-PAGE gel below in Figure 8 illustrates the composition and relative abundance of proteins, separated by molecular weight, for OrthoFlo and FloGraft FREEDOM, compared to fresh amniotic fluid. The protein composition of OrthoFlo appears very similar to fresh amniotic fluid (A); however, FloGraft FREEDOM (B) contains few distinct bands of protein and does not possess the protein composition of fresh amniotic fluid, suggesting that it is highly processed, either to remove essential amniotic fluid components or to alter the natural distribution of proteins in fresh amniotic fluid. The chart below in Figure 9 illustrates the relative content of growth factors, cytokines, and chemokines present in OrthoFlo, compared to FloGraft FREEDOM, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). The content of FloGraft FREEDOM (as depicted by the vertical red bars) is normalized to the content in OrthoFlo (as depicted by the horizontal blue line = 100%). 66 out of 78 factors (85%) important for healing and repair are higher in OrthoFlo than in FloGraft FREEDOM. In fact, 56 out of 78 factors (72%) measured in OrthoFlo were not detected in FloGraft FREEDOM. These results suggest that FloGraft FREEDOM loses or removes a significant number of important signaling molecules, which are retained in OrthoFlo, during processing. FIGURE 8 SDS-PAGE analysis of FloGraft FREEDOM, compared to amniotic fluid and OrthoFlo. FIGURE 9 Relative content of growth factors, cytokines, and chemokines present in FloGraft FREEDOM, compared to OrthoFlo, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). LQ OrthoFlo Scientific & Clinical Monograph MiMedx 15

16 OrthoFlo Comparison to PalinGen Flow PalinGen Flow flowable tissue matrix is processed by Pinnacle Transplant Technologies (Phoenix, AZ) and distributed by Amnio Technology, LLC (Phoenix, AZ). PalinGen Flow is described as cryofractured amnion in amniotic fluid. The SDS-PAGE gel below in Figure 10 illustrates the composition and relative abundance of proteins, separated by molecular weight, for OrthoFlo and PalinGen Flow, compared to fresh amniotic fluid. The protein composition of OrthoFlo appears very similar to fresh amniotic fluid (A); however, PalinGen Flow (B) contains few distinct bands of protein and does not possess the protein composition of fresh amniotic fluid, suggesting that it is highly processed, either to remove essential amniotic fluid components or to alter the natural distribution of proteins in fresh amniotic fluid. The chart below in Figure 11 illustrates the relative content of growth factors, cytokines, and chemokines present in OrthoFlo, compared to PalinGen Flow, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). The content of PalinGen Flow (as depicted by the vertical red bars) is normalized to the content in OrthoFlo (as depicted by the horizontal blue line = 100%). 59 out of 78 factors (76%) important for healing and repair are higher in OrthoFlo than in PalinGen Flow. In fact, 51 out of 78 factors (65%) measured in OrthoFlo were not detected in PalinGen Flow. These results suggest that PalinGen Flow loses or removes a significant number of important signaling molecules, which are retained in OrthoFlo, during processing. FIGURE 10 SDS-PAGE analysis of PalinGen Flow, compared to amniotic fluid and OrthoFlo. FIGURE 11 Relative content of growth factors, cytokines, and chemokines present in PalinGen Flow, compared to OrthoFlo, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). 16 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

17 OrthoFlo Comparison to PX50 PX50 flowable placental tissue matrix is manufactured by Human Regenerative Technologies, LLC (HRT ) and distributed by Skye Biologics. PX50 is described as a placental connective tissue matrix product. The SDS-PAGE gel below in Figure 12 illustrates the composition and relative abundance of proteins, separated by molecular weight, for OrthoFlo and PX50, compared to fresh amniotic fluid. The protein composition of OrthoFlo appears very similar to fresh amniotic fluid (A); however, PX50 (B) contains no distinct bands of protein and does not possess the protein composition of fresh amniotic fluid, suggesting that it is highly processed to remove the essential distribution of proteins that are naturally found in placental tissues. The chart below in Figure 13 illustrates the relative content of growth factors, cytokines, and chemokines present in OrthoFlo, compared to PX50, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). The content of PX50 (as depicted by the vertical red bars) is normalized to the content in OrthoFlo (as depicted by the horizontal blue line = 100%). 75 out of 78 factors (96%) important for healing and repair are higher in OrthoFlo than in PX50. In fact, 67 out of 78 factors (86%) measured in OrthoFlo were not detected in PX50. These results suggest that PX50 loses or removes a significant number of important signaling molecules, which are retained in OrthoFlo, during processing. FIGURE 12 SDS-PAGE analysis of PX50, compared to amniotic fluid and OrthoFlo. FIGURE 13 Relative content of growth factors, cytokines, and chemokines present in PX50, compared to OrthoFlo, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). LQ OrthoFlo Scientific & Clinical Monograph MiMedx 17

18 OrthoFlo Comparison to FlowerFlo FlowerFlo placental tissue matrix allograft is processed by Human Regenerative Technologies, LLC (HRT; El Segundo, CA) and distributed by Flower Orthopedics (Horsham, PA). FlowerFlo is described as a human tissue allograft, derived from decellularized particulate human placental connective tissue. The SDS-PAGE gel below in Figure 14 illustrates the composition and relative abundance of proteins, separated by molecular weight, for OrthoFlo and FlowerFlo, compared to fresh amniotic fluid. The protein composition of OrthoFlo appears very similar to fresh amniotic fluid (A); however, FlowerFlo (B) contains no distinct bands of protein and does not possess the protein composition of fresh amniotic fluid, suggesting that it is highly processed to remove the essential distribution of proteins that are naturally found in placental tissues. The chart below in Figure 15 illustrates the relative content of growth factors, cytokines, and chemokines present in OrthoFlo, compared to FlowerFlo, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). The content of FlowerFlo (as depicted by the vertical red bars) is normalized to the content in OrthoFlo (as depicted by the horizontal blue line = 100%). 67 out of 78 factors (86%) important for healing and repair are higher in OrthoFlo than in FlowerFlo. In fact, 60 out of 78 factors (77%) measured in OrthoFlo were not detected in FlowerFlo. These results suggest that FlowerFlo loses or removes a significant number of important signaling molecules, which are retained in OrthoFlo, during processing. FIGURE 14 SDS-PAGE analysis of FlowerFlo, compared to amniotic fluid and OrthoFlo. FIGURE 15 Relative content of growth factors, cytokines, and chemokines present in FlowerFlo, compared to OrthoFlo, as measured by an independent contract research organization (Raybiotech, Inc., Norcross, GA). 18 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

19 In further comparison of some of these competitive products, viability and morphology of human synoviocytes in response to each product was assessed in vitro. Healthy synoviocytes are adherent fibroblast-like cells that extend processes and form a monolayer on tissue culture plastic; however, dead or dying synoviocytes will retract their processes, becoming round in shape, and detach from the culture surfaces. Also, non-viable cells are not metabolically active; therefore, certain cellular assays are specific to detect viable, metabolically active cells and will not detect dead or dying cells. FIGURE 16: Viability and morphology of human synoviocytes in vitro Viability of human synoviocytes in vitro after 3 days when cultured in the presence of cryopreserved PalinGen Flow and FloGraft FREEDOM allografts, compared to OrthoFlo lyophilized amniotic fluid allograft. Results indicate the number of viable cells in human synoviocyte cultures when treated with equivalent volumes of the three products for 72 hours. Human Synoviocytes Viability of human synoviocytes was monitored in vitro over 3 days when cultured in the presence of cryopreserved PalinGen Flow and FloGraft FREEDOM allografts, compared to OrthoFlo lyophilized amniotic fluid allograft. Human synoviocytes remained healthy and viable when treated with OrthoFlo; however, human synoviocytes treated with PalinGen and FloGraft appeared unhealthy and demonstrated a reduction in cell viability, as shown in Figure 16, suggesting that the processing method for these products may alter the composition of the amniotic fluid and impart a cytotoxic effect on cells. One possibility is the cryopreservation agents that are added to both PalinGen Flow and FloGraft FREEDOM may be responsible for the cytotoxicity. LQ OrthoFlo Scientific & Clinical Monograph MiMedx 19

20 CLINICAL APPLICATIONS The application of amniotic fluid in a variety of clinical settings dates back more than seventy five years, with the use of amniotic fluid as a treatment for orthopedic conditions recorded as early as 1938, in the treatment of patients with joint disease for various orthopedic conditions. 5 Additional clinical research, including prospective randomized controlled trials, is ongoing to further confirm the unique properties of LyoPur Processed OrthoFlo and support its application within multiple clinical settings. OrthoFlo has been utilized clinically in multiple applications to protect and cushion, provide lubrication for enhanced mobility and modulate inflammation; some of these potential applications are illustrated below. Anterior Ankle Great Toe Metatarsophalangeal Joint (MTP) 20 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

21 Knee Posterior Elbow Glenohumeral Joint LQ OrthoFlo Scientific & Clinical Monograph MiMedx 21

22 SUMMARY The use of human amniotic fluid over the past 75 years has generated data in multiple areas of medicine. Relevant ELISA, cell migration and proliferation studies conducted by MiMedx and independent laboratories have made significant contributions to this knowledge base. It is clear that the patent pending LyoPur Process produces a minimally manipulated and carefully preserved amniotic fluid that contains essential growth factors. This sterilized LyoPur Processed fluid provides an easy to use allograft for multiple applications with a 5 year shelf life at ambient conditions. Many of the key components present in natural amniotic fluid are preserved during the gentle LyoPur Process, which accounts for the advantageous clinical properties observed when the allografts are used in the clinical applications described to protect and cushion, provide lubrication for enhanced mobility and modulate inflammation. Terminally sterilized for enhanced patient safety Stores at ambient conditions with a 5 year shelf life Eighty-three growth factors, cytokines, and regulatory molecules that promote healing and modulate inflammation have been identified in OrthoFlo Contains hyaluronic acid to protect, cushion, and provide lubrication for enhanced mobility The multitude of factors preserved in all MiMedx products, their inherent benefits, and the Company s rigorous safety standards provide the critical advantage and differentiation of the MiMedx products. 22 OrthoFlo Scientific & Clinical Monograph MiMedx LQ

23 About MiMedx: MiMedx is an integrated developer, processor and marketer of patent protected and proprietary regenerative biomaterial products and bioimplants processed from human amniotic membrane and other human birth tissues, such as amniotic fluid, umbilical cord and placental collagen, and human skin and bone. Innovations in Regenerative Biomaterials is the framework behind our mission to give physicians products and tissues to help the body heal itself. We process the human amniotic membrane utilizing our proprietary PURION Process, to produce a safe and effective implant. MiMedx proprietary processing methodology employs aseptic processing techniques in addition to terminal sterilization. MiMedx is the leading supplier of amniotic tissue, having supplied over 800,000 allografts to date for application in the Wound Care, Burn, Surgical, Orthopedic, Spine, Sports Medicine, Ophthalmic and Dental sectors of healthcare. REFERENCES: 1. Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid: not just fetal urine anymore. J Perinatol May;25(5): Hui AY, McCarty WJ, Masuda K, Firestein GS, Sah RL. A systems biology approach to synovial joint lubrication in health, injury, and disease. Wiley Interdiscip Rev Syst Biol Med Jan-Feb;4(1): Burns C, Hall ST, Smith R, Blackwell C. Cytokine levels in late pregnancy: are female infants better protected against inflammation? Front Immunol Jun 16;6: Nyman E, Huss F, Nyman T, Junker J, Kratz G. Hyaluronic acid, an important factor in the wound healing properties of amniotic fluid: in vitro studies of re-epithelialisation in human skin wounds. J Plast Surg HandSurg Apr;47(2): Shimberg M. The Use of Amniotic-Fluid Concentrate in Orthopaedic Conditions. J Bone Joint Surg Am Jan;(20)1: Sun Q, Li F, Li H, Chen RH, Gu YZ, Chen Y, Liang HS, You XR, Ding SS, Gao L, Wang YL, Qin MD, Zhang XG. Amniotic fluid stem cells provide considerable advantages in epidermal regeneration: B7H4 creates a moderate inflammation microenvironment to promote wound repair. Scientific Reports. 2015;5: LQ OrthoFlo Scientific & Clinical Monograph MiMedx 23

24 Innovations in Regenerative Medicine since 2006 Since 2006, as the premier leader in regenerative medicine, MiMedx has been dedicated to advancing healing through innovative biomaterial products and bioimplants West Oak Commons Court NE, Marietta, GA All cited products are registered trademarks of their respective owners. Patents and patents pending see: PURION and MiMedx are registered trademarks of MiMedx Group, Inc MiMedx Group, Inc. All rights reserved. LQ OrthoFlo is processed with LyoPur TM

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