Use of Placental Tissue for Orthopedic Injuries: Potentials and Pitfalls. Daniel Kuebler, PhD Franciscan University of Steubenville

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1 Use of Placental Tissue for Orthopedic Injuries: Potentials and Pitfalls Daniel Kuebler, PhD Franciscan University of Steubenville

2 Benjamin D. Smith & Daniel A. Grande. The current state of scaffolds for musculoskeletal regenerative applications Nature Reviews Rheumatology 11, (2015) Placental and Extra-embryonic Membrane Tissue: The Tissue Engineering Triad Create a microenvironment that is hospitable to healing Scaffolding Cells Bioactive molecules

3 Placental Tissues: Options Chorionic Plate Chorionic Villi Amnion/Chorion Umbilical Cord Decidua

4 Stem Cells in Placental Tissue Stem Cells Amniotic epithelial cells (haec) Amnion Reduced immunogenicity Mesenchymal stem cells Amnion, Chorion, Decidua, Umbilical cord Maternal and fetal origin Reduced immunogenicity Hematopoietic stem cells Chorion plate/villi and decidua Tabatabaei et al. AJMB 6, (2014).

5 MSCs in Placental Tissue Mesenchymal stem cells Amnion, Chorion, Decidua, Umbilical cord, Amniotic Fluid, Chord Blood In culture CD73+, CD90+, CD105+ CD45-, CD34- Relative abundance? Amnion/Chorion Chorion Plate Umbilical cord

6 Placental Membranes as Scaffolds: Amnion or Chorion Membranes Amnion Chorion Collagen based matrix ~25-35% collagen by dry weight Laminins Fibronectins Hyaluranic acid Niknejad et al. Eur Cells and Materials 15, (2008).

7 Placental Membranes: Bioactive molecules Growth Factors EGF, FGF, PDGF, TGF-beta Tissue remodeling enzymes TIMPs Immunomodulators IL-4, IL-10 IL-4 Expression TIMP-4 Expression Moreas-Pinto et al., Immunology Jan; 90(1): Fortunato et al., AM J OF REPRO IMMUNO VOL. 40, 1998.

8 Preparations of Fresh Membranes Separate amnion from chorion Wash membrane(s) Sterilize using antibiotics Screen for pathogens Ready for use Storage issues 4 o C: stability -80 o C: Freeze/thaw cycles Tabatabaei et al. AJMB 6 (2014).

9 Commercially Available Membranes Do They Maintain Structural Integrity? Preserved tissues Dehydration, lyophilization, chemical cross-linking, cryopreservation, sterile solution Products HRT Dehydrated membranes Amniox (HydraTek Process) Amnion/Chorion-based Room temp Cryopreserved and RT Amnion and Umbilical Cord MiMedx NuTech Some layered with additional particulates Dehydrated Amnion, Amnion/Chorion AlloFresh EpiFix, Koob et al., J Biomed Mater Res B Appl Biomater 102 (2014) Amnion ActiveBarrier 200 ActiveBarrier 45 Chorion-Based Amnion

10 Injectable Products: Fluid and Membrane Particles NuTech NuCel Bioactive amnion suspension Amnion and amniotic fluid MiMedx OrthoFlow (amniotic fluid) Amniox Neox and Clarix : amnion + umbilical cord product Particulate, no fluid HRT ActiveMatrix, CryoMatrix and RX Flow Placental tissue matrix with fluid Cryo and room temp

11 Do They Maintain Bio-active Molecules? Growth Factors EGF, FGF, PDGF Tissue remodeling enzymes TIMPs Immunomodulators IL-4, IL-10 EpiFix, Koob et al., Int J of Wound Heal. 10 (2013)

12 Do They Maintain Bioactivity? Immuno-modulatory ability Chemo-attractant

13 Do They Maintain Bioactivity? Adipose-derived Stem Cells (ASCs) Bind to placental tissue matrix of RXFlow and ActiveMatrix (HRT) Increase in proliferation in response to certain concentrations of EpiFix (MiMedix) Koob et al., Int J of Wound Heal. 10 (2013)

14 Do They Maintain Live Cells? Advertising claims vs. Reality Cryopreservation and dehydration likely destroy all viable cells Based on FDA regulations and guidance Regulated as a drug, device, and/or biological product (section 351)

15 Potential Orthopedic Uses Packing bone defects Covering damaged articular cartilage Wrapping damaged tendons (ActiveBarrier, tendon) (ActiveBarrier metatarsal head)

16 Potential Orthopedic Uses Packing bone defects Covering damaged articular cartilage Wrapping damaged tendons Injections (Willett et al. Arthritis Research & Therapy 16 (2014).

17 Orthopedic Studies With Placental Tissue Very few studies Injectable amnion/chorion mix for plantar fasciitis Zelen, et al., Foot and Ankle International 34:

18 Orthopedic Studies With Placental Tissue Very few studies Injectable amnion/chorion mix for tendonitis Lullove, Cureus. (2015) 7(6): e275. Werber, J of Sports Medicine. (2015)

19 Orthopedic Studies With Placental Tissue Very few studies Injectables of human amnion and amniotic fluid for spine fusions Nunley et al., Inter J of Spine Surgery. (2016) 10: 12.

20 Current Active, not recruiting Amniotic Membrane as an Adjunct Treatment for Hallux Rigidus Condition:Hallux Rigidus Interventions:Procedure: Dorsal Cheilectomy without Amniotic Membrane Tissue Implantation; Procedure: Dorsal Cheilectomy with Amniotic Membrane Tissue Implantation ] Active, not recruiting Evaluation of Amniotic Fluid Product in Knee Osteoarthritis Condition: Osteoarthritis of the Knee Interventions: Other: Amniotic Fluid 4.0ml dose; Other: Amniotic Fluid 2.0ml dose; Other: Placebo Control Recruiting Peroneal and Achilles Tendon Repair Indications With CLARIX CORD 1K Condition:Peroneal and Achilles Tendon Tears Intervention:Biological: CLARIX CORD 1K graft Recruiting ReNu vs. Corticosteroids for the Treatment of Plantar Fasciitis Condition:Fasciitis, Plantar Interventions:Device: ReNu Injection; Device: Corticosteroid Injection Recruiting NuTech Affinity for the Treatment of Chondral Defects Conditions:Chondral Lesions; Cartilage Intervention:Other: NuTech Affinity Membrane Recruiting Study of Nucel for One and Two Level Lumbar Interbody Fusion Conditions:Degenerative Disc Disease;Spondylolisthesis;Spondylosis Interventions:Procedure: One or two level lumbar interbody fusion surgery; Other: Nucel Recruiting An Investigation of ReNu Knee Injection in Patients With Osteoarthritis Condition:Osteoarthritis Interventions:Procedure: Knee injection; Device: ReNu amniotic allograft; Device: placebo saline; Device: Hyaluronic Acid

21 Summary Placenta tissues contain a variety of factors that can be of benefit in orthopedic applications Matrix: collagen Growth factors Anti-inflammatory cytokines TIMPs Mesencymal stem cells Key in evaluation products is to ensure maintenance of bioactivity, and structure Promising but preliminary results in a variety of orthopedic applications