Article Figures & Data
Figures
- Figure
Preferred reporting items for systematic reviews and meta-analyses flowchart outlining the literature review and selection process.
Tables
- Table 1
Summary of literature review for amniotic membrane–derived biologic agents on postoperative outcomes following spinal surgery.
Study Design Tissue Type Objective Methods Results Animal Studies Bolat et al33 (2013) Retrospective animal (rat) study HAF Evaluate effects of mitomycin-C, sodium hyaluronate, and amniotic fluid on prevention of spinal epidural fibrosis A total of 4 groups (10 each): control, mitomycin-C, sodium hyaluronate, and amniotic fluid. L5 total laminectomy performed and assessed for epidural fibrosis 4-wk postoperative Significant difference in amount of scar tissue (none) in experimental groups compared with control group Choi et al34 (2011) Experimental animal (rat) study FAM Evaluate effects of amniotic membrane on epidural adhesions after laminectomy A total of 20 rats, 2 groups. Laminectomy with or without amniotic membrane. Assessment at 1-, 3-, and 8-wk postoperative Significant decrease in amount and tenacity of scar tissue in amniotic membrane group Cunningham et al35 (2019) Experimental animal (sheep) study Dual-layer, chorion-free amnion patch from HAM Evaluate effect of dual-layer, chorion-free amnion path following lumbar laminectomy A total of 12 sheep, 2 groups: control and amnion. Laminectomy performed with or without amnion, and half were evaluated at 4 wk, half at 10 wk Significant decrease in amount of fibroblast infiltration and tissue tenacity with the use of amnion Goldschlager et al36 (2011) Experimental animal (sheep) study AECs Comparison of allogeneic mesenchymal precursor cells to AECs in promoting osteogenesis A total of 29 sheep divided into 5 groups: (1) C3-C4 ACDF with autograft IC and IBC, (2) HA/TCP Mastergraft granules alone, (3) HA/TCP with 5 million MPCs, (4) HA/TCP with 5 million AECs, and (5) nonoperative MPCs lead to significantly more fusion than any other group, and all AECs failed to have any fusion at all Kara et al38 (2015) Experimental animal (rat) study HAF and HAM Evaluate effectiveness of amniotic fluid and membrane on prevention of postlaminectomy spinal epidural fibrosis A total of 27 rats underwent 2 nonconsecutive lumbar laminectomies were divided into either: (1) laminectomy alone, (2) laminectomy + AM, (3) laminectomy + AF. Sacrificed at 6 wk No significant differences between groups in regard to epidural scar formation and mean fibroblast count Luo et al39 (2019) Experimental animal (rabbit) study Amniotic suspension allograft containing particulated HAM and HAF Evaluate whether amniotic suspension allograft increases intervertebral disc height and morphology after disc degeneration A total of 12 rabbits underwent disc puncture and then 4 wk later were injected with either amniotic suspension allograft, sham control, or were left untreated. Assessed over 12 wk At 12 wk, experimental group had significantly greater disc height, magnetic resonance imaging T2 relaxation times, and improved morphology compared with control and untreated groups Oner et al40 (2015) Experimental animal (rat) study HAF Assessment of 2 different bone grafts and amniotic fluid on vertebral fusion in rat model A total of 48 rats were randomized into 1 of 4 groups: allograft group, allograft plus AF, DBM group, or DBM plus AF. Fusion of spine was assessed at 8 wk Amniotic fluid significantly enhanced posterior spinal fusion when combined with allograft Tao and Fan42 (2009) Experimental animal (dog) study FAM, CAM, and AFF Evaluate whether AM can reduce epidural scar adhesion after laminectomy in canine model A total of 24 dogs underwent laminectomy at L1, L3, L5, and L7 with FAM, CAM, AFF, and no treatment assigned randomly to each of the 4 sites. Animals were sacrificed at 1, 6, and 12 wk postoperative CAM group had significantly lower amounts of epidural fibrosis compared with controls Human Studies Anderson et al32 (2017) Prospective, RCT Cryopreserved amniotic membrane (cAM) Compare pain, functional outcomes and recurrent herniation follow lumbar microdiscectomy w/ or w/o amniotic tissue graft A total of 80 patients randomized to either amniotic tissue or no tissue following elective lumbar microdiscectomy AM group had greater functional outcomes and no recurrent herniations at 2 years Kamson and Smith37 (2020) Prospective, RCT Cryopreserved amniotic-derived products Comparison of PROM after use of orthobiologic supplementation during endoscopic-assisted lumbar decompression surgery A total of 269 patients randomized to receive either amniotic membrane, bone marrow aspiration, both, or none during lumbar decompression Patients receiving either bone marrow aspirate or amniotic membrane had significantly decreased pain at all timepoints compared with control Subach and Copay41 (2015) Retrospective case series Dehydrated human amnion/chorion membrane Evaluation of AM on epidural scar formation after transforaminal lumbar interbody fusion A total of 5 patients who had transforaminal lumbar interbody fusion with AM who subsequently underwent epidural re-exploration Four of 5 cases had easily detachable tissue during epidural re-exploration Walker et al43 (2018) Retrospective case series HAM Evaluate HAM in the prevention of spinal retethering after detethering A total of 14 patients received HAM after detethering. Followed for minimum of 6 mo Only 1 patient required subsequent detethering Abbreviations: ACDF, anterior cervical discectomy and fusion; AECs, amnion-derived epithelial cells; AF, amniotic fluid; AFF, autologous-free fat; AM, amniotic membrane; CAM, cross-linked amniotic membrane; DBM, demineralized bone matrix; FAM, freeze-dried human amniotic membrane; HAF, human amniotic fluid; HA/TCP, hydroxyapatite-tricalcium phosphate; IBC, interbody cage; IC, iliac crest autograft; MPCs, mesenchymal precursor cells; RCT, randomized controlled trial.
Note: Boldface indicates the primary variables being measured or outcomes of interest in each selected study.
Term Distinctions Amniotic membrane epithelial cells These are cells that can be derived from the inner lining of the placenta after birth. As such, there are fewer ethical concerns. Mesenchymal stem cells These are cells that can be derived from a variety of sources, adult, and embryo, including bone marrow, liver, kidney, muscle, adipose, connective tissue, placenta, and the umbilical cord. Chorion cells These calls can be derived from the placenta, specifically the yolk sac, which is the outermost fetal membrane surrounding the embryo. Umbilical cord tissue The umbilical cord contains large amounts of mesenchymal stem cells. These cells are distinct from the stem cells found in umbilical cord blood. Umbilical cord blood The stem cells are contained in the umbilical cord blood. However, it can be difficult to obtain a unit large enough to be used in an adult. - Table 3
Summary and unique distinctions of more specific amnion terminology used throughout the selected articles. Additional summary of spine surgery uses among the selected articles.
Term Distinctions Potential Uses in Spine Surgery HAF Amniotic fluid surrounds the embryo contained in the amniotic sac and is highly proliferative. This fluid can be obtained through amniocentesis with little risk to the fetus and the mother. Bolat et al33 used to examine the effects of HAF on spinal epidural fibrosis. Kara et al38 used to examine prevention of postlaminectomy spinal epidural fibrosis. Luo et al39 used to examine impact on intervertebral disc height and morphology after disc degeneration. Oner et al40 used to determine effect on vertebral fusion. Walker et al43 used to determine prevention of spinal retethering after detethering. HAM The amniotic membrane is the inner lining of the placenta. This membrane can be harvested after cesarean section. Kara et al38 used to examine prevention of postlaminectomy spinal epidural fibrosis. Luo et al39 used to examine impact on intervertebral disc height and morphology after disc degeneration Freeze-dried HAM Freeze drying is more abrasive than drying alone, as the process requires drying and freezing, both of which impose stress on biomaterials. Choi et al34 used this to evaluate the effects on epidural adhesions after laminectomy. Tao and Fan42 used to reduce epidural scar adhesion after laminectomy. Cryopreserved HAM Cryopreservation includes storing the specimen in liquid nitrogen. Kamson and Smith37 used this to study PROM after endoscopic-assisted lumbar decompression. Anderson et al32 studied the use of this to compare functional outcomes and recurrent herniation after lumbar microdiscectomy. Dehydrated HAM Amniotic membranes undergo a process that desiccates and removes all water from the tissue. Dried samples can be stored at room temperature and typically have a much longer shelf life. Subach and Copay41 used this to evaluate epidural scar formation after transforaminal lumbar interbody fusion. Cross-linked amniotic membrane Amniotic membrane can be cross-linked through exposure to chemicals and radiation to increase stability of the biomolecules within the membrane. Tao and Fan42 used to reduce epidural scar adhesion after laminectomy. Amnion-derived epithelial cells These are cells that can be derived from the inner lining of the placenta after birth. As such, there are fewer ethical concerns. Goldschlager et al36 used to observe effect on promoting osteogenesis. Dual-layered, chorion-free, amnion patch This is derived from HAM and consists of 2 layers of amniotic membrane stacked on top of each other. Cunningham et al35 used to follow effect following lumbar laminectomy. Abbreviations: HAF, human amniotic fluid; HAM, human amniotic membrane; PROM, patient-reported outcome measures.
- Table 4
Summary of 10 commonly utilized amnion-derived biologic agents used in orthopedics.
Product (Company) Composition Growth Factors Processing Storage Shelf Life Available Configurations Proposed Effects and Uses Affinity (Organogenesis); Canton, MA, USA Fresh amniotic membrane NL NL Refrigerator NL Liquid Tendon repair
Cartilage and osteochondral defect repair
Wound healing
Protective barrier formation
Allogen (ViVex); Atlanta, GA, USA Frozen allograft derived from amniotic fluid TIMP-2, HGF, IL-6, TIMP-1, IL-1ra, GRO-a, TGF-B1, TGF-B2, TIMP-4 NL Ambient conditions, refrigerator, or frozen 2 y at −40°C for frozen configuration and 2 y at 2–30°C in liquid configuration AlloGen: frozen
AlloGen liquid
Joint cushioning and preservation
Wound healing
Skin regeneration
AlloWrap DS (Allosource); Centennial, CO, USA Amniotic membrane TGF-B1-B3, TGF-A, EGF, KGF, HGF, bFGF, IL-1, IL-2, IL-10, MMP-1–4 NL Ambient conditions 2 y Sheet/membrane
Decrease scar and adhesion formation
Anti-inflammatory
Amniofix (MiMedx Group Inc); Marietta, GA, USA Amniotic tissue membrane composite EGF, KGF, HA, IL-6 PURION processa Ambient conditions 5 y Sheet/membrane
Wrap
Particulate
Reduce postsurgical scar formation
Anti-inflammatory
Enhances soft tissue healing
Barrier for scar formation
Surgical, neurologic, soft tissue, and tendon applications
Clarix Surgical Matrix (Amniox Medical Inc); Miami, FL, USA Cryopreserved human amniotic membrane EGF, KGF, HA, IL-6 CRYOTEK processb Refrigerator or freezer 3 mo at 1–10°C; 1 y at −49 to 0°C; 2 y at −85 to −50°C Sheet/membrane
Particulate
Surgical covering/barrier
Modulates wound environment to reduce scar formation
FloGraft (Applied Biologics); Scottsdale, AZ, USA Amnion and amniotic fluid NL NL Refrigerator or freezer NL Liquid Soft tissue trauma
Tendinitis/tendinosis
Wound healing
Anti-inflammatory
Muscle, ligament, and tendon strains or partial tears
NuCel (Organogenesis); Canton, MA, USA Amnion and amniotic fluid NL NL NL NL Liquid Promotion of tissue growth and healing
Inhibits scar formation
Anti-inflammatory
PalinGen Flow/Sports Flow (Amnio Technology); Phoenix, AZ, USA Amnion and amniotic fluid components FGF, EGF, PDGF A and B, VEGF, TGFβ NL Freezer NL Liquid Anti-inflammatory
Improved wound healing
Decreased scar formation
ReNu (Organogenesis); Canton, MA, USA Cryopreserved amniotic suspension allograft NL NL Freezer NL Liquid Soft tissue healing
Knee osteoarthritis
Anti-inflammatory
ViaShield (Globus Medical); Audubon, PA, USA Chorion-free, dual-layer amnion patch NL NL NL NL Sheet/membrane NL Abbreviations: bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; GRO, growth regulated protein alpha; HA, hyaluronic acid; HGF, hepatocyte growth factor; HGF, hepatocyte growth factor; IL, interleukin; KGF, keratinocyte growth factor; MMP, matrix matalloproteinase; NL, not listed; PDGF A and B, platelet derived growth factor alpha and beta; TGF, transforming growth factor; TIMP-2, tissue inhibitor of metalloproteinases 2; VEGF, vascular endothelial growth factor.
↵a The PURION process of cleaning, dehydration, and sterilization safely and carefully separates placental tissues, cleans and reassembles layers, and subsequently dehydrates the tissue to preserve the key elements associated with healing. The amniotic membrane scaffolding is protected while blood components are removed, so an intact extracellular matrix is left behind. No chemical cross-linking or decellularization occurs during the process.
↵b The CRYOTEK process uses cryopreservation (deep freezing) to maintain the innate biological and structural integrity of the natural tissue while maintaining its natural hydrated state.
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