Amniotic membrane extract and eye drops: a review of literature and clinical application

Figures & data

Figure 1 Proposed mechanism of AMEED role in promoting wound healing.

Abbreviations: AMEED, amniotic membrane extract eye drops; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IL, interleukin; KGF, keratinocyte growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.

Table 1 Studies on AME and AMEED

Author/year	AM preparation	Application	Results
Chang et al (2002)^Citation30	AME	UVB irradiation of HaCaT cell	Downregulation of inducible nitric oxide synthase mRNA and decreased generation of nitric oxide; decreased destruction of normal cells and tissues
Bonci et al (2005)^Citation38	AMEED	Burns, ulcers	Negative corneal staining to fluorescein after 15–20 days in all patients’ eyes
He et al (2008)^Citation23	AME	Anti-inflammatory; low immunogenity	Downregulation of macrophage activation and promotion of macrophage apoptosis; pro-inflammatory cytokines reduced; anti-inflammatory cytokines upregulated; downregulation of surface markers and major histocompatibility complex class 2 antigen expression
Shahriari et al (2008)^Citation37	AMEED	Alkaline corneal epithelial wound in rabbits	Acceleration of wound healing with AM suspension compared with autologous serum or preservative-free artificial tears
Liang et al (2009)^Citation31	AMEED	Acute or chronic chemical burns	Inflammation reduced in all patients’ eyes
Sheha et al (2010)^Citation32	AMEED	Acute chemical burn	Pain significantly relieved and inflammation was markedly reduced in all cases of chemical burn
Guo et al (2011)^Citation28	AMEED	Artificial corneal wounds in rabbit eyes	AM homogenate as effective as AM transplant
Gourabi et al (2012)^Citation39	AMEED	Unilateral corneal stem cell damage	Promotion of corneal epithelial healing in unilateral LSCD
Dudok et al (2015)^Citation18	AME	Acute corneal injury	Acceleration of healing in human corneal epithelial cells
Gourabi et al (2015)^Citation40	AMEED	Corneal epithelial healing	Acceleration of corneal epithelial healing (Phase I and II clinical trial)

Abbreviations: AM, amniotic membrane; AME, amniotic membrane extract; AMEED, amniotic membrane extract eye drops; LSCD, limbal stem cell deficiency; UVB, ultraviolet B.

Table 2 Summary of the commercially available AM derivatives

Company/product name	Product type	Method of production	Manufacturer’s storage/dosage recommendation	US-FDA regulated (Y=Yes N=No)	Mechanism of action/applications (manufacturer’s notes)
Genesis: Amniotic Cytokine Extract (ACE)™; Ocular Science, Inc. Palm Beach, CA, USA	AME	Proprietary cryopreservation to extract cytokines from AM; titrated to 10,000 pg/mL	Arrives on dry ice; store in freezer; 30-day treatment; twice daily drops	N; under Section 361 of Public Health Service Act; no clearance, or pre-market approval needed	Use in treatment of dry eye disease; active cytokines, growth factors and anti-inflammatory molecules; prostaglandin E2 promotes wound healing
Keera Lyophilized AME; Veneto Tissue Bank; Treviso, Italy	AME	Amnion-derived eye drops; reconstituted with saline	Non-preserved; refrigerate and use within 72 hours	N; Internationally available	Use in place of, or following AMT; use in PED secondary to herpes simplex or zoster, trigeminal nerve defect or diabetes (multicenter European clinical trials)
Barcelona Tissue Bank (Banc de Sang i Teixits); Catalonia, Spain	AME	Freeze-dried product from AM; vial is reconstituted in 4 mL of sterilized water	Treatment is 30 days (6 vials of extract)	N; internationally available	Use in dry eye, epithelial defects of the cornea, dry eye secondary to autoimmune syndrome, corneal ulcers, adjuvant in cornea transplant, pterygium and symblepharon excision
Amnion-derived Cellular Cytokine Solution (ACCS); Noveome Biotherapeutics (formerly Stemnion), Pittsburgh, PA, USA	AME	Proteins secreted by amnion-derived multipotent progenitor cells grown to confluency	Four times a day dosage	Clinical trial ongoing	Used for wound healing, dry eye
Regener-Eyes™; Regenerative Processing Plant), Palm Beach, FL, USA	AF	Amniocleanse patent pending process (placental-derived biomaterials); sterile and acellular amniotic fluid drops	Cooler packed box; 30-day supply droppers; apply 1–4 times per day	N; under Section 361 of Public Health Service Act; no clearance, or pre-market approval needed	Increases cytokines, growth factors, hyaluronic acid; no human studies; multiple animal studies
PDA-AF™; Cryoactiv Regenerative Processing Plant; Palm Harbor, FL, USA	AF	Fluid harvested close to 40 weeks gestation; hyaluronic acid mainly; patent pending sterilization process	AF eye drops	N; under Section 361 of Public Health Service Act; no clearance, or pre-market approval needed	Use for dry eye
Optiserum™; Next Biosciences; Johannesburg, South Africa	UC only	Umbilical cord blood serum; non-preserved; frozen to −80°C	5 mL eye dropper bottles; use within 7 days	N; internationally available	Use in severe dry eye syndromes, chemical burns, corneal ulcers and erosions, neurotrophic keratitis, post LASEK surgery, and post corneal transplant

Abbreviations: AF, amniotic fluid; AM, amniotic membrane; AME, amniotic membrane extract; AMT, amniotic membrane transplant; FDA, Food and Drug Administration; N, no; PED, persistent epithelial defect; UC, umbilical cord; Y, yes.

ChangDSSeoSJHongCKThe effect of amniotic membrane extract on the expression of iNOS mRNA and generation of NO in HaCaT cell by ultraviolet B irradiationPhotodermatol Photoimmunol Photomed200218628028612535023

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BonciPBonciPLiaASuspension made with amniotic membrane: clinical trialEur J Ophthalmol2005154441445

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HeHLiWChenSYSuppression of activation and induction of apoptosis in RAW264.7 cells by amniotic membrane extractInvest Ophthalmol Vis Sci200849104468447518614802

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ShahriariHATokhmehchiFRezaMHashemiNFComparison of the effect of amniotic membrane suspension and autologous serum on alkaline corneal epithelial wound healing in the rabbit modelCornea200827101148115019034130

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LiangLLiWLingSAmniotic membrane extraction solution for ocular chemical burnsClin Exp Ophthalmol200937985586320092594

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ShehaHLiangLHashemHRamzyMZakiAAmniotic membrane extract for acute ocular chemical burnsTech Ophthalmol201084146150

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GuoQHaoJYangQGuanLOuyangSWangJA comparison of the effectiveness between amniotic membrane homogenate and transplanted amniotic membrane in healing corneal damage in a rabbit modelActa Ophthalmol2011894e315e31921310014

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Royan InstituteThe Improvement of Limbal Stem Cell Deficiency (LSCD) in Unilateral Stem Cell Damage by Amniotic Membrane Extract Eye Drop (AMEED) Available from: https://www.clinicaltrials.gov/ct2/show/NCT02649621?cond=amniotic+membrane+extract&rank=2. NLM Midentifier: NCT02649621Accessed May 1, 2018

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DudokDVNagdeeICheungKEffects of amniotic membrane extract on primary human corneal epithelial and limbal cellsClin Exp Ophthalmol201543544344825495256

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Royan InstituteUtilization of Amniotic Membrane Extract Eye Drop (AMEED) on Human Corneal Healing Available from: https://www.clinicaltrials.gov/ct2/show/NCT02746848?cond=amniotic+membrane+extract&rank=1. NLM identifier: NCT02746848Accessed May 1, 2018

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