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Research – Regenerative Therapy for pain


Amniotic membrane and amniotic cells: Potential therapeutic tools to combat tissue inflammation and fibrosis?

Placenta. 2011 Oct;32 Suppl 4:S320-5. doi: 10.1016/j.placenta.2011.04.010. Epub 2011 May 12.
Manuelpillai U1, Moodley Y, Borlongan CV, Parolini O.
1Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.


In addition to the placenta, umbilical cord and amniotic fluid, the amniotic membrane is emerging as an immensely valuable and easily accessible source of progenitor cells. This concise review will focus on the progenitor cell properties of human amniotic epithelial and mesenchymal stromal cells and evaluate the effects exerted by these cells and the amniotic membrane on tissue inflammation and fibrosis.
Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID: 21570115 [PubMed – indexed for MEDLINE]

Review preclinical studies on placenta-derived cells and amniotic membrane: An update

Placenta. 2011 Mar;32 Suppl 2:S186-95. doi: 10.1016/j.placenta.2010.12.016. Epub 2011 Jan 19.
Parolini O1, Caruso M.
1Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy.


Recent years have seen considerable advances in our knowledge of the biology and properties of progenitor cells isolated from placental tissues. This has encouraged researchers to address the potential effects of these cells in animal models of different diseases, resulting in increasing expectations regarding their possible utility for cell-based therapeutic applications. This rapidly evolving research field is also enriched by studies aimed at expanding the use of the whole amniotic membrane (AM), a well-known surgical material, for pathological conditions other than those tested so far and for which clinical applications already exist. In this review, we provide an update on studies that have been performed with placenta-derived cells and fragments of the entire AM to validate their potential clinical applications in a variety of diseases, in particular those associated with degenerative processes induced by inflammatory and fibrotic mechanisms. We also offer, as far as possible, insight into the interpretation and suggested mechanisms to explain the most important outcomes achieved to date.
Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID: 21251712 [PubMed – indexed for MEDLINE]

Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix

Clin Exp Allergy. 2005 Jul;35(7):941-8.
Solomon A1, Wajngarten M, Alviano F, Anteby I, Elchalal U, Pe’er J, Levi-Schaffer F.
1Department of Ophthalmology, Hadassah University Hospital, The Hebrew University–Hadassah Faculty of Medicine, Jerusalem, Israel.


BACKGROUND: The amniotic membrane (AM), which is the innermost layer of the placenta, was shown to possess anti-inflammatory and anti-fibrotic properties in various in vitro and clinical studies.
PURPOSE: To evaluate the anti-fibrotic and anti-inflammatory effects of the AM matrix (AMM) on human conjunctival and lung fibroblasts in an in vitro system that tests fibrotic and inflammatory responses at the effector stages of allergic inflammation.
METHODS: Human conjunctival or lung fibroblasts were seeded on plastic or on the stromal aspect of the AM, which was mounted on plastic inserts. Sonicates of human peripheral blood eosinophils activated with lipopolysaccharide (LPS), or human mast cell (HMC-1) leukaemia cell sonicates, were added to sub-confluent fibroblast monolayers. Proliferation of the sub-confluent fibroblasts was assessed using the [3H]-thymidine incorporation assay. The production of transforming growth factor (TGF)-beta1, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-8 in conjunctival or lung fibroblasts was measured in conditioned media from these cultures by ELISA.
RESULTS: After 4 days in culture, the [3H]-thymidine incorporation assay indicated a reduced proliferation of activated conjunctival and lung fibroblasts when cultured directly on the AMM. The production of both TGF-beta1 and IL-8 was significantly suppressed in activated conjunctival fibroblasts cultured on the AMM compared with those cultured on plastic, while the production of both TGF-beta1 and GM-CSF was decreased in human lung fibroblast cultured on the AMM.
CONCLUSIONS: The AMM is capable of suppressing fibrotic responses in an in vitro system of effector stages of ocular allergic inflammation. These data may provide a basis for exploring matrix components in the AM for the treatment of allergic eye disease.
PMID: 16008682 [PubMed – indexed for MEDLINE]


Implantation of amniotic membrane to reduce postlaminectomy epidural adhesions.

Eur Spine J. 2009 Aug;18(8):1202-12. doi: 10.1007/s00586-009-1013-x. Epub 2009 Apr 30.
Tao H1, Fan H.
1Department of Orthopaedics and Traumatology, Xi-jing Hospital, The Fourth Military Medical University, 710032, Xi’an, China.


Postlaminectomy epidural adhesion is implicated as a main cause of “failed back surgery syndrome” and associated with increased risk of complications during revision surgery. Various materials acting as mechanical barriers to reduce fibroblasts infiltration into epidural space have met with limited success. In present research, amniotic membrane (AM) was studied to investigate its effects on reducing epidural scar adhesion after laminectomy in a canine model. Laminectomy sites were created at L-1, L-3, L-5, and L-7 levels in 24 adult mongrel dogs. Freeze dried AM (FAM), cross-linked AM (CAM), and autologous free fat (AFF) were implanted, respectively, at a randomly assigned site in each dog with the remaining untreated site serving as internal control. The animals were sacrificed at 1, 6, and 12 weeks postoperatively. Then, gross pathologic observation including scar amount and adhesion tenacity, qualitative histology evaluation, and quantitative histology analysis were compared. Gross observation demonstrated that scar amount and adhesion tenacity of CAM group were significantly lower in comparison with those of FAM and non-treatment groups. A white, slightly vascularized CAM layer covered the dura mater without tenacious scar adhesion. The histology analysis also indicated reduced fibroblasts infiltration and consequent epidural fibrosis, which were similar to the results of AFF group. In conclusion, the CAM is effective in reducing epidural fibrosis and scar adhesion after laminectomy in canine model. It is a promising biomaterial for future clinical applications.
PMID: 19404691 [PubMed – indexed for MEDLINE] PMCID: PMC2899499

Effect of amniotic membrane to reduce postlaminectomy epidural adhesion on a rat model.

J Korean Neurosurg Soc. 2011 Jun;49(6):323-8. doi: 10.3340/jkns.2011.49.6.323. Epub 2011 Jun 30.
Choi HJ1, Kim KB, Kwon YM.
1Department of Neurosurgery, College of Medicine, Dong-A University, Busan, Korea.


OBJECTIVE: Epidural fibrosis and adhesion are the main reasons for post-laminectomy sustained pain and functional disability. In this study, the authors investigate the effect of irradiated freeze-dried human amniotic membrane on reducing epidural adhesion after laminectomy on a rat model.
METHODS: A total of 20 rats were divided into two groups. The group A did not receive human amniotic membrane implantation after laminectomy and group B underwent human amniotic membrane implantation after laminectomy. Gross and microscopic findings were evaluated and compared at postoperative 1, 3 and 8 weeks.
RESULTS: The amount of scar tissue and tenacity were reduced grossly in group of rats with human amniotic membrane implantation (group B). On a microscopic evaluation, there were less inflammatory cell infiltration and fibroblast proliferation in group B.
CONCLUSION: This experimental study shows that implantation of irradiated freeze-dried human amniotic membrane reduce epidural fibrosis and adhesion after spinal laminectomy in a rat model.
PMID: 21887388 [PubMed] PMCID: PMC3158473


Cell Tissue Bank. 2010 May;11(2):183-95. doi: 10.1007/s10561-009-9144-1. Epub 2010 Apr 13.

Potential use of the human amniotic membrane as a scaffold in human articular cartilage repair.

Díaz-Prado S1, Rendal-Vázquez ME, Muiños-López E,
Hermida-Gómez T, Rodríguez-Cabarcos M, Fuentes-Boquete I, de Toro FJ, Blanco FJ.
Author information


The human amniotic membrane (HAM) is an abundant and readily obtained tissue that may be an important source of scaffold for transplanted chondrocytes in cartilage regeneration in vivo. To evaluate the potential use of cryopreserved HAMs as a support system for human chondrocytes in human articular cartilage repair. Chondrocytes were isolated from human articular cartilage, cultured and grown on the chorionic basement membrane side of HAMs. HAMs with chondrocytes were then used in 44 in vitro human osteoarthritis cartilage repair trials. Repair was evaluated at 4, 8 and 16 weeks by histological analysis. Chondrocytes cultured on the HAM revealed that cells grew on the chorionic basement membrane layer, but not on the epithelial side. Chondrocytes grown on the chorionic side of the HAM express type II collagen but not type I, indicating that after being in culture for 3-4 weeks they had not de-differentiated into fibroblasts. In vitro repair experiments showed formation on OA cartilage of new tissue expressing type II collagen. Integration of the new tissue with OA cartilage was excellent. The results indicate that cryopreserved HAMs can be used to support chondrocyte proliferation for transplantation therapy to repair OA cartilage.
PMID: 20386989 [PubMed – indexed for MEDLINE]
Arthritis Rheumatol. 2014 Feb;66(2):327-39. doi: 10.1002/art.38206.

Therapeutic effect of human amniotic membrane-derived cells on experimental arthritis and other inflammatory disorders.

Parolini O1, Souza-Moreira L, O’Valle F, Magatti M, Hernandez-Cortes P, Gonzalez-Rey E, Delgado M.
Author information


Rheumatoid arthritis (RA) is an autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Cells isolated from human amniotic membrane (HAMCs) were recently found to display immunosuppressive properties. The aim of this study was to characterize the effect of HAMCs on antigen-specific T cell responses in RA patients and to evaluate their therapeutic potential in a preclinical experimental model of RA.
We investigated the effects of HAMCs on collagen-reactive T cell proliferation and cytokine production, on the production of mediators of inflammation by synoviocytes, and on the generation of Treg cells in peripheral blood mononuclear cells and synovial membrane cells isolated from RA patients. Mice with collagen-induced arthritis (CIA) were treated with HAMCs after disease onset, and clinical scores and joint levels of mediators of inflammation were evaluated. We determined Th1/Th17-mediated autoreactive responses in the mice by measuring the proliferation and the cytokine profile of lymph node cells restimulated with collagen.
Treatment with HAMCs suppressed synovial inflammatory responses and antigen-specific Th1/Th17 activation in cells isolated from RA patients. Moreover, HAMCs stimulated the generation of human CD4+CD25+FoxP3+ Treg cells with a capacity to suppress collagen-specific T cell responses. Systemic infusion of HAMCs significantly reduced the incidence and severity of CIA by down-regulating the 2 deleterious components of disease: Th1-driven autoimmunity and inflammation. In mice with CIA, HAMC treatment decreased the production of various inflammatory cytokines and chemokines in the joints, impaired antigen-specific Th1/Th17 cell expansion in the lymph nodes, and generated peripheral antigen-specific Treg cells. HAMCs also protected the mice from experimental sepsis, inflammatory bowel disease, and autoimmune encephalomyelitis.
HAMCs have emerged as attractive candidates for a cell-based therapy for RA.
PMID: 24504805 [PubMed – indexed for MEDLINE]