The human body has a limited ability to efficiently repair or replace damaged tissue. For years, the standard therapy is to replace damaged tissue or organs with replacements donated by the patient or from a compatible donor. Organ and tissue transplantation has been hampered by a lack of suitable donors. More and more joints are being replaced with artificial ones, however, this practice is costly and has significant potential side effects. Also, joints do not last forever and often need to be replaced with a second procedure.
With tissue and organ replacement, there is always the potential for rejection, and lifelong drug therapy is often needed. The cost is enormous for these anti-rejection drugs.
Tissue engineering and regenerative medicine (TERM) has now developed as an innovative field of medicine to confront these issues. Great advances have been made in this field over the past few years. However, despite great advances, the search for adequate cell sources continues to be the problem and is the limiting factor preventing widespread use.
In the normal healing process, where a blood clot forms to halt the blood flow initially after trauma, the platelets simultaneously begin the three phases of healing of the damaged tissue. Platelets first, begin adhesion, then are activated releasing multiple bioactive proteins from their granules and finally aggregate to bridge the area and form a scaffold until the entire process is complete. Completely functional tissue is then formed at the end of this sequence of events.
Biomaterials from both natural and synthetic sources have been harvested or created to mimic the natural process of healing. Natural sources fall short of achieving the goal of total healing and synthetic derived materials do not have the complexity to interact with the cells involved in this environment.
Over the last 10 years, there has been an increased interest in the use of biologics for regenerative tissue applications in medicine. Biologics currently used worldwide in clinical practice include platelet rich plasma, bone marrow aspirate, adipose tissue aspirate, amniotic fluid, amniotic membrane, umbilical cord Wharton’s jelly and cord blood.
Tissue engineering and regenerative medicine has focused on human based sources of materials. There have been four main areas to harvest these materials, bone marrow, adipose tissue, blood and embryological derived tissues.
The utilization of autologous bone marrow or adipose tissue has safety concerns due to the procedure used to harvest them. These are invasive procedures and can get infected or have bleeding post procedure. The use of these tissues has also been less successful due to the donor age and other concurrent comorbidities. Platelet rich plasma is an autologous blood derived concentrate with increased levels of growth factors and cytokines that has been used in virtually all fields of medicine to restore and regenerate damaged tissues. However, PRP is not always 100% successful due to the senescence of the patient’s tissues.
Perinatal tissues possess numerous types of bioactive cells that make them attractive candidates for the use in tissue engineering and regenerative medicine. However, ethical and safety concerns have limited the research and subsequent use of these tissues. Placental derived cells are discarded after birth and considered medical waste. The fetal membranes and the umbilical cord have been found to be an abundant source of human derived biomaterials and cells that overcome most, if not all ,of the obstacles currently imposed by other technologies and therefore could be considered as an excellent source of material needed for tissue engineering and regenerative medical use.
The placenta is a temporary organ that forms during pregnancy to ensure fetus nourishment and development. Tissues obtained from the placenta have demonstrated anti-microbial, anti-inflammatory and immunomodulatory properties. The placenta is considered medical waste and can be used ethically in both clinical and laboratory settings. The placenta is considered safe, and as a waste product, is cost effective. The amniotic membrane and umbilical cord have been used in clinical practices for over a century.
The healing capabilities of these products are attributed to the presence of,
- Stem cells
- Growth factors
- Hyaluronic acid
- Extracellular vesicles including exosomes
Stem cells can be isolated from bone marrow and adipose tissues. Stem cells can differentiate in response to signals mediated by growth factors and cytokines. Growth factors and cytokines are able to target stem cells and guide cell division, differentiation and regeneration of different tissues and organs.
Hyaluronic acid is a major component of the extracellular matrix of the eyes, skin, joints and eyes. Hyaluronic acid has chondroprotection properties and is involved in glycosaminoglycan synthesis with anti-inflammatory, mechanical, subchondral and analgesic actions.
Exosomes are small vesicles developed from a sequential process of the remodeling of the cell membrane. Exosomes represent an important mode of cell-to-cell communication. The cells have significant regenerative potential.
Wharton’s jelly is a mucous connective tissue of the umbilical cord between the amniotic epithelium and the umbilical vessels. The function of Warton’s jelly is to provide cushion, protection, and structure to the umbilical vessels by preventing their torsion and bending. The umbilical vessels are the lifeline to the developing fetus providing oxygen and nutrition and expelling the carbon dioxide.
Wharton’s jelly contains stem cells, growth factors, cytokines hyaluronic acid and exosomes. These are all the components needed in regenerative medicine. The volume of stem cells contained in WJ significantly surpasses the amount found in bone marrow or adipose tissue. Wharton’s jelly also contains high amounts of extracellular matrix components including collagen and sulfated proteoglycans.
One study analyzed the growth factors contained in Wharton’s jelly. Numerous growth factors were detected in large quantities. Some notable growth factors present are,
IGF-1 improves osteogenic differentiation, induces chondrogenic differentiation and stimulates extracellular matrix production.
TGF-alpha, transforming growth factor which is a ligand for epidermal growth factor. This promotes proliferation and survival of osteoprogenitors and plays an anabolic role in bone metabolism.
Platelet derived growth factor (PDGF) which exhibits effects toward human osteoblasts.
Vascular endothelial growth factor which stimulates blood vessel formation.
Cytokines were also detected in high quantities. Some notable cytokines present:
Several immunomodulatory cytokines such as,
Cytokine ligand 5 also called RANTES which upon activation is involved in modulation of macrophage phenotype M1 (pro-inflammatory) to M2 (anti-inflammatory). RANTES plays a vital role in the survival of osteoblasts and bone remodeling.
Intercellular adhesion molecule-1 (ICAM-!) which in wound healing promotes leukocyte accumulation into the wound required for healing. ICAM-1 can also have an immunosuppressive effect of Tcells which may aid in graft vs. host diseases.
Tissue inhibitor of metalloproteinases (TIMP) which aid in the regulation of matrix metalloproteinases. MMP can degrade all components of connective tissue. TIMP levels are decreased in all areas of aged tissues. TIMP regulate several biologic processes such as cell growth, differentiation and apoptosis independent of the activity on metalloproteinases.
Regenerative cytokines including growth hormone which stimulates cell growth, reproduction and regeneration and plays an important role in cartilage regeneration.
Interleukin 6 (IL-6) plays a role in immune regulation and tissue regeneration.
Interleukin 1 receptor antagonist (IL-1RA) that completely binds to the same receptor as IL-1. This receptor stimulates pro-inflammatory properties. Blocking this receptor stops inflammatory mediated cellular changes. IL-1RA are now being used to slow the progression of knee osteoarthritis.
The umbilical cord contains high molecular weight hyaluronic acid. This is associated with high fluid retention in joint space for lubrication and cushioning. HA has strong anti-inflammatory properties. HA also has mechanical, subchondral and analgesic actions. HA has been shown to accelerate tendon to bone healing in the treatment of many orthopedic diseases such as patellar tendinopathy, Achilles’ tendinopathy and plantar fasciitis.
Extracellular vesicles were also detected in the Wharton’s jelly. These exhibit pro-regenerative effects for inducing healing in different tissue types. They positively affect cell proliferation and viability. Exosomes stimulate secretion of bioactive molecules required for the healing response.
The number of bio-active substances in Wharton’s jelly is higher when compared to other biologics such as bone marrow aspirate and adipose tissue. Wharton’s jelly contains growth factors, cytokines, hyaluronic acid and exosomes in clinically relevant quantities. These multiple factors help reduce inflammation, decrease pain and promote the healing of damaged tissue.
Dr. Robert McGrath
Studies and Articles
Acta Biomater 2020 Jul 1;110:1-14 PMID 32418650
Genes 2020 Dec 23;12(1):6 PMID 33374593
Front Bioeng Biotechnol 2020 Mar 10;8:117 PMID 32211387
J Orthop Surg Res 2020 Feb 13;15(1):49 PMID 32054483
- Regenerative Potential of Wharton’s Jelly Derived Mesenchymal Stem Cells: A New Horizon of Stem Cell Therapy
J Cell Physiol 2020 Dec;235(12):9230=9240 PMID 32557631
Curr Res Transi Med 2020 Jan;68(1):5-16 PMID 31543433