Heparan sulfate analogue
Encyclopedia
Heparan sulfate analogues are polymers engineered to mimic several properties of heparan sulfate
s. They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates or a polyester such as co polymers of lactic or malic acid to which sulfates, sulfonate or carboxylgroups are added in controlled amounts and location. They have a molecular weight that can range from a few thousands to several hundred thousand Dalton
.
Heparan sulfates can sequester growth factor
s (GFs) and cytokines in the extracellular matrix
(ECM) thereby protecting them from degradation. This ensures local presence of these signaling proteins to fulfill their function in the ECM which contributes to the preservation of anatomical form and function. Heparan sulfates bind to matrix proteins on specific sites called "heparan sulfate binding sites" on ECM macromolecules like collagen, fibronectin and laminin, to form a scaffold surrounding the cells and to protect ECM proteins and growth factors from proteolytic degradation by steric hindrance. However, at any site of inflammation
, so also in wound areas, heparan sulfates are degraded, mainly by heparanase
s giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins. However, heparan sulfate analogues are resistant to enzymatic degradation. This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM.
In many characteristics heparan sulfate analogues are similar to the natural heparan sulfate. The most important difference is their resistance to enzymatic degradation. The resistance of RGTA is caused by the coupling of the subunits internal bond of the molecules. The β2-4 carbon-carbon binding of the subunits of heparan sulfate is prone to enzymatic cleavage whereas the α1-6 carbon-carbon binding of the subunits of heparan sulfate analogues are resistant to cleavage by all known mammalian glycanases and heparanases. This way RGTA can recreate a scaffold with the ECM proteins and will reposition GFs back into the matrix where they can re-unfold their natural action in wound repair. This way heparan sulfate analogues may contribute to chronic wound healing as will be discussed later on.
. Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind at sites where natural heparan sulfate is absent. Also the function of the heparan sulfate analogues is the same as heparan sulfate: structuring the ECN scaffold and protecting a variety of protein ligands such as ECM proteins growth factors and cytokines. By positioning and holding them in place, in a reconstituted organization mimicking that of before the wound, the tissue can then use these different proteins properly and spatially displayed for inducing cell migration, proliferation
and differentiation
. This results in improved tissue repair and sometimes a real regeneration process.
and inflammation
, proliferation
and tissue remodeling. In disturbed wound healing, these stages cannot be completed often resulting in a reduced anatomical and functional outcome.
Multiple factors determine the average healing time of the different phases. These factors can be classified into local factors such as infection
and ischemia
, and systemic factors such as age, stress, Diabetes Mellitus
and smoking. In chronic wounds, factors as mentioned above, make it impossible for the tissue to regenerate properly. After injury, the extracellular matrix, and thereby also the heparan sulfate is broken down by different local enzyme
s, produced by macrophages such as, heparanases, serine proteases and metalloproteinases (MMPs). Heparan sulfate analogues replace the broken heparan sulfate at the wound site and bind to the free heparan sulfate binding sites of the extracellular matrix. Heparan sulfate is slightly negatively charged and so it can bind the positively charged units of the proteins and secure the ECM scaffold. That ensures a supply of the different protein ligands at the wound site.
is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function." Heparan sulfate analogues are one of the early examples of regenerative medicine that reached daily clinical use.
Multiple articles of animal wound models demonstrated vast effects on improving wound healing heparan sulfate analogues. These findings formed a rationale for its clinical application. The first clinical studies also show a significant improvement in wound healing.
Different cases have shown improvement and better wound healing over time and persistent ulcer healing after usage of heparan sulfate analogues. As an example this case of a a 60 year-old diabetic patient who suffered from obesity, heart-, kidney- and liver failure, alcohol abuses and nicotine abuses has shown a significant improvement. He had a diabetic ulcer that didn’t heal for 8 months but completely healed 6 weeks after treatment with a heparan sulfate analogue.
Even though several studies show that heparan sulfate analogues contribute to the wound healing, more research in the form of a Randomized controlled trial
is needed to obtain conclusive evidence.
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
s. They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates or a polyester such as co polymers of lactic or malic acid to which sulfates, sulfonate or carboxylgroups are added in controlled amounts and location. They have a molecular weight that can range from a few thousands to several hundred thousand Dalton
Dalton
Dalton may refer to:-In Canada:* Dalton, Algoma District, Ontario* Dalton Armoury, a Canadian Forces facility primarily used by the Queen's Own Rifles of Canada- In the United Kingdom :* Dalton, Cumbria, England* Dalton, Dumfries and Galloway, Scotland...
.
Heparan sulfates can sequester growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s (GFs) and cytokines in the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM) thereby protecting them from degradation. This ensures local presence of these signaling proteins to fulfill their function in the ECM which contributes to the preservation of anatomical form and function. Heparan sulfates bind to matrix proteins on specific sites called "heparan sulfate binding sites" on ECM macromolecules like collagen, fibronectin and laminin, to form a scaffold surrounding the cells and to protect ECM proteins and growth factors from proteolytic degradation by steric hindrance. However, at any site of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, so also in wound areas, heparan sulfates are degraded, mainly by heparanase
Heparanase
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.-Synthesis and structure:...
s giving free access to protease to degrade the ECM and a subsequent loss of GFs and cytokines that disrupts the normal tissue homeostasis. Heparan sulfate analogues obtain many of the characteristics of heparan sulfates including the ability to sequester GFs and bind and protect matrix proteins. However, heparan sulfate analogues are resistant to enzymatic degradation. This way they strengthen the healing potential of the wound bed by repositioning GFs and cytokines back into the ECM.
Heparan sulfate analogues
Several Heparan sulfate analogues (also known as ReGeneraTing Agents, RGTA) have been developed from a poly glucose backbone. One named OTR4120 is a 85KD biopolymer and used for topical or ophthalmological application and marketed under the name CACIPLIQ20 or CACICOL20, respectively. Heparan sulfate analogues will occupy the free heparan sulfate binding sites on ECM macromolecules like collagen, fibronectin and laminin that become available following heparan sulfate degradation.In many characteristics heparan sulfate analogues are similar to the natural heparan sulfate. The most important difference is their resistance to enzymatic degradation. The resistance of RGTA is caused by the coupling of the subunits internal bond of the molecules. The β2-4 carbon-carbon binding of the subunits of heparan sulfate is prone to enzymatic cleavage whereas the α1-6 carbon-carbon binding of the subunits of heparan sulfate analogues are resistant to cleavage by all known mammalian glycanases and heparanases. This way RGTA can recreate a scaffold with the ECM proteins and will reposition GFs back into the matrix where they can re-unfold their natural action in wound repair. This way heparan sulfate analogues may contribute to chronic wound healing as will be discussed later on.
Target and function
Heparan sulfate analogues are thought to display identical properties as heparan sulfate with exception of being stable in a proteolytic and glycolytic environment like a woundWound
A wound is a type of injury in which skin is torn, cut or punctured , or where blunt force trauma causes a contusion . In pathology, it specifically refers to a sharp injury which damages the dermis of the skin.-Open:...
. Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind at sites where natural heparan sulfate is absent. Also the function of the heparan sulfate analogues is the same as heparan sulfate: structuring the ECN scaffold and protecting a variety of protein ligands such as ECM proteins growth factors and cytokines. By positioning and holding them in place, in a reconstituted organization mimicking that of before the wound, the tissue can then use these different proteins properly and spatially displayed for inducing cell migration, proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
and differentiation
Differentiation
Differentiation may refer to:* Differentiation , the process of finding a derivative* Differentiated instruction in education* Cellular differentiation in biology* Planetary differentiation in planetary science...
. This results in improved tissue repair and sometimes a real regeneration process.
Wound repair
Normal wound repair consists of three different phases: hemostasisHemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...
and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
and tissue remodeling. In disturbed wound healing, these stages cannot be completed often resulting in a reduced anatomical and functional outcome.
Multiple factors determine the average healing time of the different phases. These factors can be classified into local factors such as infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
and ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, and systemic factors such as age, stress, Diabetes Mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and smoking. In chronic wounds, factors as mentioned above, make it impossible for the tissue to regenerate properly. After injury, the extracellular matrix, and thereby also the heparan sulfate is broken down by different local enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s, produced by macrophages such as, heparanases, serine proteases and metalloproteinases (MMPs). Heparan sulfate analogues replace the broken heparan sulfate at the wound site and bind to the free heparan sulfate binding sites of the extracellular matrix. Heparan sulfate is slightly negatively charged and so it can bind the positively charged units of the proteins and secure the ECM scaffold. That ensures a supply of the different protein ligands at the wound site.
Clinical use
Regenerative medicineRegenerative medicine
Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore orestablish normal function". This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair...
is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function." Heparan sulfate analogues are one of the early examples of regenerative medicine that reached daily clinical use.
Multiple articles of animal wound models demonstrated vast effects on improving wound healing heparan sulfate analogues. These findings formed a rationale for its clinical application. The first clinical studies also show a significant improvement in wound healing.
Different cases have shown improvement and better wound healing over time and persistent ulcer healing after usage of heparan sulfate analogues. As an example this case of a a 60 year-old diabetic patient who suffered from obesity, heart-, kidney- and liver failure, alcohol abuses and nicotine abuses has shown a significant improvement. He had a diabetic ulcer that didn’t heal for 8 months but completely healed 6 weeks after treatment with a heparan sulfate analogue.
Even though several studies show that heparan sulfate analogues contribute to the wound healing, more research in the form of a Randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
is needed to obtain conclusive evidence.