Hydrogels in wound healing BITS G Submitted by

Hydrogels in wound healing
BITS G
Submitted by, Shafik s. shaikh (2017H1460153H) Under the supervision of
Dr. swati biswas Assistant Professor Department of Pharmacy

21101054191000
BIRLA INSTITUTE OF TECHNOLOGY & SCIENCE, HYDERABAD CAMPUS
March 2018

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Table of content
Contents
TOC o “1-3” h z u 1Abstract PAGEREF _Toc512549830 h 12Introduction PAGEREF _Toc512549831 h 13Wounds PAGEREF _Toc512549832 h 24Types of wounds PAGEREF _Toc512549833 h 24.1Acute wounds PAGEREF _Toc512549834 h 24.2Chronic wounds PAGEREF _Toc512549835 h 25Physiology of wound healing PAGEREF _Toc512549836 h 25.1Hemostasis PAGEREF _Toc512549837 h 25.1.1Intrinsic pathway PAGEREF _Toc512549838 h 25.1.2Extrinsic pathway PAGEREF _Toc512549839 h 25.1.3Platelet activation PAGEREF _Toc512549840 h 35.2Inflammation PAGEREF _Toc512549841 h 35.3Proliferation PAGEREF _Toc512549842 h 35.3.1Angiogenesis PAGEREF _Toc512549843 h 35.3.2Fibroblast migration PAGEREF _Toc512549844 h 35.3.3Epithelialization PAGEREF _Toc512549845 h 35.3.4Wound retraction PAGEREF _Toc512549846 h 45.4Remodeling PAGEREF _Toc512549847 h 45.5Timeline of wound healing PAGEREF _Toc512549848 h 46Existing treatments for wound healing PAGEREF _Toc512549849 h 47Hydrogels PAGEREF _Toc512549850 h 48Hydrogels in wound healing PAGEREF _Toc512549851 h 58.1Amorphous hydrogel PAGEREF _Toc512549852 h 58.2Impregnated hydrogel PAGEREF _Toc512549853 h 58.3Sheet hydrogel PAGEREF _Toc512549854 h 59Classification of hydrogels PAGEREF _Toc512549855 h 59.1Based on Crosslinking in hydrogels PAGEREF _Toc512549856 h 59.1.1Crosslinking by chemical reaction of complementary groups PAGEREF _Toc512549857 h 59.1.2Crosslinking by ionic interactions: PAGEREF _Toc512549858 h 69.1.3Crosslinking by crystallization: PAGEREF _Toc512549859 h 69.2Based on types of monomers: PAGEREF _Toc512549860 h 69.2.1Homo-polymeric hydrogel PAGEREF _Toc512549861 h 69.2.2Co-polymeric hydrogel PAGEREF _Toc512549862 h 69.2.3Semi-inter penetrating network (semi-IPN) PAGEREF _Toc512549863 h 69.2.4Inter penetrating network (IPN) PAGEREF _Toc512549864 h 79.3Stimuli-sensitive swelling-controlled release systems PAGEREF _Toc512549865 h 79.3.1environmental stimulus PAGEREF _Toc512549866 h 79.3.2Biochemical stimulus PAGEREF _Toc512549867 h 89.4Based on source PAGEREF _Toc512549868 h 810Methods of preparation of hydrogels PAGEREF _Toc512549869 h 910.1Bulk polymerization. PAGEREF _Toc512549870 h 910.2Grafting to a support. PAGEREF _Toc512549871 h 910.3Polymerization by irradiation PAGEREF _Toc512549872 h 911Marketed formulations of hydrogel for wound healing PAGEREF _Toc512549873 h 912Polymers used in hydrogel for wound dressing PAGEREF _Toc512549874 h 1013Paper published on hydrogel PAGEREF _Toc512549875 h 1113.1Title PAGEREF _Toc512549876 h 1113.2Introduction PAGEREF _Toc512549877 h 1113.3Conclusion PAGEREF _Toc512549878 h 1214References: PAGEREF _Toc512549879 h 12
Hydrogels in wound healing.

AbstractThe hydrogels are found to be more effective, less expensive method over existing methods as its ability to keep the wound moist and capability of holding a drug makes it one of the promising method for the management of wounds. This study includes in depth knowledge about the wounds including types of wounds, mechanism of wound healing, existing methods which are widely used in the management of wound healing along with in detail about hydrogels which includes the types of hydrogels, types of polymers used in hydrogels, detail on types of crosslinking present in hydrogels, method of preparation of hydrogels, application of hydrogels in wound healing and detail on existing hydrogel formulations and formulations on which the clinical trials are going on.
Introduction
Hydrogel dressings consist of 90 percent water in a gel base and serves to help monitor fluid exchange from within the wound surface, in new studies scientists has suggested that the wound healing is much faster in the case of moist wound as compare to the dry wound because in dry wound the platelet plug formed during the hemostasis prevent the migration of the epithelial cells over the wound and which can be prevented in the moist condition wherein by keeping the wound moist the hydrogel dressing assists the rapid wound healing with less scar as compare to the dry wound healing and it also protect the wound from infection and can act as a carrier for the drugs used in wound healing such as antibacterial, growth factors etc. As hydrogel dressing is the cheaper and more effective compare to the existing treatments for the wound it attracted the scientists for the research in this field.

WoundsWound is the Disruption of the integrity of skin, mucosal surfaces or organ tissue. Or it’s an injury to living tissue caused by a cut or other impact, typically one in which the skin is cut or broken. Which can be caused by the presence of disease such as gangrene or may be due to intentional or accidental impact. Wounds are generally healed by the natural healing mechanism which involves the different phases such as hemostasis, inflammation, proliferation and remodeling.

Types of woundsWound has been mainly categorized in to the two types that is acute wound and chronic wound, the acute wounds generally passed through the healing phase relatively quickly compare to the chronic wounds as acute wounds takes less than 12 weeks to heal where as chronic wound takes more than 12 weeks to heal following are the examples of the types of wounds.

Acute wounds
E.g. surgical incisions, bites, burns.

Chronic wounds
E.g. pressure sores, diabetic ulcers, venous stasis ulcers and wounds due to ischemia.
Physiology of wound healingPhysiology of wound healing can be classified into four overlapping phases on the basis of the function of each phase and cellular mechanism involved in that particular phase.

Hemostasis41332151564005Figure a. Formation of blood clot
00Figure a. Formation of blood clot
392874518351500This phase starts immediately after the injury and can last for 3-5 days depending upon the different factors (i.e. age of the patient, dietary factor, disease condition etc.). the major function of this phase is to prevent the blood loss after injury by vasoconstriction mediated through increasing in Ca+ level in cytoplasm. Now this decreasing in blood flow leads to hypoxia at the site of injury which stimulate the production of nitric oxide and adenosine radicles which causes reflux vasodilation. The further blood loss is prevented through clotting mechanisms (intrinsic pathway, extrinsic pathway, and platelet activation pathway).

Intrinsic pathwayIntrinsic pathway of the clotting cascade (contact activation pathway) e endothelial damage as a result of tissue injury exposes the sub-endothelial tissues to blood which results in the activation of factor XII (Hageman factor). This initiates the proteolytic cleavage cascade which results in the activation of factor X which converts prothrombin to thrombin resulting in the conversion of fibrinogen to fibrin and the formation of a fibrin plug.

Extrinsic pathwayExtrinsic pathway of the clotting cascade (tissue factor pathway) e endothelial damage results in exposure of tissue factor (which is present in most cells) to circulating blood. This results in activation of factor VII and the rest of the extrinsic pathway of the clotting cascade which eventually results in thrombin activation.

Platelet activation
following activation by thrombin, thromboxane or adenosine diphosphate (ADP), platelets undergo a change in morphology and secrete the contents of their alpha and dense granules. Activated platelets adhere and clump at sites of exposed collagen to form a platelet plug and temporarily arrest bleeding. This plug is strengthened by fibrin and von Willebrand factor as well as the actin and myosin filaments within the platelets.

Histamine release from mast cells which increases the permeability of vessels and allows the inflammatory cells around the wound and causes reddening, warming and swelling of wound.

Inflammation46221651496695Figure b. formation of scab
00Figure b. formation of scab
385600715353900This stage starts from the 2nd day of injury and can last for 2-4 days, the main function of this phase is to prevent the occurrence of the infection at the site of injury by neutrophils, the neutrophils are attracted towards the site of injury upon activation of complement cascade, Interleukins and transforming growth factor ? (TGF ?). This process also called as chemotaxis. Neutrophils destroys microorganism by three mechanisms, Phagocytosis, releasing toxic substances, Producing chromatin and protease trap.
36227716566800Proliferation 
This stage lasts for 2 days to 3 weeks and involves the wound healing through healing cascade and this stage can again subdivided into 4 parts.
Angiogenesis4514850424815Figure c. fibroblast migration
00Figure c. fibroblast migration
In this stage TGF ?, PDGF, FGF, VEGF along with cytokines induces the endothelial cells to triggers neovascularization and repairing of blood vessels.

Fibroblast migration In this stage TGF ? and PDGF stimulates the proliferation of fibroblast and Fibroblast produces collagen and fibronectin. (pink vascular fibrous tissue replaces the clot at the site of wound also called as granulation tissue).

EpithelializationIn this stage Epithelial cells migrate from the edges of the wound and form a layer all over the wound. this process is also called as epithelial-mesenchymal transition (EMT).

Wound retractionThis stage of proliferation involves the contraction of the wound mediated by the interaction between actin and myosin which pulls the cells closer leads to contraction of wound, with the rate of 0.75 mm/day.

Remodeling46291501419225Figure d. Remodeling
00Figure d. Remodeling
35566351270000This stage can take up to 2 years. This stage involves the Development of natural epithelial and maturation of scar tissue and Regaining of structure similar to unwounded tissue. Wounds never reach to same level of strength as of unwounded stage. It reaches to 50% strength in 3 months and maximum 80% strength in long term. During the process of wound healing the Color of wound changes from red to pink to gray.
Timeline of wound healing8318512446000
1524000182245Figure e. Timeline of wound healing
00Figure e. Timeline of wound healing

Existing treatments for wound healingSome the existing methods for the treatment of wounds includes Surgical treatment, removing nonviable tissue, Antimicrobial therapy, Dressings and devices Skin substitutes, Tissue sealants and platelet gels, Cytokines and growth factors but all of them are either an expensive or less or found to be not effective in certain types of wounds when compare to hydrogels.

Hydrogels41243252029460Figure f. structure of hydrogel
00Figure f. structure of hydrogel
3332480571500Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of holding large amounts of water or biological fluids. The networks are composed of homopolymers or copolymers and are insoluble due to the presence of chemical crosslinks (tie-points, junctions), or physical crosslinks, such as entanglements or crystallites. These hydrogels exhibit a thermodynamic compatibility with water which allows them to swell in aqueous media. The hydrogels can be classified on the basis of the type of crosslinking, type of monomeric unit used to make polymeric chain, type of polymeric chains used to make three-dimensional structure, on the basis of type of stimuli responsive polymer used, bio responsive hydrogels.

Hydrogels in wound healing
Because of the moisture provided to the wound from the hydrogel dressing, common healing phases such as granulation, epidermis repair and the removal of excess dead tissue become simplified. The cool sensation provided by the hydrogel to the wound offers relief from pain for at least six hours. When hydration is provided for the wound bed, discomfort experienced from changing the dressing becomes reduced, and the risk of infection also becomes decreased. Hydrogel dressing for the wound management can be categorized as follows.

Amorphous hydrogel A free-flowing gel, distributed in tubes, foil packets and spray bottles
Impregnated hydrogel Typically saturated onto a gauze pad, nonwoven sponge ropes and/or strips.

Sheet hydrogel A combination of gel held together by a thin fiber mesh.

Classification of hydrogels
Based on Crosslinking in hydrogelsCross linking can impart visco-elasticity or sometimes pure elasticity in hydrogels. Cross linking can be chemical and physical but now days chemical cross linking is predominantly used to ovoid the toxicity of chemical cross linkers. Cross linking can also affect the swelling property and can be used to prepare stimuli sensitive polymer.

Crosslinking by chemical reaction of complementary groupsMost of the water-soluble polymer has functional groups (mainly OH, COOH, NH2) which can be used for the formation of hydrogels. Covalent linkages between polymer chains can be formed by the reaction of functional groups with complementary reactivity, such as an amine-carboxylic acid or an isocyanate–OH/NH2 reaction, the cross linking involves the chemical reactions such as condensation reaction, addition reactions, high energy irradiation and using enzymes.

Crosslinking by ionic interactions:19335752381885Figure g. sodium alginate crosslinking
00Figure g. sodium alginate crosslinking
left101473000Alginate is a well-known example of a polymer that can be crosslinked by ionic interactions. Alginate is a polysaccharide with mannuronic and glucuronic acid residues and can be crosslinked by calcium ions. alginate gels are frequently used as the matrix for the encapsulation of living cells and for the release of proteins. A synthetic polymer that, like alginate, can also be crosslinked with Ca-ions is poly di (carboxylate phenoxy) phosphazene (PCPP).
Crosslinking by crystallization:Poly vinyl alcohol (PVA) is a hydrophilic polymer which forms a gel at room temperature with poor integrity but upon freeze thawing it forms an elastic structure because of formation of PVA crystals in structure which impart the physical crosslinking in to the structure.
Based on types of monomers: Homo-polymeric hydrogel
Homo-polymers refer to polymer networks derived from single species of monomer. It is the basic structural unit, comprising of any polymer network. Homo-polymers may have a crosslinked skeletal structure depending on the nature of the monomer and polymerization technique. Chemically crosslinked PEG hydrogels are a classic example of this class.

Co-polymeric hydrogelCo-polymeric hydrogels are composed of two types of monomer in which at least one is hydrophilic in nature. e.g. poly (ethylene glycol)-poly(?-caprolactone)-poly (ethylene glycol) (PECE)
Semi-inter penetrating network (semi-IPN)right1872615Figure h. semi-interpenetrating network
00Figure h. semi-interpenetrating network
27908258318500If one polymer is linear and penetrates another crosslinked network without any other chemical bonds between them, it is called a semi inter penetrating network. The main advantage of this hydrogels is it gives modified pore size, slow drug release and high mechanical strength. E.g. linear cationic poly allyl ammonium chloride in acrylamide/acrylic acid copolymer hydrogels.
Inter penetrating network (IPN)32575501776730Figure i. interpenetrating network
00Figure i. interpenetrating network
27051008572500IPNs are conventionally defined as the intimate combination of two polymers, at least one of which is synthesized or crosslinked in the immediate presence of the other. The main advantage of IPN is higher mechanical strength and higher drug loading with compare to conventional hydrogels. Poly (aspartic acid) (KPAsp) and carboxymethyl chitosan (CMCTS) Ac di sol/cross Carma lose sodium.
Stimuli-sensitive swelling-controlled release systemsStimuli responsive hydrogels respond to environmental stimuli and experience unexpected changes in their growth actions, network structure, mechanical strength and permeability, hence called environmentally sensitive.

environmental stimulus290068014732000 pH-sensitive hydrogels
38004751972310Figure j. PH sensitive system
00Figure j. PH sensitive system
PH sensitive polymers are ionized at specific PH which expand the structure due to electrostatic repulsion. There are two types of PH sensitive hydrogels, anionic and cationic hydrogels the anionic hydrogel having a functional group such carboxylic acid or sulfonic acid and cationic hydrogels has amine functional group. e.g. poly diethyl aminoethyl methacrylate (PDEAEMA) and their copolymer, alginate-N, O-carboxymethyl chitosan (NOCC).
Temperature-sensitive hydrogels:
Temperature sensitive hydrogels are defined by their ability to swell and shrink when the temperature changes in the surrounding fluid, which means the swelling and deswelling behavior mostly depend on the surrounding temperature. Temperature sensitive hydrogels into two different classes, positive temperature sensitive and negative temperature sensitive. Positive temperature sensitive hydrogels contracts when temperature is fall and expands upon higher temperature. E.g. N isopropyl acrylamide (NIPAAm), Poly(N-isopropylacrylamide) (PNIPAAm), Negative temperature sensitive polymers are expanded at lower temperature and contracted at higher temperature.

Biochemical stimulus
Glucose responsive hydrogels
Mainly used for the diabetic patients in which the insulin is loaded into the hydrogel which also has the bounded glucose oxidase in system when the glucose come into contact with hydrogel it converted the glucose into gluconic acid and gluconic acid lowers the PH of surrounding which leads to contraction of hydrogel and insulin is released.

3343275952500Antigen-responsive hydrogels
35623501711960Figure k. Antigen responsive swelling
00Figure k. Antigen responsive swelling
Antigen-responsive hydrogels are designed by grafting antigens on hydrophilic polymeric backbones to deliver biomolecules at a specific targeted site. In this hydrogel the antibody bounded on polymeric chain and antigen bounded on different polymeric chain and they form intrachain antigen-antibody complex this complex act as crosslinking in hydrogel and dissolves when another antigen competitively binds to bounded antibody which results in breaking of crosslinking and releasing of drug.
Based on source
Natural polymers used in hydrogel synthesis: those which are obtain from natural source e.g. alginate, chitosan, starch, dextran, glucan, gelatin.

Synthetic polymer used in hydrogel synthesis: e.g. PNIPAAM, PVP, polymer composite (MMT) clay, ZnO nanoparticles, HEMA, HEEMA, HDEEMA, MEMA, MEEMA.

34004258191500Methods of preparation of hydrogelsBulk polymerization.This is a simplest type of technique in which large number of monomers are added in vessel along with small number of cross linkers and react in is activated by the initiators which can be chemical or radiation. This involves polyaddition (chain polymerization) type of reaction. The degree of cross linking in this method is depend upon the number of cross linkers added.
Grafting to a support.4000500260985Figure l. bulk polymerization
00Figure l. bulk polymerization
Hydrogels prepared by bulk polymerization have inherent weak structure. To improve the mechanical properties of a hydrogel, it can be grafted on surface coated onto a stronger support. This technique that involves the generation of free radicals onto a stronger support surface and then polymerizing monomers directly onto it as a result a chain of monomers are covalently bonded to the support.

Polymerization by irradiationIonizing high energy radiation, like gamma rays and electron beams, has been used as an initiator to prepare the hydrogels of unsaturated compounds. The irradiation of aqueous polymer solution results in the formation of radicals on the polymer chains. This radicals attack on different polymeric chains and form crosslinks. This process yields purest and initiator free hydrogel
Polymers used in hydrogel for wound dressingMarketed formulations of hydrogel for wound healingcenter50292000
Natural polymers Synthetic polymers
Collagen
Chitin derivatives and chitosan
Alginic acid and sodium alginate
Starch and starch derivatives
Dextran
Glucan
Gelatin
Poly-N-acetyl glucosamine
Hyaluronic acid or hyaluronan
Bacterial cellulose (BC)
Keratin and silk Polyurethane
Poly (methyl methacrylate)
Proplast or alloplasticsPoly(N-vinylpyrrolidone) (PVP)
Polyethylene glycol (PEG)
Poly(N-isopropylacrylamide) (PNIPAm)
Nanoparticles composite-polymers
Clay nanocomposite-membranes
Carbon-based materials composite-membranes
Metal oxides composite-membranes
10001256350Figure m. marketed formulations of hydrogels in wound healing
00Figure m. marketed formulations of hydrogels in wound healing

formulation ingredients application
TegaGelcalcium salt of alginic acid  leg ulcers, pressure sores, ischaemic and diabetic wounds.

CarrasynMethylparaben, Panthenol, Potassium Sorbate, PVP, Sodium Benzoate, NACL, Sodium Meta bi sulfite, Triethanolamine  Carrasyn is ideal for dry to low exudating wounds.

NuGelsodium alginate debrides necrotic tissue
CarraSorb Acemannan HydrogeI™, Hydroxyethylcellulose, Polyvinylpyrrolidone. low to medium exudating wounds for horses, dogs, cats and other companion animals.

Paper published on hydrogel
Title A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing.

Introduction The objective of the study is to prepare A biodegradable in situ gel-forming controlled drug delivery system composed of curcumin loaded micelles and thermosensitive hydrogel to repair cutaneous wound. Curcumin is believed to be a potent antioxidant and anti-inflammatory agent. Due to its high hydrophobicity and presence of polyphenolic groups curcumin was encapsulated in polymeric micelles (Cure-M) with high drug loading and encapsulation efficiency. Cure-M loaded thermosensitive hydrogel (Cure-M-H) was prepared and applied as wound dressing to enhance the cutaneous wound healing. Cure-M was prepared by a one-step solid dispersion method with curcumin and poly (ethylene glycol)-poly (3-caprolactone) (PEG-PCL) copolymer. In addition, Cur-M loaded thermosensitive poly (ethylene glycol)-poly (3-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG) hydrogel composite (Cur-M-H) was prepared and investigated in detail. Then Cur-M-H composite was assigned for in vivo wound healing activity test in both linear incision and full-thickness excision wound model. in the in vivo tests biomechanical tests, biochemical analysis, and histopathological examinations were conducted to investigate the therapeutic effects of Cur-M-H on cutaneous wound models.

Conclusion Cur-M with small size, high DL, and high EE was prepared, which was then encapsulated in thermosensitive PEG-PCL-PEG hydrogel to form Cur-M-H composite. In vitro tests showed that Cur-M-H composite could convert to a gel at around body temperature, adhere to the tissue, and sustained release curcumin in an extended period. In the in vivo experiments, Cur-M-H composite exhibited excellent wound healing activity in both linear incision and full-thickness excision wound model in rats. Overall results suggested that combination of bioactivity of curcumin and thermosensitive hydrogel in the in-situ gel-forming composite promoted tissue reconstruction processes, indicating that Cur-M-H composite is a potential wound dressing for cutaneous wound healing.

References:
1. Alistair Young, Clare-Ellen McNaught. The physiology of wound healing. Surgery (Oxford) Volume 29, Issue 10, October 2011, Pages 475-479.

2. N.A. Peppasa,*, P. Buresa , W. Leobandunga , H. Ichikawab. Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 27±46.

3. Heather L. Orsted, David H. Keast, Louise Forest-Lalande, Janet L. Kuhnke. Skin: Anatomy, Physiology and Wound Healing.

4. ChangYang Gong a, QinJie Wu a, YuJun Wang a, DouDou Zhang b, Feng Luo a, Xia Zhao c, YuQuan Wei a, ZhiYong Qian a,*. A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing. Biomaterials 34 (2013).

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