systematic Review © Regenerative For reprint orders, please contact: [email protected] eos Medicine The effects of polydeoxyribonucleotide on wound healing and tissue regeneration: a systematic review of the literature Maria T Colangelo"®, Carlo Galliv?@ & Stefano Guizzardi"® Deparment of Meine & Sarge, Hise & Embryology ab Uniesy af Fame, Parma ay “ator for corespondence +39 052 190 6740, ao gai@un ‘Aim: The present study evaluated the effects of polydeoxyribonucleetide (PDRN) on tissue regeneration, paying special attention to the molecular mechanisms that underlie its tissue remodeling actions to better identify its effective therapeutic potential in wound healing, Materials & methods: Strategic searches were ‘conducted through MEDLINE/PubMed, Google Scholar, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials, from their earliest available dates to March 2020. The studies were included with the following eligibility criteria: studies evaluating tissue regeneration, and being an in vitro, in vivo and clinical study, Results: Out of more than 90 articles, 34 fulfilled the eligibility criteria, All data ‘obtained proved the ability of PDRN in promoting a physiological tissue repair through salvage pathway ‘and adenosine A2A receptor activation. Conclusion: Up to date PDRN has proved promising results in term ‘of wound regeneration, healing time and absence of side effects. First draft submitted: 18 September 2019; Accepted for publication: 28 June 2020; Published online: 6 August 2020 Keywords: cell culture # PORN « polydeoxytibonucleotide « purin gic receptor « wound healing ‘Wound healing consists of coordinated and regulated events, in other words, an iniial inflammation and a later neovascularization, followed by the formation of granulation tissue, of new epithelial layer and, eventually, a scar, which then contracts and is remodeled, A well-orchestraced integration of the biologic and molecular events of ce ‘growth, migration and matrix deposition is required for complete tissue recovery and functional homeostasis (1 However, tissue healing can be deranged, thus causing undue extracellular matrix (ECM) production (2. This clinical condition is known as tissue brosis and occurs asa physiological feature of aging, though ic is also found in chronic tissue injury 3. Impaired wound healing is also typical of several diseases such as diabetic foot ulcers 45), ‘Sjgren syndrome (6) and pressure sores The final organization and functional quality of the ECM depend on the lst stage of wound healing, in other ‘words, the remodeling phase. An inefficient repair results in hypotrophic or atrophic scars, whereas an excess of ‘broblast activity and matzix accumulation results in hypertcophie scars, which can be confined to the wound site ‘or extend beyond the original injury atea, thus impairing organ funetion ( Fibrosis mostly occurs in tissues tha ae frequently exposed to iological and chemical insults, which in tuen lead to the chronic stimulacion of immune and nonimmune cells in the injured organs s, Fibross isthe main driving factor in progressive los of organ function and eventual failure, specially in epithelial organs, for example, kidney, liver, lung and skin (9 Dermal fibrosis is due o pathological skin remodeling and entails the excessive deposition of matrix components, for example, collagen. Dermal fibrosis encompasses a wide range of diseases, for example, hypertrophic scatting, keloid and scleroderma 10, Several stimuli initiate distinct profibrotic programs in epithelial cells, leading ro organ fibrosis: cell deach — in che _most extreme cases ~ but also metabolic impaizment, with higher production of reactive oxygen species (ROS) and ‘endoplasmic reticulum stress, epthelial-mesenchymal transition (EMT) or latent TGI-# activation and immune cells recruitment with subsequent release of profibrotic eytokines Future’: Medicine” 102217/me 201901818 2000Futue Medicine Led Regen. Med, (262011516), 1807-182 Iss 7460751. 1601Systematic Review Colangelo, Galli & Guizzardi Polydeoxyribonucleotide an —— Proper matrix deposition Angio Infammation resolution Caan = veor a fort Yio fs. be Cel growth Elastin SS EEE ‘Wound healing and tssue regeneration Figure 1. Schematic representation 3f polydeoxyribonucleotide activity in accelerating tissue repair. Although the origin of fibrosis in injured cissues has been debated for decades, EMT has been recently proposed as & pro-fbrotic mechanism (11-15}, EMT has been indicated as a key mechanism underlying fibrosis in multiple organ including che skin ta. During EMT, epithelial cells gradually lose thei original phenotype and function and acquire a mesenchymal phenotype (17. Albeit a fundamental process during embryogenesis and morphogenesis, it also seems to play a pivoral role in wound healing and or scar formation in adults by stimulating proinflammatory ‘mediators (1s). Due to its profibrotic effect in many cell types, TGFBI, has been considered the major driver of fibrosis (9,2, in part, chrough its role in promoting the activation of myofibroblasts (21-25. Myofibroblasts, identified in wounded skin and contractures and originally defined as ‘wound fibroblast, actin (-SMA)-expressing cells chat mostly secrete type T and IIT collagen and that accumulate in virtual spaces between organ structures (aj, Ie was suggested that fibrosis results from the conversion of resting fibroblasts to profibrogenic myofibroblasts in response to growth factors. TGF-BI is considered one of the most pocent activators of experimentally induced EMT via canonical pathways involving Smad 2/3/4 phosphorylation (27,2 and via non-Smad mechanisms (9,30. An inctease in TGE-1, TGE-B receptor levels and an enhanced TGF-B signaling have ‘of myofibroblasts (3,2). The literature concerning the contribution of EMT to fibrotic skin conditions other than scleroderma is scarce. However, high expression of mesenchymal markers found in the epidermis and dermis ‘of human hypertrophic seats, accompanied by increased levels of inflammatory cytokines, Sbotic markers and EMT-related gene, demonstrated a link berween unresolved inflammation and the development of EMT during fibrogenesis in hypertrophic scar cssues in vio (38). Though the actual mechanisms underlying fibrosis are still a topic of considerable debate, suppressing FMT (334) as well as inhibiting the recruitment and activation of these fibrogenic cells have been suggested as viable approaches to prevent tissue fibrosis (11-1,5,97,38 Preventing and reversing the critical pathological conditions that are found in fibrosing disorders is sorely needed, because these give rise to multiple morbidities that heavily impinge on the qualiey of life of patients, for ‘example, disfigurement and reduced range of movements as well as premature mortality due to renal and cardiac dysfunctions (9). Importantly, ithas been recently acknowledged that Sbrotic diseases are becoming therapeutically tractable |A great therapeutic potential seemed co be harbored by the EGF and PDGE-BB, bioactive molecules that promote keratinocytes growth and migration (oy. However, in spite of promising initial clinical results 42, they have yet co be proven to achieve reliable long-term clinical success ‘4. Similarly, glucocorticoids, routinely used, smooth muscle cderected in skin fibrosis in scleroderma, supporting the role ofthis cytokine in the activation to teat inflam ion in Sbrosis, reduce collagen deposition by blocking protein synthesis and are associated with numerous side effects that make their prolonged use challenging forthe patient's, ‘Novel therapies should therefore build on the existing results and minimize their side effects, Polydeosyt bonucleatide (PRN) is a compound chat has long been used to improve wound healing thanks to its ability ¢o promote cell migration and growth, proper ECM deposition, angiogenesis and to reduce inflammation (Figure 1) ‘Noninvasiveness and the variability of administration routes have proven to be the attractive characteristics chat en) Regen, Med, (2020) 151 staPORN for physiological tisue repair Systematic Review Energy saving DNA synthesis. (a AIR_AMP_feerosine~ Fast wound healing — Figure 2._ Schematic representation of the action of polydeoxyribonucleotide through the salvage pathway and AZAR activation. Improved wound healing _make the use of PDRN preferable over conventional therapies with a shorter half life, limited injection routes and possible adverse events. Furthermore, the strong therapeutic effect with low immunogenicity and no toxic effects, in primary organs, even when administered by systemic injection, makes it posible co use PDRN in compromised patients such as diabetics. PDRN systemic administration would stabilize blood levels that are needed to assure an ideal control of the impaited wound-healing process ‘Thus, this evidence has prompted researcher to support the hypothesis that PDRN may ameliorate the clinical success of existing therapies and, ultimately, the quality of life of patients Polydeoxyribonucleotide PDRNisa DNA-derived deug. cis linear polymer consisting ofa mixture of double stranded deoxyribonucleotides with a chain length of 80-2200 base pairs and 2 molecular weights ranging becween 50 and 1500 kDa, considered the optimal PDRN size promoting wound healing 4:1. More precisely, daily intraperitoneal injections of PDRN of different weights, in other words, low PDRN (<50 kDa), mid PDRN (50-1500 kDa) and high molecular weight PDRIN (1500 kDa), have been administered to hairless mice for a week in an excisional skin wound model. Immunohistochemistry revealed thar the molecular weight of PDRN does not affect wound closure but does affect the quality of wound regeneration. Among he examined sizes, mid-weight PDRN promoted eazlier collagen deposition as well a bercer wound closure with increased re-pichelialization. PDRN is commonly extracted from salmon trout (Oncorhynchus mpkis) gonads. Gonads supply high quality DNA with the absence of pharmacologically ative proteins and peptides ensuing a lack of immunological side effects and drug safety (5) Afer extraction, PDRN is purified and sterilized at high temperature through a process thae achieves a >95% purity 46. Thanks to its chemical structure, the compound is found free in the plasma and is distributed to the tissues according to the blood supply with a bioavailability inthe range of 80-90% with peak levels at 1h and a halflife (of 3.5 h, as assed in in vivo model and confirmed in clinical stad: leis not metabolized by th liver bu is degraded by unspecific plasma or membrane-bound DNA nucleases and is finaly exeveted through urine and, co a lesser extent, feces (47. Squad isnot really a reference! PDRN degradation generates active oligo- and mononucleotides, purines and pyrimidines, which become available for the biological activity, which is carried out through two distinct mechanisms (Figure 2). PDRN may be considered « pro-drug providing active deoxyribonucleotides that interact with purinergic receptors. More specifically, the released adenosine acts on adenosine A2A receptors (A2ARS), as suggested by Thellung et al 48) using DMPX, a ‘The selectivity of PDRN for this subtype of purinergic receptor might explain the safe profile of PDRN respect 10 A2A agonists, which, followis ‘apable to engage several types of purinergic eceprots 4 re adenosine A2A receptor antagonist, which abolishes PDRN effects their 5'-esonucleclease-mediated degradation, may generate small-sized fragments Bircescerce gop vv tuneSystematic Review Colangelo, Galli & Guizzardi A dramatical 1000-fold increase in the extracellular adenosine concentration (from nanomolar to micromolar ange) was observed in tissue or cellular necrosis and hypoxia, as ATP catabolism increases (6. Thus, as farther confirmation of PDRN safety; in in vivo model of incisional wound healing, the absence of angiogenesis as well as toxic effects in primary organs, such as heart, brain, liver and skeletal muscle, even after PDRN systemic administration, suggested that AZAR activation would only occur under hypoxic conditions i “These observations have prompted researchers to hypothesize chat PRN, through A2AR stimulation, could be a viable therapeutic strategy to promote wound healing. ‘Second, PDRN has been shown to act by promoting DNA synthesis or repair and restoring cell proliferation and growth through the socalled ‘salvage pathway’. This efficient energy-saving metabolic pathway through which PDRN supplies cells with nucleotides and bases deriving from ies degradation represents 2 unique feature, not shared with other DNA-derived drug from different origin, molecular weight and manufacturing process Purinergic receptors & wound healing ‘Adenosine, AMP, ADP and ATP ate released by cells into the extracellular environment as a result of direct stimulation, inflammation, injury, hypoxia, metabolic stressor other pathological conditions (305 ‘Adenosine isa ubiquitous purine nucleoside generated by the spontaneous hydrolysis or the serial dephospho- tylation of ATP to AMP by nucleoside tiphosphate dephosphorylase (CD39), followed by dephosphorylation 1 adenosine by 5'-ectonucleotidase (CD73) (31. Adenosine modulates cell and tissue functions by interacting with the PY receptors family, which includes 4 G-protein-coupled receptors (GPCRS), through which adenosine regulates adenylate cyclase activity. Specifically, A2A and AZB receptors, associated with Gs proceins, stimulate adenylate cyclase and increase intracellular AMP. cAMP activates then PKA, which is more sensitive co cAMP, and Exchange protein activated by cAMP (Epa), which is less sensitive to CAMP. ‘Adenosine, acting by its receprors, has been shown ¢o accelerate the resolution of acute inflammation 15,36, upregulate VEGF promoting vessel formation by endothelial cells and support granulation tissue formation (7.58 Purinergic receptors are expressed in a variety of cell and essue types. For this reason, numerous studies focused ‘on the pathophysiology and therapeutic potential of purinergic signaling and several purinergic compounds have bbeen developed for the crearment of a wide variery of diseases (8) such as cardiovascular (60) and musculoskelecal dlscases (6, disorders affecting the airways (, the central nervous system (6), kidney (liver (65,65, the lower urinary tract (67, the reproductive system res, gut 16971 and diseases of special senses (eye, ar, olfactory system and tongue) 71 74. Moreover, purinergic receptor agonists and antagonists are being evaluated for the treatment of obesity 73, infection (74, immunity and inflammation (77 and diabetes (7 A growing amount of erature has highlighted the role of nucleotides and purinergic signaling in wound healing, Ic is known that nucleotides are released from cells as a consequence of injury and promote wound repair (7.0 For this reason, che effect of purinergic signaling is widely being explored in healthy and disease skin, suggesting a ‘therapeutic use in the treatment of psoriasis, scleroderma, ski inflarimation and wound healings. Interestingly, the eficacy of adenosine receptor agonists was confiemed in che treatment of diabetic foot ulcers, which is used in literature as a model for wound healing studies because ofits complex pathogenesis characterized by healing impairment. Methods For the present review, the MEDLINE database (via PubMed), Google Scholar, Scopus, Web of Science and the Cochrane Central Register of Controlled ‘Trials were searched, from their earliest available dates to March 2020. Search cerms included subheadings and keywords for polydeoxyribonucleotde, wound healing, soft issue and tissue regeneration. Reference lists of included studies and relevant reviews were also searched. No language restriction ot filters were applied. The tile and abstracts of retrieved studies were screened by owo authors (CG and MTC) for inclusion, Experimental studies concerning the regenerative effects of PDRN were evaluated. Out ofa total of more than. 90 articles, 34 articles were selected and grouped in three categories including,in vitro models, animal models and clinical models Extracted data fiom each study type were used to create tables summarizing study designs, interventions and outcomes. In addition, clinical studies were graded for quality: Randomized controlled tials (RCT) were independently scored by two authors (CGand MTC) and graded according.o the Scottish Incercllepiare Guidelines tare scence group MDPORN for physiological tisue repair Systematic Review Neowork instrument (SIGN). RCTs were rated as ++ (high quality with very lite risk of bias), + (well conducted ‘wit vory rs lite of bias) and ~ (high rsk of bias). No score was applied to case series and case reports. Results ‘Theva evidence onthe ole oprnergic agorss on wound hing has provided 2 thesepneraive fc of PDRN Mast eerinenal sade oeasng onthe ees of PDRN to promot th depen of new sound sue in wounds have confirmed is pret a ssue regeneration inching skin bone carlage and tendon sue Ue seve diferent polis und wih fet donpe and aminstraon routes em top apicon Forth ke of cig wehve chsifed thse aud according thir xprienta model jonale to investigate In vitro studies Several studies investigated the effects of PDRN jin stimulating the growth and proliferation of numerous cell phenotypes (Table 1), including human iis pigment epithelium cells), chondrocytes (2, pre-adipocytes ] and osteoblasts 45 Unsurprisingly, most studies on wound healing focus on Gbroblasts. Muratore eral. 6) showed that 20~ 100 mg/ml PDRN enhanced the growth of human knee skin diploid fibroblasts in primary culture, especialy from ‘older donors, where cell growth may be physiologically impaired. A few yeas later, Sini eral. 6 observed growch significant increase in PDRN-treated fibroblasts. Theit analysis revealed a high amount of 3H*-proline-abel in- corporation into collagen chains and an increase in (35S]-Methionine incorporation in proteins, particularly in fibronectin, released in the medium of fibroblasts cultured in the presence of DNase-digested PORN. Immunoblot- ting, moreover, showed a higher amounc of fibronectin in the medium of PDRN- antagonist DPMK reduced the increase in [Ca**] «evoked by PDRN. Chen et al. (8) investigated whether PDRN affected human embryonic fibroblast cells and vascular en- dothelal cells by treating chem with short poly-N-acety glucosamine nanofibers and polydeoxyribonucleotide (NAG+PDRN) or PDRN alone. The authors observed an increase in cll proliferation ater PDRN treatment by CCK8 assay, and an increase in cytokine and VEGF levels. Genero er al 9) demonstrated that a specific PDRN-based formulation improved the ex-vivw maintenance of tissue biopsies for more than 1 year, with an increase in epithelial and fibroblastic markers, for example, Collagen T and Collagen TY, from cel extracts, Interestingly, in a recent in vitro study by Kim et al. 90) PDRN has been shown to exert anti-melanogenic and anc-aging effects. A decrease in tyrosinase activity and melanin contents observed in murine melanoma cells indicated chat PDRN promotes a suppression of hypopigmentation and melanogenesis, while an increase in mitochondrial deosity indicated that the anti-oxidative activity of PDRN induces mitochondrial biogenesis. Furthermore, the inhibition of elastase activity and MMPI expression in human fibroblast cells suggested that PDRN exert a protective fect against skin aging, by modulating connective tissue proteins. PDRN effectively prosected human dermal fibroblasts from UVB:induced DNA damage 1, a reduced levels of eyelobutane pyrimidine dimers (CPDs) were detected by immunocytochemisty in iradiated cells. No positive «cls for -HI2AX, a marker of double-strand breaks in nuclear chromatin, were observed, and western blot analysis showed a stronger activation of p53 protein in the ist 24 h after stimulation followed by a rapid decrease. This ‘evidence suggested that che protective effect could resule from salvage pathway through which PDRN promotes DNA synthesis and repair: When using an in vitro model of electrical wound healing (electric eell-substrate impedance sensing, ECIS), Koo and Yoon is demonstrated increased viability and mobility of primary human Birvescencegoop vwnfuttemeddcinecom 1805,Systematic Review Colangelo, Galli & Guiezardi Tab ieee ‘call model subject an ae renging dota cle 6 ‘Murine melnoma cel and primary oman deal Taran dendrogtical [BH pain or Passteinine 1 ugimi (rac or 2.26 0, 72.96 deand 72 Uimmunogpacher ison Geten 0) 0: 12.24andaan re “Dat praline or 355 “ipuigreine or [a5shmetnonine «PORN me =PoAN- OMX, = proto agens eto (eat CTR ren (negative TR). 10% FS (pestve TR pasties iepntve CTR ra: % e+ PORN CTA Mitomycin low PON + Mitomycin “hth PORN «Mitomycin (paral donors over ayearsof 290) “eal gro pari riochondrial biogeesg dove dependet manne: Sound eng area we ro va) ro 0) ve) cs ves dermal fibroblasts and U2OS osteosarcoma cell Recently, Baek ef al om) obtained similar resules with an in vitro model of osteoarthritis. A human chondrocyte cell line, pre-stinwulated with IL-1B, showed increased levels of PDGE, ANG-2, VEGF and increased cell migration, as assessed by scratch assay in the presence of PDRN, suggesting thac PDRN promotes angiogenesis and wound healing, Likewise, Hwang et al. s) investigated PDRN- 1806 Regen. Med.PORN for physiological tisue repair Systematic Review rmediaed cellular behavior and molecular signalingin an attempt to clarify whether the regenerative effec of PDRN promotes cell proliferation or migration. In ths regard, human fibroblasts were treated with PDRN in the presence ‘of mitomycin C, a proliferation inhibitor. The increased JNK actviy, assessed by western blot, and the rate of ‘wound closure, assessed by scratch assay, suggested chat PDRN may promote wound healing, by enhancing cell migration via eJun N-terminal kinase signaling. Animal studies [An abundant literarue investigating the effect of PORN in improving tissue regeneration is available in preclinical models of various type (Table 2), including tendon repair 495, bone regeneration 6-9) and liver regeneration 10) ‘Skin regeneration was, however, among the most thoroughly investigated applications of PDRN. Although it may be speculated that PDRN, by activating purinergic signaling, could promote the formation of fibrotic tissue ich in type I collagen, AZARS have been accually shown to regulate the collagen: collagen3 balance (11, which may have important consequences for skin regeneration. The ratio of Coll to Col3 in normal skin is 4:1, and it decreases to approximately 2:1 in immature scars, due to increased levels of Col3. Col3 is ‘then replaced by Coll in mature scars (6. Ie has been shown that A2A receptor activation directly and indirectly promotes Coll and Col3 synthesis by fibroblasts through different mechanisms and that, additionally, different levels of A2AR activation promoce different types of collagen synthesis (11,112. AZARS have been proven to ‘modulate this ratio by differencal activation of PKA and Epac (1s. At lower concentrations of A2AR agonists, PKA promotes isroblat activation, Coll deposition and suppresses Col3 expression; ar supra-physiological levels of purinergic agonists, and therefore higher concentrations of cAMP, Epac induction suppresses inhibition of ‘Col3 by PKA tii. The paradoxical effects of cAMP on collagen expression may he explained by the fact that ‘cAMP is a concentration-dependent switch fr collagen production via noncanonical, AKT-dependent, Smad2/3- independent signaling (1. These results may justify why previous works using high concencrations of cAMP analogs (250 tM) [15.11] or eAMP-increasing agents (210 4M) (1:6.18,120,12) report inhibition of collagen and proliferation. So, cAMP, acting as an all-ot-nothing switch for fibroblast growth and collagen deposition, has been suggested to integrate profibrosic and antifbrote signals (117). Buffering cAMP within a specific range has been proposed asa new pharmacological strategy to prevent tissue fibrosis 13. Additionally, adenosine eceptors contzol collagen expression through other signaling pachways, such as CTI ‘which promotes collagen secretion by reducing the expression of the transcriptional regulator Flil, a constcutive CTGE repressor 113 Finally, adenosine has also been shown to play a rolein che remodeling of newly formed granulation tissue, a repair process during which the definitive, Coll-rich matrix sequentially replaces the provisional extracellular matrix, asthe later, sich in Col3, is degraded by serine proteases and metlloproteases. Administration of ineraareral infusions ‘of ATP to healthy volunteers has been shown to promote the release of rssue plasminogen activator (BPA), a key facto inthe proveolyti degradation of extracellular matrices, required for normal skin repaie (122 “The transition from the inflammatory to the proliferative phase is a crucial event in rissue repair, bes tunconteolled and persistent inflammation results in excessive scarring (12. It has been shown that dermal i fammation extending co 1-2 weeks can result in aberrant scarring and eventually pathological scars in surgical ‘wounds (124 So, blunting inflammation and accelerating wound healing are though to be correlated in decreasing scar formation (12512. In this regard, Jeong el) investigated scar Formation in rats after injection of PDRN, To this purpose, dorsal skin excision was performed in 30 rats, which then received intraperitoneal (ip) vebicle or 8 mg/kg PDRN for 3 oF 7 days. On day 7, hematoxylin and eosin (HEE) and Masson’ trichrome staining demonstrated complete wound re-pithelalization and the formation of sound granulation tissue; on day 14, more collagen ‘was deposited within significantly narrower scar areas in the presence of PDRN. western blor analysis revealed increased levels of ype I and type III collagen in the PDRN group. The histological and iemmunohistochemical analysis showed a signifcanely reduced inflammatory eel inflerare after administration of PDRN at both 7 and 14 days post-surgery. Most interestingly, PDRN treatment significantly reduced che expression of the HMGB-1, and addition of exogenous IIMGB-I abolished the effects of PDRN on scar reduction and collagen deposition. “Thus, these results suggest that PDRN effecs on wound healing are mediated by its ant-inflammatory and collagen synthesis properties. Moreover, the serum levels of HMGB-1, a key player in orchestrating inflammation, have been shown to be positively associated to skin thickness in systemic slerosis 27 leavin, a drug that is currently used for the treatment of erectile dysfunction and that inhibics HMGB-1 increas 121 has been also proven ro reduce Bircescerce gop vv tuneSystematic Review Colangelo, Galli & Guiezardi Table 2. The tabl ee one een ‘Doeewmodel—Animalmodel ABE PORN dove /roite—Therapydosing Stud groupe PORNCTROUCoMe Ae Ecslooal wound Hailesmice weeks Smgikgip Dally forest ere ‘wound dtu 1 resing Tom PORN (<50 408); ber wound done gulty (sons09 koa ‘epoeton incre CiSo0%0m, eciionalwound sprogueDawiy weeks emaikain Daly or3or7 das shat Searreducing tec; ‘0H Thom 368 + HME. Fultknes New Zeandwhte “Bwests 4875 gine PORE wee fr CTR (Rendon arses waar lator et eaing rabbis Ponuiyecion VC foursnes SrGRN + SHAMAN fealogen foes meaaiyfort» —~ponN mie Feganerton Sugialincion obbeicmice —Y2weeks Sagi Diy forays vehicle; taransation aoe iar TORN: polferaton Surgjialinesion Dibetemice «weeks —=«Xcreams10mgh Gey 24K unl ——APagonia COS.21680 Wound doure ve Fons Learnting, — woundesure — Goste eT. tester esting ‘aicum ioe and Scamnattne cea protec agents wth conte cr Excionawound Sprague Danley opal appiation aly fordweeks—Fuean (CW) ‘woond e roa nealing? i rome th apoptoticettas che Uaierindvedatn SpragueDewiey — @weeks —@mgitgin. Day fort week Vere, iver: vest ‘wound a cre merovesl dea vchionaiwound — Obetcnice ——“Mweeks ~~ amgiRgin Daly or 2 das —=NOW wicks —VEGE TG Mang ost neslng Tne TbHPx move! dra foo «ron + MX, =08 + one ‘Sin er ibe mee NO 08 conmon jreephelznion and wound (em, vreitormedorenlaton wound rsnaGr”Trmovest foraton ‘wound ne wound + Pon oR Oreos 1808, Regen. Med. future tence grounPORN for physiological tisue repair Systematic Review een Random pattem SpragueDawley weeks Emeka Dslyfor days veri: Sura of anger 1071 imeroesldesty Tichemiciin fap Sprague Davey ‘eroigin Dsiy fra, Sandie {bleed ow: 08) Ba todays ron weer Nos trelstormed ranlation Sioeimental STALE mice Sroigie Daly or 2 weeks voice: {VEGF INOS, NOS NO; (105) ‘hema! y oR ines Seroverel dest Disbeicweund —Dibetcmice ——in sno study on tured macrophages. Ade Bin Bcbol 0801), 13-26 2017) inl nld , Ramanathan M, Hasko Ge a An angogenie switch a macrophage invohing nergy betwen Tl ike sept 2 4,7, and 9 and adenosine A2A rcepote. 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