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Biomedical Applications of Natural Rubber Latex From The Rubber Tree - Compressed

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Biomedical Applications of Natural Rubber Latex From The Rubber Tree - Compressed

Mantap

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Daniz Samosir
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aerials Science & Engineering 126 (2021) 112126 tt it Tabi SSD Materials Science & Engineering C Journal homepage: vwv.clsevier.comiocatelmsee gi Biomedical applications of natural rubber latex from the rubber tree Hevea brasiliensis ‘Nayrim Brizuela Guerra", Giovana Sant’Ana Pegorin", Miguel Henrique Boratto‘, ‘Natan Roberto de Barros‘*’, Carlos Frederico de Oliveira Graeff’, Rondinelli Donizetti Herculano"” 1 rea fat Se nd Beng, Ur of Card Su (UC), Cava do Sl io Gade do ut AR * pan svg ad Reyoces Bing $0 Pn Sia Unveray (UNESP, Sel of Pharma Ses KO ara Rod, Araagurs San Po, rst {Diprmer of Phys, ao Pol Se Unie (UNESP, cool of Sees, Ba, 0 Pal, Bri "Til te or Rome! Bora (IB, 1570 Wa Lp Bola Las Aly, A 9004, USA ARTICLEINFO AsTRACT Koper ‘ome pplentons ogee meine “The past decades have witnesed tremendous progres in biomaterial inven of fanetonlites ad apples tion To elie various fntions such sss engineering, ate repaiand controled release of thereat, 1 biocompatible spd biologically seve material is often needed. However is «dificult task to find elher ‘yada or natural materi stable for in vw spplcations. Nature has provided us with tbe aural eubber latex from the cubber wee Hevea Draliens, «maura polyne that i biocompatible and hasbeen proved 3s Indlog usue reals by eahancng the vasculogenels proces, guiding and rerun calls responsible far loseogenes, end sein 26 solid max for contlled Gog release. It woulé be extremely useful if medial devices can be abate with materials that have these bilopel properties. Recent, various pes of atural rer latexcased biomedical devices have been developed enhance tssve repair by taking advantage ofits biologie! properties, Mom of them were zed to enhance tee repair in chronic wounds and real bone defects, Others were used to design drug release systems to loealyseease therapeu in a sustained and Controlled manne. Here, we summarize recent progress made in these areas. Specially, we compare varieus Applications and ter performance mets. Weslo discs rita problems with thew of marl ribberIatex In biomedieal applications and highlight facie opportunites for biomedical devices produced either with pr- tweated natural rer latex or wit proteins purified from the nraral rubber latex 1, Introduction sia have shown interesting results for biomedical aplications using natural rubber latex (NRL) [5-5]. NRLis ‘extracted from the rubber tee H.braienis, a tre originally from the ‘basin ofthe Amazon River. NRL is found inthe form of a colloidal sus- Pension, extracted manually, and composed mainly of particles of long “The search for materials with biological properties is constant and researchers worldwide are constantly applying effort in hei discovery ‘and development. Materials that restore function or facilitate patient recovery after injury or iliness ate classified as functional biomaterials (12. They can be of natural or synthetic origin, being widely used in biomedical applications as support, improvement, or even in the replacement of damaged tissve or biological function. Various materials ‘of natural origin have gained space in academic research, mostly due to the properties of assistance or even inliction of tissue repair, These biomaterials ean be of marineorigin (2) of animal-origin (3), and of ‘vegetal-rigin [4], Among the materials of plant origin, researchers fom. * Corresponding ators poly(is-1,4isoprene) chains. Due to its physical and chemical proper Les, Its widely used in Industry, but It has also conquered is space in biomedical applications, mainly in the area of tissue cepair (9-11. Nowadays, wound dressings such as simple gauze, which only pro- idea mechanical barsier preventing the deposition of dirt, are no longer interesting, The new generation of dresings brings not ony the function ‘of mechanical protection but also the support and stimulation of tissue ‘repair influencing the eel cycle ané the overlapping stages of healing mal eres: ros tersaiong (NR, de Bare) aos groef@unesp br (CF, de Oliveira Gre. ‘nups//doLorg/101016,).nse 2021112126 Received 15 Pbranry 2021; Received in revise form 14 April 2021; Accepted 1 April 2021, ‘Available online 22 Apri 2021 (0928-1951/6 2021 Hsevier BV Al ight reserved (22) Im addition, the incorporation of therapeutic compounds into the £ e Release surface skin in Drug release through diffusion Fig. 4. Schematic examples fr NR. dressing sold sealed ia deug release appliealons. A) Deuploaded NR. membranes used a contoled release sates ‘Comparison between traditional syste methods of medication ad controled relate systems. A sustained deg leas sytem allows covtoling the enecstration ‘of drugs above minim eetve and below tue evel isthe psa (ashe lies). C) Mechanism of phumaceogial delivery fom dg-loaded NRL-bssed ‘resags on the lta or wounded sia fr sustained pharmacologiel release otc” Miforcis——Stypnedndon cote) (2 (sovam ben” on Mewondare — stai (emmy (I Prope Genmmice foul ="1 Cyrene nian) nists, Conant BC 3 fsa on o aetna cot Othe ee © Ropuaely Mnowa as “barbatina™ ® Algo inown a guagatngs, ere deagono or een do-mate ‘modifying the surface morphology end porous density of the NRL ‘matrices is the easier way to tune the drug release kinetics [105] Furthermore, most of the works have shown the starting materials are stable not only after the therapeutics loading into NRL but also after release. Moxiflovacin [122], a broad-spectrum antibiotic; and ketopro- fen [129,130], an antiinflammatory, after integration with the NRL membranes have not shown different bands in FTIR tests, indicating the preservation ofthe integrity of the drugs, and the mechanical properties ‘of the elastic biomaterial. The matrx of NR. can release moxifioxaca, showing activity against major bacterial strains presented in wound infections. Foriano etal. (1251 showed that 60% of ketoprofen loaded. into NRL membranes was released wp to 50 h, presenting no cell damaging effects, with hemolysis level less than 5%, which showed that the controlled delivery is ideal to minimize the adverse side effects ‘normally observed for high doses in systemic drug administration. In a similar work, ciprofloracn, a synthetic antibiotic of broad- spectrum, was loaded into the NRL matrix. The addition of ciprofloxs- in into NRL membranes induced changes inthe mechanical properties ‘ofthe biopolymer [119]. The release kinetics was shown to obey a bi- ‘exponential function, with burst release up to 25 h and saturation after 7 days, releasing up to 60% of drug content in 13 days [115] ‘According to their resis, the authors concluded thatthe ciprofloxacin Feleasng from NRL matrices fllows a super ease I mechanism, where the drug-release depends onthe solubility of the compound, degrada- tion/erosion, swelling, and relaxation of the latex matrix, Their results Were similar to the Kinetics of eiprofoxacin releasing from chitosan Mari Scene 8 rgmering 126 a1 122126 capsules, demonstrated by Verma etal [244] through a non-Ficklan transport mechanism. In this particular mechanism, the velocity of sl ‘vent penetration inthe polymer is higher than the swelling and relax ation of the matrix, probably due to the natural cross-linking in the polymer asi is found also in NRL, with low swelling and degradation due to ts hydrophobicity (245,142 ‘Aiming to achieve greater contol of drug release kineties when using NAL membranes, Almelda et a [105] deseribed a method to create ad conteol pore density on NRL. membranes, For sich, a femtosecond (8) laser was employed t prepare mierodrilled NRL membranes with pore densities varying from 2000 to 10,000 pore/em?, The microdiled NRL ‘membranes were further used to load ciprofloxacin as a drug model, a5, shovin ing, 5A. The membranes showed that the final concentration of the drug released presents a linear dependence with the pore-density due toa superficial release process and burst release of just 8 min. The ‘micto-holes of approximately $0 ym radius were fabricated using a ‘wavelength laser of 775 nm, 100 pulses/pore with 185 p/palse. How. ever, its important to nosice that inthis method, the drug is loaded 10 ‘the NR, matrix only ater the feassisted microdriling process, which provides the burst release and makes it difficult to control the drug release overtime. To solve this problem, an intermediate layer would be integrated between the microdrilled NRL matrix and the skin, providing greater adhesion to the skin, and beter tunability of the drug release inti, Metronidazole, an antinfetive drug used for protozoa and anaer- bic bacterial infections, previously studied for drug release from sl- cone elastomer (147] was later succesfully incorporated int the NRL ‘membranes for controled release (123-125). The authors assessed the changes in drug release by varying the temperature of the polymeriza- tion of the NRL matrix, ranging from ~100 °C to 40 °C [123]. The different temperatures were reponsible for changing the distribution of ‘pores, number, and size, im the membrane, resulting in more porous membranes when polymerized at lower temperatures, as shown in Fig. 58. In this drug-delivery system, the best release was found for mem- ‘branes polymerized at ~100 °C, with a higher pore density, releasing up to 77% of is content n 310. In another study of metronidazole longed into NRI, membranes polymerized at room temperature, the authors showed that metronidazole structural and spectroscope properties were retained even after its encapsulation into the NRL matrix, keeping ts antibacterial activity The drug release was prolonged fra longa 100 |nwith a bi-exponential function release (125 [NRL was also investigated for the release of sodium diclofenac (Dic- 1Na) (84) and potassium diclofenac (Die-K) (127), loaded into the polymeric matrix, and polymerized at room temperature. Both are non- Seroidal, antiinflammatory, and analgesic drugs indicated for the treatment of osteoarthritis, sheumatoid arthritis, inflammation, and pain relief fr postoperative and postraumatic cass. The Dic-Na release fred asa double exponential function, with characteristic times of0.9h and 32.1 b, releasing about 60% of the initial Di-Na during 74 h. On the other hand, Dick loaded membranes released only 20% ofits initial content after 9 days, Dick release kinetics was also b-exponential with slower characteristic times of 7 and 64 h. This considerable slow drug- release was associated with the compact NRL membrane and the mos release of Die fom the membrane surface. The presence of both deugs, as aggregates, on the NRL. membrane surface were accounted for as ‘responsible for the fastiniial release Gentamicin sulfate (6S), an aminoglycoside antibioie used for the teeatment of bacterial infections, was loaded into modified porous NRL ‘membranes, The NRL. membranes were modified by the addition of seanthan gum and triethyl citrate, acting as plasticizers (108), These compounds promoted the hydrophilicity ofthe membrane with a more porous character, releasing the GS in 7 days. This membrane demon- rated angiogenic activity and satisfactory activities against S. aureus and P. aeruginosa {108}. In another work [226], Gemeinder etal. sug- gested the use of GS loaded into NRL. membranes (NRIAGS) for the A Femtosecond Laser Maur Seene 8 gnering 61262021) 112125 PT) Fig 5. Methods vary pores size, volume, ane density NR. dressings to ron drug loading capacity and releasing kinetics. A) NRL membranes canbe merce ‘sing felaser methods to produce superficial pres wih high contr! in ems of density, diameter, volume, and sharpness. Scanning eleon microscopy images) 20 pares/em, 6000 pare/em’™. Adapted om (105), Copyigh (2020, with permision fom lever. B) NRL membranes can be fabric by feeze-cyin ‘metho, by employing diferent temperatres or varying hein water content, he pores and desily ca also be Lune. However, the laser method provides pores wih higher deity. Oa the other bid, treez-ying methods ean rode ports hat are deeper ad interconnected within the NAL self, SEN anges of NRL of membranes polymerized st (@) 20°C and Gi) 100°. Adapted from (12), Copyright 2010), under CC BY-NG 40. ‘treatment of skin ulcers infected with S. aureus and Escherichia coi. The (GS cease was studied in diferent solutions such asa buffer with pH5.7, and a physiological solution of NaCl at 0.9% (pH ~ 6:9). A greater solubility in aid ambiance was noticed through the release of 659 of GS Uup to 64 h, while in physiological solution it was released about 39% ‘long 39h, The NRL-GS membranes did not show hemolytic aetivity and did not change the GS sntimierobial activity against both bacterial sirains, Both works showed thatthe NRL-GS biomembrane has the po- tential to be employed in wound dressings. ‘A seudy on the release of nitric oxide (NO) [228] encapsulated by iron(l}-diethylithiocarbamate complex (FeDETC) in an NRL matrix ‘was presented by Herculano et al. NO is commonly used in wound healing and may play a key ole in patients with diabetes melitus with ‘impaired wound healings due to low NO production. The release ‘occurred over 300 h with the membrane exposed inthe air at 25 “Cand. {603 humiiry, and the rate of NO diffusion from the NRI-FeDETC membranes was measured by Electron Paramagnetic Resonance (EPR) and Fourier Transform Ineared (FTIR). The long release time and me- ‘chanical properties of the membrane indicated that NRL. would be an Interesting biomaterial fori situ delivery of NO for wound healing. Fluconazole was incorporated into the NRL. membranes to study the antifungal suscepubiliy against C.ebicans (171, responsible for st perfcial candidiasis on skin, nails, and vagina. The sustained release of this drug inhibited the growth of C. albicans, along 48 b, presenting promising charaterstis for application a transdermal patches. A burst release of about 30% of the fluconazole content has occurred during the first 10h, and about 15% was released along the remaining 38h ofthe ‘experiment ‘Voriconazole loaded into the NRL membranes was studied for the antifungal treatment of infected ulcers with C. parapllass (198) and. showed maintenance of the FTIR characteristics ofthe drug, no hemo- Iytic effect, and mechanical suitability for dermal application. The drug release resulted in two releasing steps: (i) che burst release of 13.2% of| ‘the initaly incorporated drug in 1h followed by i) slower release of an additional 11% of voriconazole upto 48 5 Patches of echanolic solution of lidocaine loaded into the NRL matrices were obtained with acceptable physicochemical properties for its employment as 2 drug-release system for the relief of acute pain [140], About 80% of the lidocaine content was released up to 24 hy ‘showing high stability although the storage ofthe membrane should be ‘made a low temperatures (T= 4 °C) to avoid loss of drug content fom, the membrane. ‘Morise et al. described a method to produce scopolamine butylbromideloaded NRL membranes [141]. The material was deve! ‘oped to be employed in salivary control in sialothea treatment. The [NRL membrence were capable of releasing about 20.2% of the inital ‘scopolamine content within the frst 24,2 maximum of 65.3% up to 72, fh. With high flexibility and elongation, and without hemolytic elects, ‘the biomembrane was considered a potential altemative forthe treat ment of sialorthea, as claimed by the authors. Differently, in thelr method to produce drug-loaded NRL membranes, the authors Rrstiy polymerized the NRL. membranes in the absence ofthe drug After that, a ‘washing step was performed to remove naturally occurring proteins from the matrix, which were interfering in drug release, according 10 additional FVIR bands observed when scopolamine was loaded before NAL polymerization (@ata not shown), Further, the drug was adsorbed ‘onto the NRL membranes by an immersion method. ‘In sit fms with nicotine loaded into deprotenized NRL acd hydroxypropylmedhylellulose (APMC) were produced by casting and letting the mixture get dried directly on th skin in less than 10 min. ‘With appropriate additives such as dibutyiphthalate, dibutylacacate, and glycerin, these flms presented adequate pH and viscosity to appl ‘ate on the skin (142,143), aiming to reduce smoking addiction as ts. readily absorbed through the skin. ‘Besides the drugs, metallic nanoparticles were alsa investigated for ‘controlled release for medical therapeutic purposes. Gold (Au) ‘nanoparticles (GNPs) loaded into NRL membranes have been studied to control the growth of Leishmania brazilensis [120], « parasite respon- sible for a disease of standard infectivity due to its high degree of Immunology specificity. The GNP5/NRL membranes demonstrated a reduction of promastgotes population growth rate, with high depen- ‘dence on the amount of GNPs into the membranes, Sliver nanoparticles (AgNPS) that present antibacterial activity against Vibrio cholera, E. cl, and Staplylecoceus, posibly de to blockage ofthe respiratory enaymne ‘pathways and alterations ofthe cell wall and microbial DNA, were also Toaded into NRL [121]. Different concentrations of AgNPs were studied ‘and showed that mos of the eleased NPs are exces not bounded to the ‘ivisoprene of the NRL. The angiogenic characteristics of NRL with the antibacterial properties ofthe AgNP are adequate to fabricate a wound dressing with potential healing action 43. Peptides ‘An carly work reported by Davis {145) presented the release of hormonal peptides by gels produced with different polymers such as polyacrylamide and polyvinyipyrolidone inside slieane rubber tubes. "The duration of peptides release was found tobe significantly longer in denser gels, presenting a logarithmic dependence on solute molecular ‘eight and implant polymer concentration [1s]. However, Langer and Folkman [105] affirmed these polymers present often inlammatory activity in animal tissues. The itl success in developing slow kinetic release systems or compounds with large molecular weight encouraged them to develop a method for Incorporating various proteins and other macromolecules into noninlammatory polymers, sch as Hydron-S nd ~Ehylene-vinylacexatecopolyner, for peciods higher than 100 days use tots advantages for biological aplication and biocompatibility, [NRL was proposed as delivery system fo several peptides and proteins. ‘Auempts of releasing the antimicrobial peptide [W6] lyin, a peptide that can increase the cell permeability by forming micro-holes on the cellular membrane conferring to it an antimicrobial activity, showed that it was degraded into new compounds by enzymes cysteine and serine proteases present in NRL [111-Inthe same study, a peptide with ‘shorter sequence (Ac-WAAAA) was evaluated and showed release with no degradation, in which the authors concluded tha the activity ofthe ‘enzymes present in the NRL depends on the amino acids inthe peptide. The incorporation of Bovine Serum Albumin (BSA) into the NRL membranes was investigated due to its bone-inductive activity to ‘aceelerate bone regeneration. The biomembrane showed that the morphology was controlled by the polymerization temperature with an increase of pore density at lower temperatures. Samples polymerized at ‘room temperature presented better performance releasing upto 66% of its protein content in 18 days (1). NRL loaded with BSA was also studied by Miranda et al. [126]. However, the authors used a different ‘method to fabricate the NRL membranes and control the density of pores Briefly, diferent volumes of water are added tothe NRL. solution, after freezedrying. The release kinetics was also dependent on the ‘porosity, presenting higher release rates for samples wit increased pore ‘densities, The samples di not show hemolytic effects or cytotoxicity in ‘experiments with eluate dilution from 40% to 80%, indicating no ef fects on the red blood cell membranes or cell viability. Using the same method described by Miranda eta. for NRL poly- merization, Bareos et a. [102], assessed the release mechanism of ‘oxytocin, @ hormonal peptide, with the function of promoting uterine ruscle contractions and reducing bleeding during childbirth, From SEM ‘and FTIR analyses it ws shown that the peptide was adsorbed into the NRL. membrane, within and on the membrane surface, with no changes inthe characteristic FTIR spectra for both materials, The release of 459 ‘of the oxytocin embedded into the membrane occurred along 10 h in ‘Phosphate-buffered saline solution. Moreover, quantified spectropho- tometry of the oxytocin-loaded NRI. membrane showed no hemolytic celfects in the erythrocytes, giving clues that this compound could effectively beused asa model to release peptides fr biological purposes. Mari Scene 8 gnering 126 a1) 122126 Barros etal. were also interested in solving the deficlency of an antid- ‘uretic peptide, arginine vasopressin (AVP). The AVP deficiency can be controlled by using desmopressin acetate (I-desamino-8-D-AVP), a synthetic AVP peptide. Thus, desmopressin peptide was loaded into the [NRL membranes and the release kinetes was assessed for up to 144 h Similarly tothe aforementioned works, the release of desmopressin from. the NRL membranes obeys a b-exponential function, showing two-step kinetics: (1) buts release, releasing 35% of incorporated desmopressin Lup to 2h; followed by Gi) stable peofile, from 35% at 2h 10 60% at 96h, dle co the desmopressin amount inside the NRL matex [10] 44, Plan extract, [NRL has also been studied forthe delivery of plant extracts with ‘medicinal properties. Borges et al. (12) assessed the release kinetics of| Suyphnodendron obovatum Bench. (popularly known as Barbatindo) extract loaded into the NRL. membranes, S, obovazum extract has ant- inflammatory and healing properties [132]. FTIR measurement shoved no new chemical bonds formed and that the NRL. obovanum extract interactions were only physical. SEM images showed the pres: tence ofthe extract ofS, obovanum a the surface of the NRL membrane, which may be the cause ofthe fst initial release, followed by a slower release. The release was related to Super-Case l, which allows a high rate of permeation through the NRI- matrix, occuring erosion, diffusion, relaxation, and swelling. Membranes loaded with 0.1 mg/ml. of '.obovatum extract released up t0 97% of its content in 7 days, while the membranes with 5.0 mg/m released less than 3% inthe same period. Corda verbenacea DC. from the Boraginaceae family, very common on the Brazilian coast, is commonly used fo teat topical inflammatory processes and is characterized as having antibacterial activity against coli and S. aureus stains (149). The combination ofthis extract with the NRL membranes shows no cell damage or cytotoxicity, as well as no ‘molecular interactions influencing the extrac’s chemical integrity 195]. The experimental release of the extract from the particular compact membrane released ess than 20% of its iital content in three days. Caseariasyvess Swartz, which presents antiinflammatory, anal ses, and antiseptic activity, was incorporated into the NRL membranes of different studies (112-114,134] to evaluate its release in aqueous solution a differen temperatures (25, 38, and 45°C) and buffer solution of NazHPOq/NallPO, with pH from 6.4 to 7.6. The release occurs in ‘oth solutions by a i-exponental function, with fst and est release from the surface followed by a slower release from the inner bulk of the ‘membrane by diffusion, The study showed that release in the aqueous solution at both temperatures of 38 °C and 45 °C are superior to at25 °C, but did not presenta significant difference between them. On the buffer solution, the alkaline pH (7-4 and 7.6) favored the higher release of ‘Another interesting natural product with biological activities such as antibacterial, and fungicidal is propolis. This resinous substance, collected and transformed by bees from parts of plant, has flavonoids responsible forthe biological activities [68,115]. Propolis of three differen types were integrated into the NRL membranes by Zancancla eal [115] which compared the potential antimicrobial of che propolis- loaded membrane agains C albicans. t was observed that red propolis compounds released theough the membrane showed an ighibitory ac- tivity as strong a that observed forthe pure red propolis extract (MIC of 78 ug/ml). These results showed that NRL-can potentialize the action of| the incorporated compound [122] and inhibit microbial growth 115-117) “The vegetable extract of Serjania marginata Casi, released from the INRL solid matrix and used as an antioxidant for chronie wounds, was investigated to evaluate is antioxidant activity against the free radical 2,2-diphenyl-1-pierylhydraryl (DPPH) [139]. AS diabetes disease is known to induce the production of free radicals, decreasing antioxidant capacity, which decreases the healing proces [139,150], the controled

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