Physics:Thiomer

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Thiolated polymers – designated thiomers – are functional polymers used in biotechnology product development with the intention to prolong mucosal drug residence time and to enhance absorption of drugs. The name thiomer was coined by Andreas Bernkop-Schnürch in 2000.[1] Thiomers have thiol bearing side chains.[2][3] Sulfhydryl ligands of low molecular mass are covalently bound to a polymeric backbone consisting of mainly biodegradable polymers, such as chitosan,[4][5] hyaluronic acid,[6] cellulose derivatives,[7] pullulan,[8][9] starch,[10] gelatin,[11] polyacrylates,[12] cyclodextrins,[13][14] or silicones.[15] Thiomers exhibit properties potentially useful for non-invasive drug delivery via oral, ocular, nasal, vesical, buccal and vaginal routes. Thiomers show also potential in the field of tissue engineering and regenerative medicine. Various thiomers such as thiolated chitosan[16] and thiolated hyaluronic acid[17] are commercialy available as scaffold materials. Thiomers can be directly compressed to tablets or given as solutions.[18][19] In 2012, a second generation of thiomers – called "preactivated" or "S-protected" thiomers – were introduced.[20]

In contrast to thiomers of the first generation, preactivated thiomers are stable towards oxidation and display comparatively higher mucoadhesive and permeation enhancing properties.[21] Approved thiomer products for human use are for example eyedrops for treatment of dry eye syndrome or adhesive gels for treatment of nickel allergy.[22]

Properties and applications

Thiomers crosslink via inter- and intrachain disulfide bonding, form disulfide bonds with thiol substructures of endogenous proteins such as mucins and keratins and bind metals (Me)

Mucoadhesion

Thiomers are capable of forming disulfide bonds with cysteine substructures of the mucus gel layer covering mucosal membranes. Because of this property they exhibit up to 100-fold higher mucoadhesive properties in comparison to the corresponding unthiolated polymers.[23][24][25] Because of their mucoadhesive properties, thiolated polymers are an effective tool in the treatment of diseases such as dry eye, dry mouth, and dry vagina syndrome where dry mucosal surfaces are involved.[26][27][28]

In situ gelation

Various polymers such as poloxamers exhibit in situ gelling properties. Because of these properties they can be administered as liquid formulations forming stable gels once having reached their site of application. An unintended rapid elimination or outflow of the formulation from mucosal membranes such as the ocular, nasal or vaginal mucosa can therefore be avoided. Thiolated polymers are capable of providing a comparatively more pronounced increase in viscosity after application, as an extensive crosslinking process by the formation of disulfide bonds between the polymer chains due to oxidation takes place. This effect was first described in 1999 by Bernkop-Schnürch et al.[29] for polymeric excipients. In case of thiolated chitosan, for instance, a more than 10,000-fold increase in viscosity within a few minutes was shown.[30] These high in situ gelling properties can also be used for numerous further reasons such as for parenteral formulations,[31] as coating material[32] or for food additives[33]

Controlled drug release

Due to a sustained drug release, a prolonged therapeutic level of drugs exhibiting a short elimination half-life can be maintained. Consequently the frequency of dosing can be reduced contributing to an improved compliance. The release of drugs out of polymeric carrier systems can be controlled by a simple diffusion process. So far the efficacy of such delivery systems, however, was limited by a too rapid disintegration and/or erosion of the polymeric network.[34] By using thiolated polymers this essential shortcoming can be overcome. Because of the formation of inter- and intrachain disulfide bonds during the swelling process, the stability of the polymeric drug carrier matrix is strongly improved. Hence, a controlled drug release for numerous hours is guaranteed. There are numerous drug delivery systems making use of this technology.[35][36][37][38][39][40]

Enzyme inhibition

Due to the binding of metal ions being essential for various enzymes to maintain their enzymatic activity, thiomers are potent reversible enzyme inhibitors. Many non-invasively administered drugs such as therapeutic peptides or nucleic acids are degraded on the mucosa by membrane bound enzymes strongly reducing their bioavailability. In case of oral administration this ‘enzymatic barrier’ is even more pronounced as an additional degradation caused by luminally secreted enzymes takes place. Because of their capability to bind zinc ions via thiol groups, thiomers are potent inhibitors of most membrane bound and secreted zinc-dependent enzymes. Due to this enzyme inhibitory effect, thiolated polymers can significantly improve the bioavailability of non-invasively administered drugs[41][42][43]

Antimicrobial activity

In vitro, thiomers were shown to have antimicrobial activity towards Gram-positive bacteria.[44][45] In particular, N-acyl thiolated chitosans show great potential as highly efficient, biocompatible and cost-effective antimicrobial compounds.[46] Metabolism and mechanistic studies are under way to optimize these thiomers for clinical applications. Because of their antimicrobial activity, thiolated polymers are also used as coatings that avoid bacterial adhesion.[47]

Permeation enhancement

Thiomers are able to reversibly open tight junctions. The responsible mechanism seems to be based on the inhibition of protein tyrosine phosphatase being involved in the closing process of tight junctions.[48] Due to thiolation the permeation enhancing effect of polymers such as polyacrylic acid or chitosan can be up to 10-fold improved.[49][50][51] In comparison to most low molecular weight permeation enhancers, thiolated polymers offer the advantage of not being absorbed from the mucosal membrane. Hence, their permeation enhancing effect can be maintained for a comparatively longer period of time and systemic toxic side effects of the auxiliary agent can be excluded.

Efflux pump inhibition

Thiomers are able to reversibly inhibit efflux pumps. Because of this property the mucosal uptake of various efflux pump substrates such as anticancer drugs, antimycotic drugs and antiinflammatory drugs can be tremendously improved.[52][53][54] The postulated mechanism of efflux pump inhibition is based on an interaction of thiolated polymers with the channel forming transmembrane domain of various efflux pumps such as P-gp and multidrug resistance proteins (MRPs). P-gp, for instance, exhibits 12 transmembrane regions forming a channel through which substrates are transported outside of the cell. Two of these transmembrane domains – namely 2 and 11 – exhibit on position 137 and 956, respectively, a cysteine subunit. Thiomers seem to enter in the channel of P-gp and likely form subsequently one or two disulfide bonds with one or both cysteine subunits located within the channel. Due to this covalent interaction the allosteric change of the transporter being essential to move drugs outside of the cell might be blocked.[55][56]

Complexation of metal ions

Thiomers have the ability to form complexes with different metal ions, especially divalent metal ions, due to their thiol groups. Thiolated chitosans, for instance, were shown to effectively absorb nickel ions.[57][58]

Tissue engineering and regenerative medicine

As thiolated polymers exhibit biocompatibility, cellular mimicking properties and efficiently support proliferation and differentiation of various cell types, they are used as scaffolds for tissue engineering.[59][60][61][62] Furthermore thiolated polymers such as thiolated hyaluronic acid[63] and thiolated chitosan[64] were shown to exhibit wound healing properties.

References

  1. ↑ Bernkop-Schnürch, A; Scholler, S; Biebel, RG (2000). "Development of controlled drug release systems based on polymer-cysteine conjugates". J. Control. Release 66 (1): 39–47. doi:10.1016/S0168-3659(99)00256-4. PMID 10708877. 
  2. ↑ Bernkop-Schnürch, Andreas; Schwarz, Veronika; Steininger, Sonja (1999). "Polymers with Thiol Groups: A New Generation of Mucoadhesive Polymers". Pharm. Res. 16 (11): 876–881. doi:10.1016/j.addr.2005.07.002. PMID 16176846. 
  3. ↑ Bernkop-Schnürch, Andreas; Steininger, Sonja (2000). "Synthesis and characterisation of mucoadhesive thiolated polymers". Int. J. Pharm. 194 (2): 239–247. doi:10.1016/S0378-5173(99)00387-7. PMID 10692648. 
  4. ↑ Bernkop-Schnürch, A; Hornof, M; Guggi, D (2004). "Thiolated chitosans". Eur. J. Pharm. Biopharm. 57 (1): 9–17. doi:10.1016/S0939-6411(03)00147-4. PMID 14729077. 
  5. ↑ Zhang, Z; Lin, S; Yan, Y; You, X; Ye, H (2021). "Enhanced efficacy of transforming growth factor-β1 loaded an injectable cross-linked thiolated chitosan and carboxymethyl cellulose-based hydrogels for cartilage tissue engineering". J Biomater Sci Polym ed 32 (18): 2402–2422. doi:10.1080/09205063.2021.1971823. PMID 34428384. 
  6. ↑ Zheng Shu, X; Liu, Y; Palumbo, FS; Luo, Y; Prestwich, GD (2004). "In situ crosslinkable hyaluronan hydrogels for tissue engineering". Biomaterials 7–8 (7–8): 1339–1348. doi:10.1016/j.biomaterials.2003.08.014. PMID 14643608. 
  7. ↑ Laffleur, F; Bacher, L; Vanicek, S; Menzel, C; Muhammad, I (2016). "Next generation of buccadhesive excipient: Preactivated carboxymethyl cellulose". Int J Pharm 500 (1–2): 120–127. doi:10.1016/j.ijpharm.2016.01.012. PMID 26773600. 
  8. ↑ Leonaviciute, G; Suchaoin, W; Matuszczak, B; Lam, HT; Mahmood, A; Bernkop-Schnürch, A (2016). "Preactivated thiolated pullulan as a versatile excipient for mucosal drug targeting". Carbohydr Polym 151: 743–751. doi:10.1016/j.carbpol.2016.06.005. PMID 27474621. 
  9. ↑ Priya, SS; Rekha, MR (2016). "Disulphide cross linked pullulan based cationic polymer for improved gene delivery and efflux pump inhibition". Colloids Surf B Biointerfaces 146: 879–887. doi:10.1016/j.colsurfb.2016.07.013. PMID 27459414. 
  10. ↑ Jelkmann, M; Bonengel, S; Menzel, C; Markovic, S; Bernkop-Schnürch, A (2018). "New perspectives of starch: Synthesis and in vitro assessment of novel thiolated mucoadhesive derivatives". Int J Pharm 546 (1–2): 70–77. doi:10.1016/j.ijpharm.2018.05.028. PMID 29758345. 
  11. ↑ Duggan, S; O'Donovan, O; Owens, E; Cummins, W; Hughes, H (2015). "Synthesis of mucoadhesive thiolated gelatin using a two-step reaction process". Eur. J. Pharm. Biopharm. 91: 75–81. doi:10.1016/j.ejpb.2015.01.027. PMID 25661588. 
  12. ↑ Hornof, M; Weyenberg, W; Ludwig, A; Bernkop-Schnürch, A (2003). "Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans". J. Control. Release 89 (3): 419–428. doi:10.1016/S0168-3659(03)00135-4. PMID 12737844. 
  13. ↑ Ijaz, M; Ahmad, M; Akhtar, N; Laffleur, F; Bernkop-Schnürch, A (2016). "Thiolated α-cyclodextrin: the invisible choice to prolong ocular drug residence time". J. Pharm. Sci. 105 (9): 2848–2854. doi:10.1016/j.xphs.2016.04.021. PMID 27233687. 
  14. ↑ Ijaz, M; Prantl, M; Lupo, N; Laffleur, F; Hussain Asim, M; Matuszczak, B; Bernkop-Schnürch, A (2017). "Development of pre-activated α-cyclodextrin as a mucoadhesive excipient for intra-vesical drug delivery". Int. J. Pharm. 534 (1–2): 339–347. doi:10.1016/j.ijpharm.2017.10.054. PMID 29111098. 
  15. ↑ Partenhauser, A; Laffleur, F; Rohrer, J; Bernkop-Schnürch, A (2015). "Thiolated silicone oil: synthesis, gelling and mucoadhesive properties". Acta Biomater. 16: 169–177. doi:10.1016/j.actbio.2015.01.020. PMID 25660565. 
  16. ↑ Federer, C; Kurpiers, M; Bernkop-Schnürch, A (2021). "Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications". Biomacromolecules 22 (1): 24–56. doi:10.1021/acs.biomac.0c00663. PMID 32567846. 
  17. ↑ Griesser, J; Hetényi, G; Bernkop-Schnürch, A (2018). "Thiolated Hyaluronic Acid as Versatile Mucoadhesive Polymer: From the Chemistry Behind to Product Developments-What Are the Capabilities?". Polymers 10 (3): 243. doi:10.3390/polym10030243. PMID 30966278. 
  18. ↑ Grosso, R; de-Paz, MV (2021). "Thiolated-Polymer-Based Nanoparticles as an Avant-Garde Approach for Anticancer Therapies-Reviewing Thiomers from Chitosan and Hyaluronic Acid". Pharmaceutics 13 (6): 854. doi:10.3390/pharmaceutics13060854. PMID 34201403. 
  19. ↑ Hock, N; Racaniello, GF; Aspinall, S; Denora, N; Khutoryanskiy, V; Bernkop-Schnürch, A (2022). "Thiolated Nanoparticles for Biomedical Applications: Mimicking the Workhorses of our Body". Adv Sci (Weinh) 9 (1): 2102451. doi:10.1002/advs.202102451. PMID 34773391. 
  20. ↑ Iqbal, J; Shahnaz, G; Dünnhaupt, S; Müller, C; Hintzen, F; Bernkop-Schnürch, A (2012). "Preactivated thiomers as mucoadhesive polymers for drug delivery". Biomaterials 33 (5): 1528–1535. doi:10.1016/j.biomaterials.2011.10.021. PMID 22118819. 
  21. ↑ Ijaz, M; Bernkop-Schnürch, A (2015). "Preactivated thiomers: their role in drug delivery". Expert Opin Drug Deliv 12 (8): 1269–1281. doi:10.1517/17425247.2015.1005598. PMID 25604394. 
  22. ↑ Federer, C; Kurpiers, M; Bernkop-Schnürch, A (2021). "Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications". Biomacromolecules 22 (1): 24–56. doi:10.1021/acs.biomac.0c00663. PMID 32567846. 
  23. ↑ Grabovac, V; Guggi, D; Bernkop-Schnürch, A (2005). "Comparison of the mucoadhesive properties of various polymers". Adv. Drug Deliv. Rev. 57 (11): 1713–1723. doi:10.1016/j.addr.2005.07.006. PMID 16183163. 
  24. ↑ Bernkop-Schnürch, A; Kast, CE; Richter, MF (2001). "Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine". J. Control. Release 71 (3): 277–285. doi:10.1016/S0168-3659(01)00227-9. PMID 11295220. 
  25. ↑ Zahir-Jouzdani, F; Mahbod, M; Soleimani, M; Vakhshiteh, F; Arefian, E; Shahosseini, S; Dinarvand, R; Atyabi, F (2018). "Chitosan and thiolated chitosan: Novel therapeutic approach for preventing corneal haze after chemical injuries". Carbohydr. Polym. 179: 42–49. doi:10.1016/j.carbpol.2017.09.062. PMID 29111069. 
  26. ↑ Partenhauser, A; Bernkop-Schnürch, A (2016). "Mucoadhesive polymers in the treatment of dry X syndrome". Drug Discovery Today 21 (7): 1051–62. doi:10.1016/j.drudis.2016.02.013. PMID 26944445. 
  27. ↑ Schmidl, D; Werkmeister, R; Kaya, S; Unterhuber, A; Witkowska, KJ; Baumgartner, R; Höller, S; O’Rourke, M et al. (2017). "A controlled, randomized double-blind study to evaluate the safety and efficacy of chitosan-N-acetylcysteine for the treatment of dry eye syndrome". J. Ocul. Pharmacol. Ther. 33 (5): 375–382. doi:10.1089/jop.2016.0123. PMID 28441068. 
  28. ↑ Bielory, L; Wagle, P (2017). "Ocular surface lubricants". Curr. Opin. Allergy Clin. Immunol. 17 (5): 382–389. doi:10.1097/ACI.0000000000000392. PMID 28796122. 
  29. ↑ Bernkop-Schnürch, Andreas; Schwarz, Veronika; Steininger, Sonja (1999). "Polymers with Thiol Groups: A New Generation of Mucoadhesive Polymers". Pharm. Res. 16 (6): 876–881. doi:10.1023/A:1018830204170. PMID 10397608. 
  30. ↑ Sakloetsakun, D; Hombach, JM; Bernkop-Schnürch, A (2009). "In situ gelling properties of chitosan-thioglycolic acid conjugate in the presence of oxidizing agents". Biomaterials 30 (31): 6151–6157. doi:10.1016/j.biomaterials.2009.07.060. PMID 19699516. 
  31. ↑ Du, H; Hamilton, P; Reilly, M; Ravi, N (2012). "Injectable in situ physically and chemically crosslinkable gellan hydrogel". Macromol. Biosci. 12 (7): 952–961. doi:10.1002/mabi.201100422. PMID 22707249. 
  32. ↑ Zhao, W; Kong, M; Feng, C; Cheng, X; Liu, Y; Chen, X (2016). "Investigation of gelling behavior of thiolated chitosan in alkaline condition and its application in stent coating". Carbohydr. Polym. 136: 307–315. doi:10.1016/j.carbpol.2015.09.049. PMID 26572360. 
  33. ↑ Chen, J; Ye, F; Zhou, Y; Zhao, G (2018). "Thiolated citrus low-methoxyl pectin: Synthesis, characterization and rheological and oxidation-responsive gelling properties". Carbohydr. Polym. 181: 964–973. doi:10.1016/j.carbpol.2017.11.053. PMID 29254061. 
  34. ↑ Bernkop-Schnürch, A; Scholler, S; Biebel, RG (2000). "Development of controlled drug release systems based on polymer-cysteine conjugates". J. Control. Release 66 (1): 39–47. doi:10.1016/S0168-3659(99)00256-4. PMID 10708877. 
  35. ↑ Huang, J; Xue, Y; Cai, N; Zhang, H; Wen, K; Luo, X; Long, S; Yu, F (2015). "Efficient reduction and pH co-triggered DOX-loaded magnetic nanogel carrier using disulfide crosslinking". Mater. Sci. Eng. C 46: 41–51. doi:10.1016/j.msec.2014.10.003. PMID 25491958. 
  36. ↑ Mishra, BJ; Kaul, A; Trivedi, P (2015). "L-Cysteine conjugated poly L-lactide nanoparticles containing 5-fluorouracil: formulation, characterization, release and uptake by tissues in vivo". Drug Deliv. 22 (2): 214–222. doi:10.3109/10717544.2014.883117. PMID 24524408. 
  37. ↑ Moreno, M; Pow, PY; Tabitha, TST; Nirmal, S; Larsson, A; Radhakrishnan, K; Nirmal, J; Quah, ST et al. (2017). "Modulating release of ranibizumab and aflibercept from thiolated chitosan-based hydrogels for potential treatment of ocular neovascularization". Expert Opin. Drug Deliv. 14 (8): 913–925. doi:10.1080/17425247.2017.1343297. PMID 28643528. 
  38. ↑ Chen, Y; liu, X; Liu, R; Gong, Y; Wang, M; Huang, Q; Feng, Q; Yu, B (2017). "Zero-order controlled release of BMP2-derived peptide P24 from the chitosan scaffold by chemical grafting modification technique for promotion of osteogenesis in vitro and enhancement of bone repair in vivo". Theranostics 7 (5): 1072–1087. doi:10.7150/thno.18193. PMID 28435449. 
  39. ↑ Ning, P; Lü, S; Bai, X; Wu, X; Gao, C; Wen, N; Liu, M (2018). "High encapsulation and localized delivery of curcumin from an injectable hydrogel". Mater. Sci. Eng. C 83: 121–129. doi:10.1016/j.msec.2017.11.022. PMID 29208269. 
  40. ↑ Arif, M; Dong, QJ; Raja, MA; Zeenat, S; Chi, Z; Liu, CG (2018). "Development of novel pH-sensitive thiolated chitosan/PMLA nanoparticles for amoxicillin delivery to treat Helicobacter pylori". Mater. Sci. Eng. C 83: 17–24. doi:10.1016/j.msec.2017.08.038. PMID 29208276. 
  41. ↑ Valenta, C; Marschütz, M; Egyed, C; Bernkop-Schnürch, A (2002). "Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH". J. Pharm. Pharmacol. 54 (5): 603–610. doi:10.1211/0022357021778907. PMID 12005354. 
  42. ↑ Bernkop-Schnürch, A; Walker, G; Zarti, H (2001). "Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase N". J. Pharm. Sci. 90 (11): 1907–1914. doi:10.1002/jps.1140. PMID 11745748. 
  43. ↑ Bernkop-schnürch, A; Krauland, AH; Leitner, VM; Palmberger, T (2004). "Thiomers: potential excipients for non-invasive peptide delivery systems". Eur. J. Pharm. Biopharm. 58 (2): 253–263. doi:10.1016/j.ejpb.2004.03.032. PMID 15296953. 
  44. ↑ Fernandes, MM; Francesko, A; Torrent-Burgues, J; Tzanov, T (2013). "Effect of thiol-functionalisation on chitosan antibacterial activity: Interaction with a bacterial membrane model". React. Funct. Polym. 73 (10): 1384–1390. doi:10.1016/j.reactfunctpolym.2013.01.004. 
  45. ↑ Geisberger, G; Gyenge, EB; Hinger, D; Käch, A; Maake, C; Patzke, GR (2013). "Chitosan-thioglycolic acid as a versatile antimicrobial agent". Biomacromolecules 14 (4): 1010–1017. doi:10.1021/bm3018593. PMID 23470196. 
  46. ↑ Croce, M; Conti, S; Maake, C; Patzke, GR (2016). "Synthesis and screening of N-acyl thiolated chitosans for antibacterial applications". Carbohydr. Polym. 151: 1184–1192. doi:10.1016/j.carbpol.2016.06.014. PMID 27474669. 
  47. ↑ Costa, F; Sousa, DM; Parreira, P; Lamghari, M; Gomes, P; Martins, MCL (2017). "N-acetylcysteine-functionalized coating avoids bacterial adhesion and biofilm formation". Sci. Rep. 7 (1): 17374. doi:10.1038/s41598-017-17310-4. PMID 29234086. Bibcode: 2017NatSR...717374C. 
  48. ↑ Clausen, AE; Kast, CE; Bernkop-Schnürch, A (2002). "The role of glutathione in the permeation enhancing effect of thiolated polymers". Pharm. Res. 19 (5): 602–608. doi:10.1023/A:1015345827091. PMID 12069161. 
  49. ↑ Bernkop-Schnürch, A; Kast, CE; Guggi, D (2003). "Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems". J. Control. Release 93 (2): 103–110. doi:10.1016/j.jconrel.2003.05.001. PMID 14636716. 
  50. ↑ Langoth, N; Kalbe, J; Bernkop-Schnürch, A (2005). "Development of a mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary adenylate cyclase-activating polypeptide)". Int. J. Pharm. 296 (1–2): 103–111. doi:10.1016/j.ijpharm.2005.03.007. PMID 15885461. 
  51. ↑ Liu, Y; Chiu, GN (2013). "Dual-functionalized PAMAM dendrimers with improved P-glycoprotein inhibition and tight junction modulating effect". Biomacromolecules 14 (12): 4226–4235. doi:10.1021/bm401057c. PMID 24219381. 
  52. ↑ Werle, M; Hoffer, M (2006). "Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine". J. Control. Release 111 (1–2): 41–46. doi:10.1016/j.jconrel.2005.11.011. PMID 16377016. 
  53. ↑ Föger, F; Hoyer, H; Kafedjiiski, K; Thaurer, M; Bernkop-Schnürch, A (2006). "In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein". Biomaterials 27 (34): 5855–5860. doi:10.1016/j.biomaterials.2006.08.004. PMID 16919723. 
  54. ↑ Madgulkar, AR; Bhalekar, MR; Kadam, AA (2017). "Improvement of oral bioavailability of lopinavir without co-administration of ritonavir using microspheres of thiolated xyloglucan". AAPS PharmSciTech 17 (1): 293–302. doi:10.1208/s12249-017-0834-x. PMID 28717974. 
  55. ↑ Gottesman, MM; Pastan, I (1988). "The multidrug transporter, a double-edged sword". J. Biol. Chem. 263 (25): 12163–6. doi:10.1016/S0021-9258(18)37730-5. PMID 2900833. 
  56. ↑ Grabovac, V; Laffleur, F; Bernkop-Schnürch, A (2015). "Thiomers: Influence of molecular mass and thiol group content of poly(acrylic acid) on efflux pump inhibition". Int. J. Pharm. 493 (1–2): 374–379. doi:10.1016/j.ijpharm.2015.05.079. PMID 26238816. 
  57. ↑ Federer, C; Kurpiers, M; Bernkop-Schnürch, A (2021). "Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications". Biomacromolecules 22 (1): 24–56. doi:10.1021/acs.biomac.0c00663. PMID 32567846. 
  58. ↑ Leichner, C; Jelkmann, M; Bernkop-Schnürch, A (2019). "Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature". Adv Drug Deliv Rev 151-152: 191–221. doi:10.1016/j.addr.2019.04.007. PMID 31028759. 
  59. ↑ Kast, CE; Fric, W; Losert, U; Bernkop-Schnürch, A (2003). "Chitosan-thioglycolic acid conjugate: a new scaffold material for tissue engineering?". Int. J. Pharm. 256 (1–2): 183–189. doi:10.1016/S0378-5173(03)00076-0. PMID 12695025. 
  60. ↑ Bae, IH; Jeong, BC; Kook, MS; Kim, SH; Koh, JT (2013). "Evaluation of a thiolated chitosan scaffold for local delivery of BMP-2 for osteogenic differentiation and ectopic bone formation". Biomed Res. Int. 2013: 878930. doi:10.1155/2013/878930. PMID 24024213. 
  61. ↑ Bian, S; He, M; Sui, J; Cai, H; Sun, Y; Liang, J; Fan, Y; Zhang, X (2016). "The self-crosslinking smart hyaluronic acid hydrogels as injectable three-dimensional scaffolds for cells culture". Colloids Surf. B Biointerfaces 140: 392–402. doi:10.1016/j.colsurfb.2016.01.008. PMID 26780252. 
  62. ↑ Gajendiran, M; Rhee, JS; Kim, K (2017). "Recent developments in thiolated polymeric hydrogels for tissue engineering applications". Tissue Eng. Part B Rev. 24 (1): 66–74. doi:10.1089/ten.TEB.2016.0442. PMID 28726576. 
  63. ↑ Bauer, C; Jeyakumar, V; Niculescu-Morzsa, E; Kern, D; Nehrer, S (2017). "Hyaluronan thiomer gel/matrix mediated healing of articular cartilage defects in New Zealand White rabbits-a pilot study". J. Exp. Orthop. 4 (1): 14. doi:10.1186/s40634-017-0089-1. PMID 28470629. 
  64. ↑ Zahir-Jouzdani, F; Mahbod, M; Soleimani, M; Vakhshiteh, F; Arefian, E; Shahosseini, S; Dinarvand, R; Atyabi, F (2018). "Chitosan and thiolated chitosan: Novel therapeutic approach for preventing corneal haze after chemical injuries". Carbohydr. Polym. 179: 42–49. doi:10.1016/j.carbpol.2017.09.062. PMID 29111069. 



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