Application of diffusion chambers for cell macroencapsulation: from concept to clinical trials (literature review)

Macroencapsulation of cells allows to isolate the donor biomaterial from the influence of the recipient’s organism. The degree of isolation can vary from mechanical isolation of donor cells within the implantation site to complete immune isolation of the transplanted biological material. The diffusion chamber was the first device used for macroencapsulation. The initial stage of research of this technique was aimed at expanding the range of cell and tissue implantation in allogenic and xenogenic models and clarifying the mechanisms underlying the graft rejection reaction. Later the design of the diffusion chamber underwent a number of changes that determined the modern application of the macroencapsulation method. The derivative of the diffusion chamber – the engineering chamber in complex with the arterio-venous shunt is used as a tissue modeling tool for creation of soft tissue flaps of different composition with the axial type of blood supply. An alternative design of the flow chamber allows the formation of soft tissue flaps on intact vessels. The engineering chamber is also used for growing various types of tissues and organ fragments (cardiac transverse striated muscle tissue, lymphoid tissue, fragments of liver, thymus, pancreas). A separate direction in studying the range of practical applications of the diffusion chamber is the development and testing of methods of transplantation of pancreatic islet cells into animals when creating allo- and xenogeneic experimental models for the treatment of diabetes mellitus. Some devices are already undergoing clinical trials and are available as a product for experimental studies.

1. Algire G.H., Weawer J.M., Prehn R.T. The diffusion chamber technique applied to the homograft resistance mechanisms. J. Natl. Cancer Inst. 1954;15(13):509–517.

2. Weawer J.M., Algire G.H., Prehn R.T. The growth of cells in vivo in diffusion chambers. II. The role of cells in the destruction of homografts in mice. J. Nat. Cancer Inst. 1955;15(16):1737–1767. URL: https://pubmed.ncbi.nlm.nih.gov/14381895/ (24.10.2024).

3. Algire G.H., Borders M.L., Evans V.J. Studies of heterografts in dif fusion chambers in mice get access arrow. J. Nat. Cancer Inst. 1958;20(6):1187–1201. DOI: 10.1093/jnci/20.6.1187.

4. Liu P., Wang W., Ma N., Li Y., Yang Z., Tang Y. Prefabrication vascularized skin flap using an arteriovenous loop prefabricated flap with arteriovenous loop: An experimental study in minipigs. J. Craniofac. Surg. 2023;34(3):255–259. DOI: 10.1097/SCS.0000000000009172.

5. Khojamuradov G.M., Shaimonov A.H., Ismoilov M.M., Saidov M.S. Reconstructive plastic surgery of long-term consequences of burns of the lower extremities. Bulletin of SurGU. Medicine. 2024;17(1):67–72. (In Russ.). DOI: 10.35266/2949-3447-2024-1-10.

6. Chen H., Mudunov A.M., Azizian R.I., Pustynskiy I.N., Stelmah D.K. Oral cancer reconstructive surgery using the free radial forearm flap (review). Head and Neck Tumors (HNT). 2020;10(2):61–68. (In Russ.). DOI: 10.17650/2222-1468-2020-10-2-61-68.

7. Sharapo A.S., Ivashkov V.Yu., Mudunov А.М. et al. The results of using free osteomyofascial flaps in the simultaneous reconstruction of combined post-resection facial defects with an intraoral component. Head and Neck Tumors (HNT). 2020;10(2):22–29. (In Russ.). DOI: 10.17650/2222-1468-2020-10-2-22-29.

8. Qiao Z., Wang X., Li Q., Zan T., Gu B., Sun Y. Total face reconstruction with flap prefabrication and soft tissue expansion techniques. Plastic & Reconstructive Surgery. 2024;153(4):928–932. DOI: 10.1097/PRS.0000000000010808.

9. Zhan W., Marre D., Mitchell G.M., Morrison W.A., Lim S.Y. Tissue engineering by intrinsic vascularization in an in vivo tissue engineering chamber. J. Vis. Exp. 2016;(111):1–7. DOI: 10.3791/54099.

10. Yap K.K., Yeoh G.C., Morrison W.A., Mitchell G.M. The vascularised chamber as an in vivo bioreactor. Trends Biotechnol. 2018;36(10):1011– 1024. DOI: 10.3791/54099.

11. Lobanova N.Yu., Chicherina E.N., Malchikova S.V., Maksimchuk-Kolobova N.C. Shear stress on the endothelium of the carotid artery wall and calcification of the coronary arteries in patients with hypertension. The South Russian Journal of Therapeutic Practice. 2022;3(3):60–67. (In Russ.). DOI: 10.21886/2712-8156-2022-3-3-60-67.

12. Rosenfeld D., Landau S., Shandalov Y., Raindel N., Freiman A., Shor E. et al. Morphogenesis of 3D vascular networks is regulated by tensile forces. Proc. Natl. Acad. Sci. 2016;113(12):3215–3220. DOI: 10.1073/pnas.1522273113.

13. Dorland Y.L., Huveneers S. Cell-cell junctional mechanotransduction in endothelial remodeling. Cell. Mol. Life Sci. 2017;74(2):279–292. DOI: 10.1007/s00018-016-2325-8.

14. Yuan Q., Arkudas A., Horch R.E., Hammon M., Bleiziffer O., Uder M. Vascularization of the arteriovenous loop in a rat isolation chamber model-quantification of hypoxia and evaluation of its effects. Tissue Eng. 2017;24(9–10):719–728. DOI: 10.1089/ten.TEA.2017.0262.

15. Hauser P.V., Zhao L., Chang H.M., Yanagawa N., Hamon M. In vivo vascularization chamber for the implantation of embryonic kidneys. Tissue Eng. Part C Methods. 2024;30(2):63–72. DOI: 10.1089/ten. TEC.2023.0225.

16. Kong A.M., Yap K.K., Lim S.Y., Marre D., Pébay A., Gerrand Y.W. et al. Bioengineering a tissue flap utilizing a porous scaffold incorporating a human induced pluripotent stem cell-derived endothelial cell capillary network connected to a vascular pedicle. Acta Biomaterialia. 2019;94:281–294. DOI: 10.1016/j.actbio.2019.05.067.

17. Weigand A., Horch R.E., Boos A.M., Beier J.P., Arkudas A. The arteriovenous loop: Engineering of axially vascularized tissue. Eur. Surg. Res. 2018;59(3–4):286–299. DOI: 10.1159/000492417.

18. Yurova K.A., Melashchenko E.S., Khaziakhmatova O.G., Malashchenko V.V., Melashchenko O.B., Shunkin E.O. Mesenchymal stem cells: a brief overview of classical concepts and new factors of osteogenic differentiation. Medical Immunology. 2021;23(2):207–222. (In Russ.). DOI: 10.15789/1563-0625-MSC-2128.

19. Eweida A.M., Nabawi A.S., Abouarab M., Kayed M., Elhammady H., Etaby A. et al. Enhancing mandibular bone regeneration and perfusion via axial vascularization of scaffolds. Clin. Oral. Invest. 2014;18(6):1671– 1678. DOI: 10.1007/s00784-013-1143-8.

20. Arkudas A., Lipp A., Buehrer G., Arnold I., Dafinova D., Brandl A., Beier J.P. et al. Pedicled transplantation of axially vascularized bone constructs in a critical size femoral defect. Tissue Eng. 2018;24(5–6):479– 492. DOI: 10.1089/ten.TEA.2017.0110.

21. Boos A.M., Loew J.S., Weigand A., Deschler G., Klumpp D., Arkudas A. et al. Engineering axially vascularized bone in the sheep arteriovenousloop model. J. Tissue Eng. Regen. Med. 2013;7:654–664. DOI: 10.1002/term.1457.

22. Kim H.Y., Lee J.H., Lee H.A.R., Park J.S., Woo D.K., Lee H.C. et al. Sustained release of BMP-2 from porous particles with leaf-stacked structure for bone regeneration. ACS Appl. Mater Interfaces. 2018;10(25):21091– 21102. DOI: 10.1021/acsami.8b02141.

23. Eweida A., Schulte M., Frisch O., Kneser U., Harhaus L. The impact of various scaffold components on vascularized bone constructs. J. Craniomaxillofac. Surg. 2017;45(6):881–890. DOI: 10.1016/j.jcms.2017.02.016.

24. Buehrer G., Balzer A., Arnold I., Beier J.P., Koerner C., Bleiziffer O. et al. Combination of BMP2 and MSCs significantly increases bone formation in the rat arterio-venous loop model. Tissue Eng. 2015;21(1–2):96–105. DOI: 10.1089/ten.TEA.2014.0028.

25. Messina A., Bortolotto S.K., Cassell O.C, Kelly J., Abberton K.M., Morrison W.A. Generation of a vascularized organoid using skeletal muscle as the inductive source. FASEB J. 2005;19(11):1570–1572. DOI: 10.1096/fj.04-3241fje.

26. Witt R., Weigand A., Boos A.M., Cai A., Dippold D., Boccaccini A.R. et al. Mesenchymal stem cells and myoblast differentiation under HGF and IGF-1 stimulation for 3D skeletal muscle tissue engineering. BMC Cell. Biol. 2017;18(1):15–31. DOI: 10.1186/s12860-017-0131-2.

27. Dippold D., Cai A., Hardt M., Boccaccini A.R., Horch R., Beier J.P. Novel approach towards aligned PCL-collagen nanofibrous constructs from a benign solvent system. Mater. Sci. Eng. C Mater. Biol. Appl. 2017;72:278–283. DOI: 10.1016/j.msec.2016.11.045.

28. Tee R., Morrison W.A., Dilley R.J. A novel microsurgical rodent model for the transplantation of engineered cardiac muscle flap. Microsurgery. 2018;38(5):544–552. DOI: 10.1002/micr.30325.

29. Hussey A.J., Winardi M., Han X.L., Thomas G.P., Penington A.J., Morrison W.A. et al. Seeding of pancreatic islets into prevascularized tissue engineering chambers. Tissue Eng. 2009;15(12):823–833. DOI: 10.1089/ten.TEA.2008.0682.

30. Tilkorn D.J., Bedogni A., Keramidaris E., Han X., Palmer J.A., Dingle A.M. et al. Implanted myoblast survival is dependent on the degree of vascularization in a novel delayed implantation/prevascularization tissue engineering model. Tissue Eng. 2010;16(1):165–170. DOI: 10.1089/ten.TEA.2009.0075.

31. Ludwig B., Ludwig S. Transplantable bioartificial pancreas devices: current status and future prospects. Langenbecks Arch. Surg. 2015;400(5):531–540. DOI: 10.1007/s00423-015-1314-y.

32. Bellofatto K., Moeckli B., Wassmer C.H., Laurent M., Oldani G., Andres A. et al. Bioengineered islet cell transplantation. Curr. Transpl. 2021;8:57–66. DOI: 10.1007/s40472-021-00318-1.

33. Hoosain J., Hamad E. Adverse effects of immunosuppression: nephrotoxicity, hypertension, and metabolic disease. Handb. Exp. Pharmacol. 2022;272:337–348. DOI: 10.1007/164_2021_547.

34. Qin T., Smink A.M., de Vos P. Enhancing longevity of immunoisolated pancreatic islet grafts by modifying both the intracapsular and extracapsular environment. Acta Biomater. 2023;167:38–53. DOI: 10.1016/j.actbio.2023.06.038.

35. Song S., Roy S. Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices. Biotechnol. Bioeng. 2016;113(7):1381–1402. DOI: 10.1002/bit.25895.

36. Lamb M., Storrs R., Li S., Liang O., Laugenour K., Dorian R. et al. Function and viability of human islets encapsulated in alginate sheets: in vitro and in vivo culture. Transplant. Proc. 2011;43(9):3265–3266. DOI: 10.1016/j.transproceed.2011.10.028.

37. Iwata H., Arima Y., Tsutsui Y. Design of bioartificial pancreases from the standpoint of oxygen supply. Artificial Organs. 2018;42(8):168–185. DOI: 10.1111/aor.13106.

38. O’Sullivan E.S., Vegas A., Anderson D.G., Weir G.C. Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain. Endocr. Rev. 2011;32(6):827–844. DOI: 10.1210/er.2010-0026.

39. Shapiro A.M.J., Thompson D., Donner T.W., Bellin M.D., Hsueh W., Pettus J. et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep. Med. 2021;2(12):1–14. DOI: 10.1016/j.xcrm.2021.100466.

40. Barkai U., Weir G.C., Colton C.K., Ludwig B., Bornstein S.R., Brendel M.D. et al. Enhanced Oxygen Supply Improves Islet Viability in a New Bioartificial Pancreas Uriel. Cell Transplant. 2013;22(8):1463– 1476. DOI: 10.3727/096368912X657341.

41. Carlsson P.O., Espes D., Sedigh A., Rotem A., Zimerman B., Grinberg H. et al. Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. Am. J. Transplant. 2018;18(7):1735–1744. DOI: 10.1111/ajt.14642.

42. An D., Wang L.H., Ernst A.U., Chiu A., Lu Y.C., Flanders J.A. et al. An atmosphere-breathing refillable biphasic device for cell replacement therapy. Advanced Materials. 2019;31(52):1–12. DOI: 10.1002/adma.201905135.

43. Groot Nibbelink M., Skrzypek K., Karbaat L., Both S., Plass J., Klomphaar B. et al. An important step towards a prevascularized islet microencapsulation device: in vivo prevascularization by combination of mesenchymal stem cells on micropatterned membranes. J. Sci. Mater. Med. 2018;29(11):174–184. DOI: 10.1007/s10856-018-6178-6.

44. Skrzypek K., Nibbelink M.G., Karbaat L.P., Karperien M., van Apeldoorn A., Stamatialis D. An important step towards a prevascularized islet macroencapsulation device-effect of micropatterned membranes on development of endothelial cell network. J. Mater. Sci. Mater. Med. 2018;29(7):91–105. DOI: 10.1007/s10856-018-6102-0.

45. Lee J.H., Parthiban P., Jin G.Z., Knowles J.C., Kim H.W. Knowles materials roles for promoting angiogenesis in tissue regeneration. Prog. Mater. Sci. 2021;117:1007–1032. DOI: 10.1016/j.pmatsci.2020.100732.

46. Liu Q., Wang X., Chiu A., Liu W., Fuchs S., Wang B. et al. A zwitterionic polyurethane nanoporous device with low foreign-body response for islet encapsulation. Adv. Mater. 2021;33(39):1–25. DOI: 10.1002/adma.202102852.

47. Tan R.P., Chan A.H.P., Wei S., Santos M., Lee B.S.L., Filipe E.C. et al. Bioactive materials facilitating targeted local modulation of inflammation. JACC Basic Transl. Sci. 2019;4(1):56–71. DOI: 10.1016/j.jacbts.2018.10.004.

48. Tan R.P., Hallahan N., Kosobrodova E., Michael P.L., Wei F., Santos M. et al. Bioactivation of encapsulation membranes reduces fibrosis and enhances cell survival. ACS Appl. Mater. Interfaces. 2020;12(51):56908– 56923. DOI: 10.1021/acsami.0c20096.

49. Qin T., Smink A.M., de Vos P. Enhancing longevity of immunoisolated pancreatic islet grafts by modifying both the intracapsular and extracapsular environment. Acta Biomater. 2023;167:38–53. DOI: 10.1016/j.actbio.2023.06.038.