The Foreign Body Response to an Implantable Therapeutic Reservoir in a Diabetic Rodent Model
Publication: Tissue Engineering Part C: Methods
Volume 27, Issue Number 10
Abstract
Advancements in type 1 diabetes mellitus treatments have vastly improved in recent years. The move toward a bioartificial pancreas and other fully implantable systems could help restore patient's glycemic control. However, the long-term success of implantable medical devices is often hindered by the foreign body response. Fibrous encapsulation “walls off” the implant to the surrounding tissue, impairing its functionality. In this study we aim to examine how streptozotocin-induced diabetes affects fibrous capsule formation and composition surrounding implantable drug delivery devices following subcutaneous implantation in a rodent model. After 2 weeks of implantation, the fibrous capsule surrounding the devices were examined by means of Raman spectroscopy, micro-computed tomography (μCT), and histological analysis. Results revealed no change in mean fibrotic capsule thickness between diabetic and healthy animals as measured by μCT. Macrophage numbers (CCR7 and CD163 positive) remained similar across all groups. True component analysis also showed no quantitative difference in the alpha-smooth muscle actin and extracellular matrix proteins. Although principal component analysis revealed significant secondary structural difference in collagen I in the diabetic group, no evidence indicates an influence on fibrous capsule composition surrounding the device. This study confirms that diabetes did not have an effect on the fibrous capsule thickness or composition surrounding our implantable drug delivery device.
Impact Statement
Understanding the impact diabetes has on the foreign body response (FBR) to our implanted material is essential for developing an effective drug delivery device. We used several approaches (Raman spectroscopy and micro-computed tomography imaging) to demonstrate a well-rounded understanding of the diabetic impact on the FBR to our devices, which is imperative for its clinical translation.
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References
1. Yu, J., Wang, J., Zhang, Y., et al. Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs. Nat Biomed Eng 4, 499, 2020.
2. Vantyghem, M., Koning, E.J.P., De, Pattou, F., and Rickels, M.R. Series type 1 diabetes advances in β-cell replacement therapy for the treatment of type 1 diabetes 6736, 2019. [Epub ahead of print];.
3. Rogal, J., Zbinden, A., Schenke-Layland, K., and Loskill, P. Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 140, 101, 2018.
4. Allen, N., and Gupta, A. Current diabetes technology: striving for the artificial pancreas. Diagnostics 9, 31, 2019.
5. Morais, J.M., Papadimitrakopoulos, F., and Burgess, D.J. Biomaterials/tissue interactions: possible solutions to overcome foreign body response. AAPS J 12, 188, 2010.
6. Major, M.R., Wong, V.W., Nelson, E.R., Longaker, M.T., and Gurtner, G.C. The foreign body response: at the interface of surgery and bioengineering. Plast Reconstr Surg 135, 1489, 2015.
7. Dolan, E.B., Varela, C.E., Mendez, K., et al. An actuatable soft reservoir modulates host foreign body response. Soft Robot 4, 7043, 2019.
8. Goswami, D., Domingo-Lopez, D.A., Ward, N.A., et al. Design considerations for macroencapsulation devices for stem cell derived islets for the treatment of type 1 diabetes. Adv Sci (Weinheim, Baden-Wurttemberg, Ger) 8, e2100820, 2021.
9. Oviedo-Socarrás, T., Vasconcelos, A.C., Barbosa, I.X., Pereira, N.B., Campos, P.P., and Andrade, S.P. Diabetes alters inflammation, angiogenesis, and fibrogenesis in intraperitoneal implants in rats. Microvasc Res 93, 23, 2014.
10. Barrientos, S., Stojadinovic, O., Golinko, M.S., Brem, H., and Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen 16, 585, 2008.
11. Guo, S., and DiPietro, L.A. Critical review in oral biology & medicine: factors affecting wound healing. J Dent Res 89, 219, 2010.
12. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 366, 1736, 2005.
13. Baltzis, D., Eleftheriadou, I., and Veves, A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther 31, 817, 2014.
14. Broadley, K.N., Aquino, A.M., Hicks, B., et al. The diabetic rat as an impaired wound healing model: stimulatory effects of transforming growth factor-beta and basic fibroblast growth factor. Biotechnol Ther 1, 55, 1989.
15. Seifter, E., Rettura, G., Padawer, J., Stratford, F., Kambosos, D., and Levenson, S.M. Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A. Ann Surg 194, 42, 1981.
16. Norris, S.O., Provo, B., and Stotts, N.A. Physiology of wound healing and risk factors that impede the healing process. AACN Adv Crit Care 1, 545, 1990.
17. Kim, Y.K., Chen, E.Y., and Liu, W.F. Biomolecular strategies to modulate the macrophage response to implanted materials. J Mater Chem B 4, 1600, 2016.
18. Papadimitrakopoulos, F., and Burgess, D.J. A review of the biocompatibility of implantable devices: current challenges to overcome foreign body response. J Diabetes Sci Technol 2, 1003, 2008.
19. Sheikh, Z., Brooks, P.J., Barzilay, O., Fine, N., and Glogauer, M. Macrophages, foreign body giant cells and their response to implantable biomaterials. Materials (Basel) 8, 5671, 2015.
20. Oviedo Socarrás, T., Vasconcelos, A.C., Campos, P.P., Pereira, N.B., Souza JPC, and Andrade, S.P. Foreign body response to subcutaneous implants in diabetic rats. PLoS One 9, e110945, 2014.
21. Siqueira, M.F., Li, J., Chehab, L., et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-α dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia 53, 378, 2010.
22. Rai, N.K., Suryabhan, Ansari, M., Kumar, M., Shukla, V.K., and Tripathi, K. Effect of glycaemic control on apoptosis in diabetic wounds. J Wound Care 14, 277, 2005.
23. Le, N.N., Rose, M.B., Levinson, H., and Klitzman, B. Implant healing in experimental animal models of diabetes. J Diabetes Sci Technol 5, 605, 2011.
24. Maruyama, K., Asai, J., Ii, M., Thorne, T., Losordo, D.W., and D'Amore, P.A. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 170, 1178, 2007.
25. Gibran, N.S., Jang, Y.C., Isik, F.F., et al. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J Surg Res 108, 122, 2002.
26. Kharbikar, B.N., Chendke, G.S., and Desai, T.A. Modulating the foreign body response of implants for diabetes treatment. Adv Drug Deliv Rev 2021. [Epub ahead of print];.
27. Ramírez-Elías, M.G., Kolosovas-Machuca, E.S., Kershenobich, D., Guzmán, C., Escobedo, G., and González, F.J. Evaluation of liver fibrosis using Raman spectroscopy and infrared thermography: a pilot study. Photodiagnosis Photodyn Ther 19, 278, 2017.
28. Griffiths, J. Raman spectroscopy for medical diagnosis. Anal Chem 79, 3975, 2007.
29. Pence, I. Mahadevan-Jansen A. Clinical instrumentation and applications of Raman spectroscopy. Chem Soc Rev 45, 1958, 2016.
30. Mieczkowski, M., Rakowska, B.M., Siwko, T., et al. Insulin, but not metformin, supports wound healing process in rats with streptozotocin-induced diabetes. Diabetes Metab Syndr Obes Targets Ther 14, 1505, 2021.
31. Goodson, W.H., and Hunt, T.K. Studies of wound healing in experimental diabetes mellitus. J Surg Res 22, 221, 1977.
32. Srivastava, L.M., Bora, P.S., and Bhatt, S.D. Diabetogenic action of streptozotocin. Trends Pharmacol Sci 3(C), 376, 1982.
33. Dolan, E.B., Hofmann, B., de Vaal, M.H., et al. A bioresorbable biomaterial carrier and passive stabilization device to improve heart function post-myocardial infarction. Mater Sci Eng C 103, 109751, 2019.
34. Coulter, F.B., Levey, R.E., Robinson, S.T., et al. Additive manufacturing of multi-scale porous soft tissue implants that encourage vascularization and tissue ingrowth. Adv Healthc Mater 10, 2100229, 2021.
35. Rezakhaniha, R., Agianniotis, A., Schrauwen, J.T.C., et al. Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech Model Mechanobiol 11, 461, 2012.
36. You, A.Y.F., Bergholt, M.S., and St-Pierre, J.-P., et al. Raman spectroscopy imaging reveals interplay between atherosclerosis and medial calcification in the human aorta. Sci Adv 3, e1701156, 2021.
37. Cárcamo, J.J., Aliaga, A.E., Clavijo, R.E., Brañes, M.R., and Campos-Vallette, M.M. Raman study of the shockwave effect on collagens. Spectrochim Acta Part A Mol Biomol Spectrosc 86, 360, 2012.
38. Biermann, A.C., Marzi, J., Brauchle, E., et al. Improved long-term durability of allogeneic heart valves in the orthotopic sheep model. Eur J Cardiothorac Surg 55, 484, 2019.
39. Marzi, J., Brauchle, E.M., Schenke-Layland, K., and Rolle, M.W. Non-invasive functional molecular phenotyping of human smooth muscle cells utilized in cardiovascular tissue engineering. Acta Biomater 89, 193, 2019.
40. Zbinden, A., Marzi, J., Schlünder, K., et al. Non-invasive marker-independent high content analysis of a microphysiological human pancreas-on-a-chip model. Matrix Biol 85–86, 205, 2020.
41. Song, Y., Li, L., Zhao, W., et al. Surface modification of electrospun fibers with mechano-growth factor for mitigating the foreign-body reaction. Bioact Mater 6, 2983, 2021.
42. Yang, J., Zhu, Y., Duan, D., et al. Enhanced activity of macrophage M1/M2 phenotypes in periodontitis. Arch Oral Biol 96, 234, 2018.
43. Jiang, G., Li, S., Yu, K., et al. A 3D-printed PRP-GelMA hydrogel promotes osteochondral regeneration through M2 macrophage polarization in a rabbit model. Acta Biomater 128, 150, 2021.
44. Jan N-J, Grimm, J.L., Tran, H., et al. Polarization microscopy for characterizing fiber orientation of ocular tissues. Biomed Opt Express 6, 4705, 2015.
45. Arun Gopinathan, P., Kokila, G., Siddeeqh, S., Prakash, R., and Pradeep, L. Reexploring picrosirius red: a review. Indian J Pathol Oncol 7, 196, 2020.
46. Shinde, A.V., Humeres, C., and Frangogiannis, N.G. The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta Mol Basis Dis 1863, 298, 2017.
47. Cutolo, M., Ruaro, B., Montagna, P., et al. Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts. Arthritis Res Ther 20, 1, 2018.
48. Karayi, A.K., Basavaraj, V., Narahari, S.R., Aggithaya, M.G., Ryan, T.J., and Pilankatta, R. Human skin fibrosis: up-regulation of collagen type III gene transcription in the fibrotic skin nodules of lower limb lymphoedema. Trop Med Int Health 25, 319, 2020.
49. Unal, M., Jung, H., and Akkus, O. Novel Raman spectroscopic biomarkers indicate that postyield damage denatures bone's collagen. J Bone Miner Res 31, 1015, 2016.
50. Talari, A.C.S., Movasaghi, Z., Rehman, S., and Rehman, I.U. Raman spectroscopy of biological tissues. Appl Spectrosc Rev 50, 46, 2015.
51. Perrone, A., Giovino, A., Benny, J., and Martinelli, F. Advanced glycation end products (AGEs): biochemistry, signaling, analytical methods, and epigenetic effects. Oxid Med Cell Longev 2020. [Epub ahead of print];.
52. Araromi, O.A., Graule, M.A., Dorsey, K.L., et al. Ultra-sensitive and resilient compliant strain gauges for soft machines. Nature 587, 219, 2020.
53. Smuđ-Orehovec, S., Mance, M., Halužan D, Vrbanović-Mijatović, V., and Mijatović, D. Defect reconstruction of an infected diabetic foot using split- and full-thickness skin grafts with adjuvant negative pressure wound therapy: a case report and review of the literature. Wounds Compend Clin Res Pract 30, E108, 2018.
54. McMurry, J.F. Wound healing with diabetes mellitus. Better glucose control for better wound healing in diabetes. Surg Clin North Am 64, 769, 1984.
55. Covington, D.S., Xue, H., Pizzini, R., Lally, K.P., and Andrassy, R.J. Streptozotocin and alloxan are comparable agents in the diabetic model of impaired wound healing. Diabetes Res 23, 47, 1993.
56. Soto, R.J., Merricks, E.P., Bellinger, D.A., Nichols, T.C., and Schoenfisch, M.H. Influence of diabetes on the foreign body response to nitric oxide-releasing implants. Biomaterials 157, 76, 2018.
57. Schaper, N.C., Apelqvist, J., and Bakker, K. Reducing lower leg Amputations in diabetes: a challenge for patients, healthcare providers and the healthcare system. Diabetologia 55, 1869, 2012.
58. Berbudi, A., Rahmadika, N., Tjahjadi, A.I., and Ruslami, R. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev 16, 442, 2019.
59. Fahey, T.J., 3rd, Sadaty, A., Jones, W.G., 2nd, Barber, A., Smoller, B., and Shires, G.T. Diabetes impairs the late inflammatory response to wound healing. J Surg Res 50, 308, 1991.
60. Matlaga, B.F., Yasenchak, L.P., and Salthouse, T.N. Tissue response to implanted polymers: the significance of sample shape. J Biomed Mater Res 10, 391, 1976.
61. Veiseh, O., Doloff, J.C., Ma, M., et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater 14, 643, 2015.
62. O'Brien, E.M., Risser, G.E., and Spiller, K.L. Sequential drug delivery to modulate macrophage behavior and enhance implant integration. Adv Drug Deliv Rev 149–150, 85, 2019.
63. Witherel, C.E., Sao, K., Brisson, B.K., et al. Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages. Biomaterials 269, 120667, 2021.
64. Wu, X., Zhao, X., Puertollano, R., Bonifacino, J.S., and Eisenberg, E.G.L.E. Adaptor and clathrin exchange at the plasma membrane andtrans-golgi network. Mol Biol Cell 14, 516, 2003.
65. Karsdal, M.A., Nielsen, S.H., Leeming, D.J., et al. The good and the bad collagens of fibrosis—their role in signaling and organ function. Adv Drug Deliv Rev 121, 43, 2017.
66. Clore, J.N., Cohen, I.K., and Diegelmann, R.F. Quantitation of collagen types I and III during wound healing in rat skin. Proc Soc Exp Biol Med 161, 337, 1979.
67. Liu, X., Wu, H., Byrne, M., Krane, S., and Jaenisch, R. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A 94, 1852, 1997.
68. Khan, N., Bakshi, K.S., Jaggi, A.S., and Singh, N. Ameliorative potential of spironolactone in diabetes induced hyperalgesia in mice. Yakugaku Zasshi 129, 593, 2009.
69. Hudson, D.M., Archer, M., King, K.B., and Eyre, D.R. Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J Biol Chem 293, 15620, 2018.
70. Glenn J V., Beattie, J.R., Barrett, L., et al. Confocal Raman microscopy can quantify advanced glycation end product (AGE) modifications in Bruch's membrane leading to accurate, nondestructive prediction of ocular aging. FASEB J 21, 3542, 2007.
71. Téllez, S.C.A. Confocal Raman spectroscopic analysis of the changes in type I collagen resulting from amide I glycation. Biomed J Sci Tech Res 1, 629, 2017.
72. Alsamad, F., Brunel, B., Vuiblet, V., Gillery, P., Jaisson, S., and Piot, O. In depth investigation of collagen non-enzymatic glycation by Raman spectroscopy. Spectrochim Acta Part A Mol Biomol Spectrosc 251, 119382, 2021.
73. Asadipooya, K., and Uy, E.M. Advanced glycation end products (AGEs), receptor for ages, diabetes, and bone: review of the literature. J Endocr Soc 3, 1799, 2019.
74. Bierhaus, A., Humpert, P.M., Morcos, M., et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 83, 876, 2005.
75. Wautier, M.P., Chappey, O., Corda, S., Stern, D.M., Schmidt, A.M., and Wautier, J.L. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280, E685, 2001.
76. Vegas, A.J., Veiseh, O., Gürtler, M., et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22, 306, 2016.
Information & Authors
Information
Published In
Tissue Engineering Part C: Methods
Volume 27 • Issue Number 10 • October 2021
Pages: 515 - 528
PubMed: 34541880
Copyright
Copyright 2021, Mary Ann Liebert, Inc., publishers.
History
Published online: 15 October 2021
Published in print: October 2021
Published ahead of production: 19 September 2021
Accepted: 13 September 2021
Received: 25 August 2021
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Disclosure Statement
No competing financial interests exist.
Funding Information
K.S.-L., G.P.D., and C.L. acknowledge funding from the DELIVER project which has received funding from the European Union's Horizon 2020 framework programme under grant agreement ID 812865. G.P.D. and R.E.L. acknowledge funding from the DRIVE project, which received funding from the European Union's Horizon 2020 framework programme under grant agreement ID 645991. R.B. and G.P.D. acknowledge funding from Science Foundation Ireland's (SFI) AMBER centre through their PhD program with grant number SFI/12/RC/2278. R.B. would like to acknowledge funding from the College of Medicine, Nursing and Health Sciences (CMNHS), NUI Galway under a co-funded PhD program with grant number RSF1591. K.S.-L. and C.L. would like to acknowledge funding from the Deutsche Forschungsgemeinschaft, under grant number INST 2388/64-1, Germany's Excellence Strategy, under grant number EXC 2180-390900677, the Ministry of Science, Research, and the Arts of Baden-Wuerttemberg, under grant number 33-729.55-3/214 and SI-BW 01222-91, and the State Ministry of Baden-Wuerttemberg for Economic Affairs, Labour and Housing Construction.
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