Philip V. PeplowIntroduction
Animal models have been developed for many human diseases including cardiovascular, respiratory, hepatic, renal, ophthalmic, metabolic, neurologic, neurodegenerative, neuropsychiatric, inflammatory, and infectious diseases or conditions. Their use has proved crucial in developing treatments for a large number of human diseases and testing implantable devices. While a single animal model may not show all the main pathophysiological changes in different human diseases, they are the most valuable tool for studying treatment strategies prior to performing clinical trials. Cell culture and molecular biology studies are used to support the findings from the use of animal models. Selective breeding, genetic modification, and advances in molecular imaging provide a better understanding of disease processes and insights into possible new interventions. There are several areas in which future research using animal models could make an important contribution to understanding disease processes and possible new treatment strategies.
Use of nanoparticles
Incorporation of therapeutic molecules into nanoparticles may be suitable for the treatment of neurodegenerative diseases and brain injury (1). Animal models of Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic stroke, amyotrophic lateral sclerosis, traumatic brain injury, multiple sclerosis, epilepsy have been developed (2–8) and could be used to test the effect of administering nanoparticles intravascularly or directly into the brain. The nanoparticles could be loaded with therapeutic agents such as neurotrophins (e.g., neurotrophin 3, brain-derived neurotrophic factor) and growth factors (9), cerium oxide or made of graphene (10), or be used as magneto-electric nanoparticles (11). The latter can be subjected to ac-magnetic field stimulation and cause stimulation of neurons in regions of the brain that the nanoparticles are guided to. It has the potential for deep brain stimulation in animal models of Parkinson's disease. In neurodegenerative diseases, passage of nanoparticles through the blood-brain barrier is facilitated due to damage occurring to the blood-brain barrier (12, 13). Nanoparticles have been used for the treatment of cancer (14, 15), liver fibrosis (16), and diabetes (17). Mouse, rat, and monkey models have been developed for many neurodegenerative diseases, and for example magnetically guided delivery of magneto-electric nanoparticles was tested in the brains of mice and their distribution to different cell types (11).
Use of bioactive scaffolds
Incorporation of therapeutic molecules into mini scaffolds to form bioactive scaffolds can be used for the treatment of neurodegenerative diseases, multiple sclerosis, epilepsy, traumatic brain injury, stroke (18), skin regeneration (19), cartilage/bone repair (20–22), cardiac repair (23), and soft tissue repair (24). Metal nanoparticles-based scaffolds have been used for bone tissue regeneration (25). Studies on skin regeneration may be performed using small or large laboratory animals (e.g., mouse, piglet), while cartilage/bone repair can be examined using large laboratory animals (e.g., dog, sheep). In a recent review of biomaterial and tissue engineering strategies for the treatment of brain neurodegeneration (26), a wide variety of biomaterials had been used including nanoparticles, carbon nanotubes for cell engraftment, microspheres and microscale scaffolds, functionalized composite scaffolds, self-assembling peptides as scaffolds, and micro-tissue engineered neural constructs, and were tested in mouse and rat models. In vitro studies involving measurement of neural aggregate + axon length, and in vivo studies examining neurorestorative effects of biomaterial and tissue-engineered constructs using animal models of traumatic brain injury or Parkinson's disease have been reported. Alginate fibres have recently received attention as a possible treatment modality of amyotrophic lateral sclerosis. Alginate fibres cross-linked with strontium and loaded with methylene blue can enhance the survival of motor neurons (27). Also, in vitro models of traumatic brain injury can be used to test therapeutic materials. Monocultures of cortical neurons can be established, and an injury created using a pipette tip or needle. Complex in vitro systems have been developed such as a mixed glial/polyglial culture system in which astrocytes, oligodendrocytes and microglia are present in reproducible ratios. This model is suited to studying glial responses to therapeutic materials. The model has evolved to include the neuronal population alongside multiple glial cells and has been used to study delivery of nanoparticles to the injury site (28).
Use of liposomes
Liposomes are nanosized vesicles consisting of a phospholipid bilayer membrane enclosing an aqueous compartment. The structure of the lipid bilayer membrane enables liposomes to immobilize both hydrophilic drugs in their aqueous core and hydrophobic drugs within the lipid bilayer, and they have great potential as smart drug delivery systems (SDDSs). They are highly biocompatible, biodegradable, and non-toxic to the body. In addition, they have high drug loading capacity and high solubility in water and blood. Incorporation of chemotherapeutic drugs into liposomes that can be injected into the vascular system and can be released upon breakdown of the liposomes by ultrasound/laser irradiation (29–31) has been used in treating tumors, and several successful liposomal formulations for cancer treatment are currently available (30). Upon injection into the bloodstream, serum proteins (called opsonin proteins) bind to the surfaces of liposomes, making them susceptible to phagocytic attack and removing them from the blood circulation and lowering their accumulation at targeted diseased sites. By coating liposomes with hydrophilic molecules such as polyethylene glycol, the adsorption of opsonin proteins on their surface is reduced, thus protecting them from phagocytic attack, increasing their circulation times to more than a day, delivering the entrapped chemotherapeutics at the targeted tumor sites, and decreasing cytotoxic effects on normal cells. Liposomes carrying therapeutic drugs have the potential to treat heart conditions (e.g., angina, coronary artery disease caused by atherosclerosis), kidney disease, and liver disease. Liposomes can cross the blood-brain barrier using receptor-mediated transcytosis (32) and could be used to treat neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) (33) for which animal models have been developed (2–8). Liposome nanoparticles conjugated with lactoferrin to deliver neuronal growth factors across the blood-brain barrier had a protective effect against amyloid beta-induced neurotoxicity in vitro (34). A magnetic (Fe3O4-nimodipine) liposomal delivery system was developed by modifying nimodipine with polyethylene glycol-coated Fe3O4. In a rat model of Parkinson's disease, enhanced protection of dopaminergic neurons was observed by reducing the neurotoxicity through nimodipine incorporated in liposomes (35).
Use of stimuli-responsive carriers
Many important food bioactive compounds have applications in health promotion and disease prevention. However, these compounds have low chemical stability and bioavailability. Recently there has been a major research effort to develop advanced delivery systems of natural bioactive molecules. Stimuli-responsive carriers have potential for improving delivery and release of intact bioactive phytochemicals to target sites in response to certain stimuli or combinations of them (e.g., pH, temperature, oxidant, enzyme, irradiation), thereby increasing therapeutic outcomes and reducing side effects (36). Hybrid formulations (e.g., organic-inorganic complexes) and multi-stimuli responsive formulations have been investigated for smart-delivery of food bioactive compounds such as quercetin, curcumin, resveratrol. In the extracellular tissues of many solid tumors the pH is around 6.5 while in healthy tissues it is 7.4–7.5. The use of certain polymers whose conformation or solubility properties are altered under particular pH conditions would result in fast nutrachemical release at a specific site. In these carriers, the pH-sensitive polymers with functional groups (e.g., carboxylic acids, amines) can act as proton donors or acceptors in response to changes in environmental pH. Protonation of polymers in acidic conditions causes structural deformation and alteration in hydrophobicity of the polymers, thereby enhancing the release of the encapsulated compounds. Other approaches involve the application of acid-labile linkages or polymers, ionizable chemical groups, and gas-generating precursors (37). A possible application could be to deliver pH-sensitive polymers to the stomach to treat gastric disease. Stimuli-responsive nanogels or hydrogel nanoparticles have application in cancer therapy, delivery of antiviral drugs, delivery of vaccines, and treatment of diabetes (38). Such systems recognize either internal physiological cues (e.g., pH, temperature, redox e.g., glutathione) (36) or respond to externally applied stimuli (e.g., temperature, magnetic fields, photons, ultrasound waves). These stimuli-responsive nanogels have an internal hydrophilic nature for drug and biomolecule encapsulation, enhanced stability for blood circulation, and controlled release of the loaded drug or biomolecule.
Use of colon-targeted drug delivery systems (smart pellets)
Colonic drug delivery systems have been used to treat intestinal diseases such as colorectal carcinoma, ulcerative colitis, diverticulitis, Crohn's disease, and irritable bowel syndrome. By reducing unwanted adsorption in other regions of the gastrointestinal tract and ensuring that the whole drug dose is specifically delivered to the colon, colon-specific drug delivery improves therapeutic effectiveness. Most colon-targeted drug delivery systems are either responsive to the pH of the colon or to enzymes produced by intestinal microbiota. Smart pellets have been developed for controlled delivery of drugs to the gastrointestinal tract, e.g., 5-fluorouracil to treat colorectal carcinoma. Polymer-based formulations were based on hydroxyethyl methacrylate copolymerized with methacrylic acid. The system was optimized to deliver 5-fluorouracil to the colon by preventing/delaying the release of 5-fluorouracil within the first 5–6 h following oral administration to ensure drug arrival to the colonic region. This enhances therapeutic outcome, reduces dosing and undesirable side effects, and increases patient compliance. Six drug-loaded formulations were produced with a drug entrapment efficiency of approximately 91% in the formulations. Less than 27% total drug release occurred for all formulations after 5 h in the in vitro release study, and the highest total release after 24 h was 69% (39). In vivo studies of smart pellets for administering drugs to the colon have been performed in rats and rabbits.
Use of smart pills and ingestible sensors
Smart pills can be used to monitor patients with chronic diseases such as heart disease, gastrointestinal disorders, and diabetes, during surgeries, in critical care settings, or in studying physical responses during physical activities such as sports performance (40). Smart pills can also be used for drug delivery. A microchip sensor in the pill monitors the effectiveness of the drug and alters the dosage to ensure the optimal amount is taken for the condition being treated. This can decrease side effects and improve treatment outcomes. Smart pills have the potential to reduce healthcare costs (41). Ingestible sensors or smart pills have been developed for the imaging of esophagus/stomach/small intestine (as a gastrointestinal tract diagnostic tool), sensing different types of gases to provide metabolic and digestive information, monitoring medication compliance or absorption of medication (e.g., in schizophrenia patients), and electrochemical signal sensing (on stools as a gastrointestinal tract diagnostic tool) (42, 43). Animal models that have been used for studying gastrointestinal disease include mice, rats, guinea-pigs, dogs, pigs (44–46).
This Speciality Grand Challenge is a personal opinion of some of the new treatment modalities that can be explored using animal models of disease. More details on the applications are available in the cited references and may include the animal models that have been used. Other important challenges are included in the mission and scope of this section, which aims through the use of animal models to improve patient health outcomes.
Author contributions
PP: Writing – original draft.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Asefy Z, Hoseinnejhad S, Ceferov Z. Nanoparticles approaches in neurodegenerative diseases diagnosis and treatment. Neurol Sci. (2021) 42:2653–60. doi: 10.1007/s10072-021-05234-x
2. Martinez B, Peplow PV. Immunomodulators and microRNAs as neurorestorative therapy for ischemic stroke. Neural Regen Res. (2017) 12:865–74. doi: 10.4103/1673-5374.198975
3. Martinez B, Peplow PV. Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease. Neural Regen Res. (2018) 13:1493–506. doi: 10.4103/1673-5374.237108
4. Martinez B, Peplow PV. Amelioration of Alzheimer’s disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer’s disease. Neural Regen Res. (2019) 14:1158–76. doi: 10.4103/1673-5374.262572
5. Martinez B, Peplow PV. MicroRNAs as disease progression biomarkers and therapeutic targets in experimental autoimmune encephalomyelitis model of multiple sclerosis. Neural Regen Res. (2020) 15:1831–7. doi: 10.4103/1673-5374.280307
6. Martinez B, Peplow PV. Altered microRNA expression in animal models of Huntington’s disease and potential therapeutic strategies. Neural Regen Res. (2021) 16:2159–69. doi: 10.4103/1673-5374.310673
7. Martinez B, Peplow PV. MicroRNA expression in animal models of amyotrophic lateral sclerosis and potential therapeutic approaches. Neural Regen Res. (2022) 17:728–40. doi: 10.4103/1673-5374.330603
8. Martinez B, Peplow PV. MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets. Neural Regen Res. (2023) 18:2108–211. doi: 10.4103/1673-5374.344830
9. Mahato AK, Saarma M. Neurotrophic factors in Parkinson’s disease: clinical trials. In: Peplow PV, Martinez B, Gennarelli TA, editors. Regenerative Medicine and Brain Repair. USA: Springer (in press). p. 109–37.
10. Kotha S, Sripama M, Tyson J, Li A, He W, Mao X. Emerging nanotechnology for the treatment and diagnosis of Parkinson’s disease (PD) and Alzheimer’s disease (AD). In: Peplow PV, Martinez B, Gennarelli TA, editors. Regenerative Medicine and Brain Repair. USA: Springer (in press). p. 139–74.
11. Kujawska M, Kaushik A. Exploring magneto-electric nanoparticles (MENPs): a platform for implanted deep brain stimulation. Neural Regen Res. (2023) 18:129–30. doi: 10.4103/1673-5374.340411
12. Teleanu DM, Chircov C, Grumezescu AM, Volceanov A, Teleanu RI. Blood-brain delivery methods using nanotechnology. Pharmaceutics. (2018) 10:269. doi: 10.3390/pharmaceutics10040269
13. Hersh AM, Alomari S, Tyler BM. Crossing the blood-brain barrier: advances in nanoparticle technology for drug delivery in neuro-oncology. Int J Mol Sci. (2022) 23:4153. doi: 10.3390/ijms23084153
14. Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, et al. Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resistance. Front Mol Biosci. (2020) 7:193. doi: 10.3389/fmolb.2020.00193
15. Yusuf A, Almotairy ARZ, Henidi H, Alshehri OY, Aldughaim MS. Nanoparticles as drug delivery systems: a review of the implication of nanoparticles’ physicochemical properties on responses in biological systems. Polymers (Basel). (2023) 15:1596. doi: 10.3390/polym15071596
16. Poilil Surendran S, George Thomas R, Moon MJ, Jeong YY. Nanoparticles for the treatment of liver fibrosis. Int J Nanomedicine. (2017) 12:6997–7006. doi: 10.2147/IJN.S145951
17. Liu Y, Zeng S, Ji W, Yao H, Lin L, Cui H, et al. Emerging theranostic nanomaterials in diabetes and its complications. Adv Sci (Weinh). (2022) 9:e2102466. doi: 10.1002/advs.202102466
18. Rey F, Barzaghini B, Nardini A, Bordoni M, Zuccotti GV, Cereda C, et al. Advances in tissue engineering and innovative fabrication techniques for 3-D-structures: translational applications in neurodegenerative diseases. Cells. (2020) 9:1636. doi: 10.3390/cells9071636
19. Hosseini M, Shafiee A. Engineering bioactive scaffolds for skin regeneration. Small. (2021) 17:2101384. doi: 10.1002/smll.202101384
20. Deng C, Zhu H, Li J, Feng C, Yao Q, Wang L, et al. Bioactive scaffolds for regeneration of cartilage and subchondral bone interface. Theranostics. (2018) 8:1940–55. doi: 10.7150/thno.23674
21. Kamboj N, Ressler A, Hussainova I. Bioactive ceramic scaffolds for bone tissue engineering by powder bed selective laser processing: a review. Materials (Basel). (2021) 14:5338. doi: 10.3390/ma14185338
22. Carrow JK, Di Luca A, Dolatshahi-Pirouz A, Moroni L, Gaharwar AK. 3D-printed Bioactive scaffolds from nanosilicates and PEOT/PBT for bone tissue engineering. Regen Biomater. (2019) 6:29–37. doi: 10.1093/rb/rby024
23. Khan K, Gasbarrino K, Mahmoud I, Dufresne L, Daskalopoulou SS, Schwertani A, et al. Bioactive scaffolds in stem cell-based therapies for myocardial infarction: a systematic review and meta-analysis of preclinical trials. Stem Cell Rev Rep. (2022) 18:2104–36. doi: 10.1007/s12015-021-10186-y
24. Mazzoni E, Iaquinta MR, Lanzillotti C, Mazziotta C, Maritati M, Montesi M, et al. Bioactive materials for soft tissue repair. Front Bioeng Biotechnol. (2021) 9:613787. doi: 10.3389/fbioe.2021.613787
25. Ghosh S, Webster TJ. Metallic nanoscaffolds as osteogenic promoters: advances, challenges and scope. Metals (Basel). (2021) 11:1356. doi: 10.3390/met11091356
26. Martinez B, Peplow PV. Biomaterial and tissue-engineering strategies for the treatment of brain neurodegeneration. Neural Regen Res. (2022) 17:2108–16. doi: 10.4103/1673-5374.330603
27. Maulding DM, Bielanin J, Cole P, Tian J, Saeeidi M, Sharma HS, et al. Alginate nanofiber scaffolds for amyotrophic lateral sclerosis. In: Peplow PV, Martinez B, Gennarelli TA, editors. Regenerative Medicine and Brain Repair. USA: Springer (in press). p. 251–70.
28. Adams C, Kabiri B, Bashit RH, Wiseman J, Chari DM. Developing high-fidelity in vitro models of traumatic brain injury to test therapeutic biomaterials. In: Peplow PV, Martinez B, Gennarelli TA, editors. Regenerative Medicine and Brain Repair. USA: Springer (2024). p. 271–315.
29. Yang Y, Yang X, Li H, Li C, Ding H, Zhang M, et al. Near-infrared light triggered liposomes combining photodynamic and chemotherapy for synergistic breast tumor therapy. Colloids Surf B: Biointerfaces. (2019) 173:564–70. doi: 10.1016/j.colsurfb.2018.10.019
30. Bahutair WN, Abuwatfa WH, Husseini GA. Ultrasound triggering of liposomal nanodrugs for cancer therapy: a review. Nanomaterials (Basel). (2022) 12:3051. doi: 10.3390/nano12173051
31. Kim MA, Lee CM. NIR-mediated drug release and tumor theranostics using melanin-loaded liposomes. Biomaterials Res. (2022) 26:22. doi: 10.1186/s40824-022-00270-w
32. Agrawal M,, Ajazuddin Tripathi DK, Saraf S, Saraf S, Antimisiaris SG, et al. Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J Control Release (2017) 260:61–77. doi: 10.1016/j.jconrel.2017.05.019
33. Seo MW, Park TE. Recent advances with liposomes as drug carriers for treatment of neurodegenerative diseases. Biomed Eng Lett. (2021) 11:211–6. doi: 10.1007/s13534-021-00198-5
34. Kuo YC, Wang CT. Protection of SK-N-MC cells against β-amyloid peptide-induced degeneration using neuron growth factor-loaded liposomes with surface lactoferrin. Biomaterials. (2014) 35:5954–64. doi: 10.1016/j.biomaterials.2014.03.082
35. Ji B, Wang M, Gao D, Xing S, Li L, Liu L, et al. Combining nanoscale magnetic nimodipine liposomes with magnetic resonance image for Parkinson’s disease targeting therapy. Nanomedicine (Lond). (2017) 12:237–53. doi: 10.2217/nnm-2016-0267
36. Liu D, Yang F, Xiong F, Gu N. The smart drug delivery system and its clinical potential. Theranostics. (2016) 6:1306–23. doi: 10.7150/thno.14858
37. Shishir MR, Gowd V, Suo H, Wang M, Wang Q, Chen F, et al. Advances in smart delivery of food bioactive compounds using stimuli-responsive carriers: responsive mechanism, contemporary challenges, and prospects. Compr Rev Food Sci Food Saf. (2021) 20:5449–88. doi: 10.1111/1541-4337.12851
38. Abedi F, Ghandforoushan P, Adeli F, Yousefnezhad M. Development of stimuli-responsive nanogels as drug carriers and their biomedical application in 3D printing. Mater Today Chem. (2023) 29:101372. doi: 10.1016/j.mtchem.2022.101372
39. Bayan MF, Jaradat A, Alyami MH, Naser AY. Smart pellets for controlled delivery of 5-fluorouracil. Molecules. (2022) 28:306. doi: 10.3390/molecules28010306
40. Peyroteo M, Ferreira IA, Elvas LB, Ferreira JC, Lapão LV. Remote monitoring systems for patients with chronic diseases in primary health care: systematic review. JMIR Mhealth Uhealth. (2021) 9:28285. doi: 10.2196/28285
41. Gladia S. Smart pills: the future of pharmaceutical technology. J Pharm Chemistry Chem Sci. (2023) 7:136. doi: 10.35841/aapccs-7.2.135
42. Sahoo S, Bagjadab AB, Priyadarshini SB. Smart pills: a complete revolutionary technology than endoscopy. InEmer Pharma Ind Growth Ind IoT App. (2020) 2020:275–303. doi: 10.1016/B978-0-12-819593-2.00010-8
43. Cummins G. Smart pills for gastrointestinal diagnostics and therapy. Adv Drug Deliv Rev. (2021) 177:113931. doi: 10.1016/j.addr.2021.113931
44. Ziegler A, Gonzalez L, Blikslager A. Large animal models: the key to translational discovery in digestive disease research. Cell Mol Gastroenterol Hepatol. (2016) 2:716–24. doi: 10.1016/j.jcmgh.2016.09.003
45. Al-Saffar A, Takemi S, Saaed HK, Sakata I, Sakai T. Utility of animal gastrointestinal motility and transit models in functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol. (2019) 40-41:101633. doi: 10.1016/j.bpg.2019.101633
Keywords: animal model, medical translation, new treatments, human, diseases
Citation: Peplow PV (2024) Animal models in medical translation: the grand challenge of developing new treatments for human diseases. Front. Med. Technol. 6:1367521. doi: 10.3389/fmedt.2024.1367521
Received: 8 January 2024; Accepted: 5 February 2024;
Published: 16 February 2024.
Edited and Reviewed by: Alicia Jennifer El Haj, University of Birmingham, United Kingdom
© 2024 Peplow. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Philip V. Peplow cGhpbC5wZXBsb3dAb3RhZ28uYWMubno=