Regenerative Therapy Programme is focused on:
Understanding and investigating regenerative therapy of cornea, including corneal cells and nerves
Investigating corneal nerve degeneration and regeneration associated with diseases or surgical procedures and developing therapeutic approaches for enhancing corneal nerve regeneration
Investigating the principles of corneal cell therapy to improve patients’ visual outcomes
Our Goal
Understanding through translational research and enabling the innovation in corneal regenerative therapy.
Projects
1. Corneal Endothelial Cell Research
The human corneal endothelium (CE) is perhaps the most important layer of the cornea, physiologically. Although cells of the CE are unable to undergo any functional regeneration within the eye, studies have demonstrated the capacity for primary human CE cells to proliferate within a laboratory setting.
We have since further improved the cultivation of isolated human CE cells using a patented dual media culture system. The cultivated human CE cells can be consistently propagated to the third passage and can retain characteristic cellular morphology and expression markers indicative of the human CE layer. This has enabled down-stream development of potential graft alternatives through tissue-engineering. In June 2024, the development of corneal endothelial cell replacement therapy has been successfully translated and carried out in Singapore National Eye Centre, Singapore, in the form of a first-in-human clinical trial entitled “Tissue-Engineered Endothelial Keratoplasty”. All 3 patients receiving the tissue-engineered graft material are doing well and will be closely monitored for the next 12 months.
Concurrently, we are also looking at the use of various scalable constructs (both synthetic and biological) as potential scaffolds for tissue engineering, while characterising the growth of the cultivated human CE cells on these constructs. We are also looking at ways to improve the expansion of human CE cells using available regulatory-approved small molecules that have shown potential in improving the adherence and/or the proliferation of cultivated human CE cells. Finally, we are working with the Health Sciences Authority (HSA) on the regulatory requirements on running two additional arms of corneal endothelial cell replacement therapies entitled “Corneal Endothelial Cell Injection” and “Simple Non-cultured Endothelial Cell Injection.”
Figure 1. Culture of Human Corneal Endothelial cells for transplant.
2. Clinical and Translational Research on Corneal Nerve and Corneal Neuropathy
Diabetic Corneal Neuropathy
Diabetic Corneal Neuropathy (DCN) is a common complication of diabetes characterised by chronic degenerative changes in corneal nerve fibres. DCN increases the risk of corneal perforation and vision loss. However, current management fails to address the underlying pathophysiology.
We investigated the effects of Fenofibrate, a peroxisome proliferator–activated receptor-a (PPAR-a) agonist, on patients with type 2 diabetes. After 30 days of oral treatment, fenofibrate significantly stimulated corneal nerve regeneration and reduced nerve edema. Fenofibrate also improved neuropathic ocular surface status, alleviated neuroinflammation, and upregulated and modulated the neurotrophin signalling pathway.
Figure 2. Representative IVCM and slit-lamp images of the type 2 diabetic patients before and after fenofibrate treatment.
Neuropathic Corneal Pain
Neuropathic Corneal Pain (NCP) is an emerging condition characterised by dysfunctional corneal nerve. Patients usually experience various ocular surface pain symptoms without corresponding clinical signs and typically do not respond to conventional dry eye treatments. Managing NCP is challenging due to its complex pathophysiology, often requiring a combination of treatment modalities. However, many patients have persistent pain despite multiple approaches. Patients with NCP present significant reduced corneal nerve metrics, which can be assessed using IVCM. Our group is dedicated to elucidating the pathogenesis of NCP in aspects of clinical manifestations, corneal nerve imaging features, tear neuromediators and proteomic profiles, and exploring innovative therapeutic approaches to alleviate patients' pain symptoms. More importantly, we focus on addressing the underlying neuropathy by promoting nerve repair and regeneration, with the ultimate goal of restoring normal corneal nerve function and enhancing patients' quality of life.
Figure 3. IVCM images in healthy individual vs NCP patients.
Refractive Surgery-related Corneal Neuropathy
Refractive surgery is among the most widely performed procedures worldwide. While providing excellent visual and refractive outcomes, it can negatively impact the ocular surface due to inevitable corneal denervation during surgery and resultant neuroinflammation. An increasing number of patients report persistent ocular symptoms after refractive surgery, including dry eye disease and NCP, which can be detrimental to both vision-related and overall quality of life.
Our group is conducting studies to evaluate corneal nerve damage and regeneration in patients undergoing various types of refractive surgery and to identify risk factors associated with refractive surgery-related corneal neuropathy. We aim to elucidate the mechanisms underlying postoperative neuroinflammation and persistent ocular symptoms to advance both the scientific understanding and clinical management of corneal neuropathy in refractive surgery. We also strive to develop more effective treatment protocols to prevent or minimise surgical-induced nerve damage, as well as to promote nerve regeneration. We seek to improve patient outcomes by developing more targeted and effective treatment protocols to prevent or minimise nerve damage caused by surgery.
Figure 4. Corneal denervation, nerve regeneration, and tear neuromediators changes after SMILE surgery. A, B. Morphological characteristics of corneal nerve plexus before and after SMILE surgery. C. Concentrations of tear neuromediators before and after surgery.
3. Corneal Imaging: Corneal Nerve Imaging and Innovative Terahertz Corneal Scans
Corneal Nerve Imaging
Corneal nerve status has been used as a surrogate marker for diabetic peripheral neuropathy and nephropathy. Our group is also conducting studies to explore the interconnections between DCN and diabetic microvascular complications, such as chronic kidney disease (CKD) and diabetic retinopathy (DR), using corneal nerve imaging, clinical ocular surface characteristics, and tear multi-omics profiles, with the application of AI techniques. We aim to utilise corneal nerve status as an early or subclinical marker, as well as a valuable screening and predictive tool for CKD and DR. This will improve patients’ outcomes and save healthcare costs, not only for eye care but also in all relevant clinics and fields.
Terahertz Corneal Scanning
The THz scanning system is a fast, instant measurement with a fast-scanning speed to meet the medical diagnostic profile. It is a non-destructive, non-invasive, and non-contact device that has the ability to help with the diagnosis and disease monitoring of a variety of corneal diseases and dry eye diseases, addressing current unmet clinical needs. We are conducting Phase I clinical trial to attest the safety profile of the application of THz scans on corneas, followed by a Phase IIa trial to evaluate the diagnostic accuracy, performance, and efficacy of the THz scanning system on corneal and ocular surface.
4. Ocular Surface Stem Cell Reconstruction
The presence of a smooth ocular surface is vital for normal vision. The corneal epithelium is the outermost region of the cornea and primarily serves to protect the eye. Its renewal relies on limbal stem cells. Their destruction is a major debilitating cause of ocular morbidity.
Transplantation to replace the damaged corneal epithelium can principally restore the vision, but allogeneic transplants in patients with bilateral disease do not have satisfactory long-term treatment due to the persistent use of immunosuppression.
We are examining the role of other autologous cell sources to develop a safe, stable, effective, and functional tissue-engineered construct for patients with bilateral ocular surface disease.
5. Corneal Stromal Regenerative Therapy
In homeostasis, Corneal Stromal Keratocytes (CSKs) produce collagens and keratan sulfate proteoglycans, such as lumican and keratocan, which regulate collagen fibril organisation. Upon stromal damage, CSKs at the injury site undergo apoptosis, while nearby CSKs transform into stromal fibroblasts (SFs), which migrate and initiate repair. Some SFs differentiate into myofibroblasts, depositing abnormal extracellular matrix and altering wound properties through contraction. Excess fibroblasts and myofibroblasts disrupt the stromal matrix, leading to corneal haze. This process is irreversible and the most effective treatment typically involves corneal transplantation. The current programme aims to address the shortage of donor material by cultivating CSKs from non-transplantable donor corneas and reintroducing them into corneas affected by haze. This approach allows for multiple treatments from a single donor tissue and simplifies the delivery of therapy, potentially enabling in-office procedures instead of operating room surgeries.
The programme also seeks to integrate biomaterials with cell therapy. Combining cell therapy with biomaterials addresses several challenges, including minimising off-target effects, reducing immune responses, and enhancing therapeutic effectiveness. Biomaterials alone provide distinct benefits, serving as structural support, protective mediums, and sources of biological cues for cell behaviour, while actively contributing to wound healing and tissue regeneration. Together, the synergistic effects of cells and biomaterials hold the potential to significantly improve treatment outcomes to restore tissue function after injury or disease.
Figure 5.
Riau AK, Look Z, Yam GH, Boote C, Ma Q, Han EJ, Yusoff NZ, Ong HS, Goh TW, Halim NS, Mehta JS. Impact of keratocyte differentiation on corneal opacity resolution and visual function recovery in male rats. Nat Comm. 2024;15:4959.
Thirunavukarasu AJ, Han E, Nedumaran AM, Kurz AC, Shuman J, Yusoff NZ, Liu YC, Foo V, Czarny B, Riau AK, Mehta JS. Electron beam-irradiated donor cornea for on-demand lenticule implantation to treat corneal diseases and refractive error. Acta Biomater. 2023;169:334-347.
Riau AK, Boey KP, Yusoff NZ, Goh TW, Yam GH, Tang KF, Phua CS, Chen HJ, Chiew YF, Liu YC, Mehta JS. Experiment-based validation of corneal lenticule banking in a health authority-licensed facility. Tissue Eng Part A. 2022;28:69-83.
Teo CHY, Lin MT, Lee IXY, Koh SK, Zhou L, Goh DS, Choi H, Koh HWL, Lam AYR, Lim PS, Mehta JS, Kovalik JP, Coffman TM, Tan HC, Liu YC. Oral Peroxisome Proliferator-Activated Receptor-α Agonist Enhances Corneal Nerve Regeneration in Patients With Type 2 Diabetes. Diabetes. 2023 Jul 1;72(7):932-946. doi: 10.2337/db22-0611. PMID: 36445944.
Liu C, Lin MT, Lee IXY, Wong JHF, Lu D, Lam TC, Zhou L, Mehta JS, Ong HS, Ang M, Tong L, Liu YC. Neuropathic Corneal Pain: Tear Proteomic and Neuromediator Profiles, Imaging Features, and Clinical Manifestations. Am J Ophthalmol. 2024 Sep;265:6-20. doi: 10.1016/j.ajo.2024.03.015. Epub 2024 Mar 21. PMID: 38521157.
Teo HY, Liu C, Lee XY, Lin TY, Liu FY, Toh JL, Koh SK, Lu D, Lam TC, Zhou L, Louis T, Mehta JS, Liu YC. Neuropathic Corneal Pain Following Refractive Surgery: Risk Factors, Clinical Manifestations, Imaging, and Proteomic Characteristics. Br J Ophthalmol; 2025; In Press.
Liu C, Wang XY, Ong HS, Ang M, Chee SP, Ching JH, Chua KV, Han HY, Mehta JS, Zhou L, Liu YC. Aqueous Proteomic and Metabolomic Profiles in Low-energy versus High-energy Femtosecond Laser-Assisted Cataract Surgery. Invest Ophthal Vis Sci 2025;66(1):10.
Yu M, Ning FTE, Liu C, Liu YC. Interconnections between diabetic corneal neuropathy and diabetic retinopathy: diagnostic and therapeutic implications. Neural Regen Res. 2025 Aug 1;20(8):2169-2180. doi: 10.4103/NRR.NRR-D-24-00509. PMID: 39359077.
Riau AK, Liu YC, Yam GH, Mehta JS. Stromal keratophakia: Corneal inlay implantation. Prog Retin Eye Res. 2020;75:100780.
Liu YC, Yam GH, Lin MT, Teo E, Koh SK, Deng L, Zhou L, Tong L, Mehta JS. Comparison of Tear Proteomic and Neuromediator Profiles Changes between Small Incision Lenticule Extraction (SMILE) and Femtosecond Laser-assisted In-situ Keratomileusis (LASIK). J Adv Res. 2020 Nov 5;29:67-81. doi: 10.1016/j.jare.2020.11.001. PMID: 33842006.
Co-Heads
Prof Jodhbir Mehta
Assoc Prof Liu Yu-Chi
Principal Investigators & Clinician Scientist
Dr Ong Hon Shing
Dr Gary Peh
Research Fellows & Clinical Research Fellows
Dr Andri Kartasasmita Riau
Dr Liu Chang
Dr Yu Mingyi
Research Officers/Assistants
Neo Jing Hui, Dawn (PhD Candidate)
Look ZhuoJian (MD/PhD Candidate)
Ng Xiao Yu
Evelina Han
Lee Xin Yu, Isabelle
Jenatta Soo
Belinda Tan
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