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Tissue Engineering & Cell Therapy


Overview

Tissue Engineering & Cell Therapy Programme is focused on:

  • Understanding and investigating the reconstruction and replacement of the cornea using novel biomaterials

  • Investigating the principles of corneal tissue engineering in order to improve surgical outcomes

  • Understanding the principles of in-vivo expansion of stem cells for the reconstruction of the cornea


Our Goal

Innovating in corneal tissue engineering and stem cell reconstruction from a basic science but primarily a translational research point of view


Projects

1. Femtosecond Laser-Assisted Ocular Surgery

The use of femtosecond lasers has revolutionised the way clinicians perform refractive surgery. The laser has become an important tool to perform accurate and fine dissections with minimal collateral damage to the ocular tissues.

The main work to date in this area of study is focused on the investigation of laser-ocular tissue interactions, the optimisation of laser technology in performing myopic ReLEx (refractive lenticule extraction) and various keratoplasties, as well as the tissue engineering of an extracted lenticule from ReLEx as corneal inlay to restore corneal volume and, in the future, to correct presbyopic errors.

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A. Whole-mount ß3-tubulin staining of cornea after undergoing LASIK procedure.

B. Helium ion micrograph of a crater on corneal stromal bed, created by a cavitation bubble during femtosecond laser photodisruption process.

C. In vivo confocal micrograph of femtosecond laser photodisrupted plane (reflective layer) and side cut (reflective line).

D. Topography of rabbit cornea captured by handheld video keratographer


2. Corneal Endothelial Cell Research

The human corneal endothelium (CE) is perhaps the physiologically most important layer of the cornea. 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.

Currently, we are looking at the use of various constructs, both synthetic and biological, as potential scaffolds for tissue engineering, while characterising the growth of the cultivated human CE cells on each of these constructs. We are also looking at ways to improve the culture of human CE cells using different small molecules that have shown potential in improving the adherence and/or the proliferation of cultivated human CE cells.

Culture of Human Corneal Endothelial cells for transplant

     

3. Anterior Segment Drug Delivery Systems

We have developed a biodegradable, prednisolone acetate-loaded microfilms made of poly (d,l-lactide-co-ε-caprolactone) (PLC). This drug delivery system is capable of delivering sustained and therapeutic drug levels to the anterior segment for over four weeks. Therefore, it eliminates patient compliance and a dependency on a frequent dosing regimen after surgery. It also circumvents the limitations of conventional eye drops, such as low bioavailability and a short duration of action.

We have demonstrated that this novel microfilm has good biocompatibility and surgical feasibility in animal models. The implantation of the microfilm into the subconjunctival space is a single, simple and non-invasive procedure. The microfilm degrades to non-toxic metabolites over time, hence no extra procedure is needed to remove the implant after the depletion of the drug. Furthermore, the microfilm can be customised to deliver different drug release profiles, depending on different clinical scenarios.

     

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. Artificial Cornea

Artificial corneas (or keratoprostheses) are commonly used, especially for chronic inflammatory and ocular surface diseases. However, keratoprosthesis technology is still lacking — these devices utilise older polymers and outdated designs.

The Osteo-odonto keratoprosthesis (OOKP) is reserved for more severe ocular surface diseases, and has a high rate of device retention, but requires a highly complex surgery to remove an autologous tooth. Our team’s goal is to develop a synthetic OOKP-type device that does not require a tooth. This will significantly improve the time for visual rehabilitation in patients requiring this surgery, as well as simplify the surgical procedure tremendously.

Our previous work shows that TiO2 has excellent biocompatibility as a substrate to support cornea fibroblast integration, enhanced surface cell spreading and adhesion. We are developing a semi-flexible carbon mesh skirt for a synthetic OOKP artificial cornea.


6. Protein Aggregation and TGFBI related Corneal Dystrophy

Stromal corneal dystrophies (CDs) are characterised as a group of bilateral, heterogeneous inherited disorders. The majority of these CDs in the stromal layer of the cornea have been attributed to mutations found on the TGFBI gene coding for a 683-amino acid transforming growth factor-induced protein (TGFβIp). Defects in this gene lead to the progressive accumulation of protein aggregates in the cornea that can result in loss of corneal transparency and hence vision.

At present, 63 distinct pathogenic mutations have been identified in TGFBI that are associated with different clinical phenotypes. Although TGFβIp is present in various other tissues, only cornea-specific aggregation is triggered by the occurrence of these mutations.

The current treatment relies on laser/surgical intervention, which often involves high recurrence rates. Since there are no effective medical treatments of TGFBI-associated CDs, this research project aims to look into the mechanisms of the disease, in order to develop viable therapeutic strategies for treating these dystrophies. Biophysical, biochemical and structural aspects of the mutations will be analysed.

The present study will involve the development of in-vitro models of protein aggregation and the evaluation of pharmacological chaperones (PCs) that are capable of inhibiting or dissolving the aggregates. This will allow us to develop a novel therapy for these stromal dystrophies.


Slit lamp photography shows the multiple radially oriented linear opacities in the anterior to midstromal depth of the central cornea with subepithelial and anterior stromal scarring in the right (A) and left eye (B) with a novel A620D mutation. Slit lamp photograph showing radially oriented linear opacities in the cornea (C) of a H626R mutation, which are more clearly seen on retroillumination (D).


Publications

  1. Liu YC, Peng Y, Lwin NC, Wong TT, Venkatraman SS, Mehta JS. Optimization of subconjunctival biodegradable microfilms for sustained drug delivery to the anterior segment in a small animal model. Invest Ophthalmol Vis Sci. 2013 Mar 21. doi:pii: iovs.12-11466v1. 10.1167/iovs.12-11466. [Epub ahead of print] PubMed.

  2. Chung HW, Mehta JS. Fibrin glue for gundersen flap surgery. Clin Ophthalmol. 2013;7:479-84. doi: 10.2147/OPTH.S42105. Epub 2013 Mar 6. 23493670.

  3. Ang M, Mohamed-Noriega K, Mehta JS, Tan D. Deep anterior lamellar keratoplasty: surgical techniques, challenges, and management of intraoperative complications. Int Ophthalmol Clin. 2013 Spring;53(2):47-58. doi: 10.1097/IIO.0b013e31827eb746.

  4. Khor WB, Teo KY, Mehta JS, Tan DT. Descemet stripping automated endothelial keratoplasty in complex eyes: results with a donor insertion device. Cornea. 2013 Feb 26. [Epub ahead of print].

Members

Principal Investigators & Clinician Scientist

  • Prof Jodhbir Mehta 

  • Adj Prof Donald Tan 

  • Dr Gary Yam Hin Fai

  • Dr Gary Peh Swee Lim

  • Dr Liu Yu-Chi 


Research Fellows

  • Dr Matthew Jason Lovatt

  • Dr Ong Hon Shing

  • Dr Hassan Mansoor

  • Dr Vidhya Venkatraman Anandalakshmi

  • Dr Andri Kartasasmita Riau

  • Dr Fernando Morales Wong


Research Officers/Assistants

  • Melina Setiawan

  • Ang Heng Pei

  • Khadijah Binte Adnan

  • Nur Zahirah Bte M Yusoff

  • Goh Tze Wei Gwendoline

  • Neo Jing Hui Dawn