Rege Lab

Research in the Rege Lab

Effective repair of tissues, including after trauma, is a significant clinical problem, and different pathologies (e.g. diabetes, obesity), organ location (e.g. nerves, intestines) and / or trauma type (acute injuries, surgical incisions), pose unique challenges. In general, leakage, reopening (dehiscence), scarring / fibrosis, and inflammation limit the efficacy of tissue repair. Research in the Rege Bioengineering Laboratory focuses on delivery of therapeutic nanomaterials and on nanomaterials innovation for therapeutics delivery for solving challenging problems in tissue sealing, repair and regeneration. Our research thrusts are are highlighted in the following sections.

(A). Light-activated Nanomaterials for Tissue Sealing, Repair and Wound Healing.

My laboratory has been at the forefront of innovating light-activated nanomaterials for immunomodulation, drug delivery, and delivery of heat energy for tissue sealing and repair[1-8] including in diabetic and obese hosts. Ongoing and emerging research focuses on:

  1. New nanomaterial sources (e.g. spider silk polypeptides) and their effect on immunomodulation for tissue repair.
  2. Innovations in nanomaterials engineering, for actively engaging the innate immune system to augment healing
  3. Use of diverse energy sources including midinfrared light for chromophore-free sealing and repair
  4. Investigations into the role of tissue and nanomaterial biomechanics for accelerating tissue repair, and
  5. Whole transcriptome analyses (RNA sequencing) to identify novel druggable targets that can augment tissue repair.

(B) Temporal Delivery of Therapeutic Nanomaterials and Mediators of Tissue Repair.

Nanomaterials facilitate biomechanical reinforcement and innate immune activation by themselves but can also serve as depots for the delivery of bioactive therapeutics that promote tissue repair and combat infection in slow healing and chronic wounds. Ongoing and emerging research focuses on:

  1. Immunomodulatory mediators: histamine, Serpin proteins[9]
  2. Antibacterial therapeutics: copper[7] and small-molecule antibiotics.
  3. Growth factor nanoparticles (collaboration with Prof. Francois Berthiaume, Rutgers U.)

for tissue repair in immunocompetent, immunocompromised, diabetic, and obese live animals.

(C). Delivery of Therapeutic Nanomaterials for Gastrointestinal (GI) Repair and Imaging.

Inflammatory bowel disease (IBD), diverticulitis (inflammation of pouches formed on the other side of the colon)[10, 11], cancer, and fistulas, require effective therapeutics for tissue repair concomitant to or after surgical intervention, and current approaches suffer from slow recoveries and / or leakage, which can lead to serious infection and fatality[12-16]; for example, up to one-third mortalities after intestinal surgery are because of leakage[17]. We are investigating the delivery of nanomaterials as a comprehensive approach for visualizing and treating GI pathologies that need surgical intervention. Our research in this area includes:

  1. A library of injectable nanomaterials for endoscopic delivery and visualization of GI disease (in collaboration with Dr. Rahul Pannala, Mayo Clinic, Phoenix).
  2. Endoscopic imaging-guided delivery of therapeutic nanomaterials.
  3. Nanomaterials for GI leakage prevention, inflammation control, and tissue repair.

(D) Delivery of Therapeutic Nanomaterials for Neural Repair and Regeneration.

Surgical repair is generally required for traumatic peripheral nerve injury but has a 50% or lower likelihood of complete restoration of function. Similarly, restoration of function in spinal cord injuries presents formidable clinical challenges[18]. An emerging research focus in my laboratory is the delivery of therapeutic biomaterials for repair and regeneration in cases of peripheral nerve and spinal cord injuries. Ongoing and emerging research focuses on:

  1. Laser-activated nanomaterials for epineural suturing, anastomosis and grafting nerve conduits in peripheral nerve injuries.
  2. Temporal delivery of bioactives in peripheral nerve and spinal cord repair.

(E). Technology Platforms for Accelerating Drug Carrier Discovery.

Identification of effective new drug carriers, especially from large libraries of potential candidates necessitates a comprehensive undertaking. We are developing a new paradigm based on synergistic use of combinatorial nanoparticle synthesis, cell-based parallel screens and chemical informatics (quantitative structure-property relationship or QSPR modeling) for accelerating the discovery of effective drug carriers (Figure 5). Ongoing and emerging research focuses on:

  1. Combinatorial synthesis and chemical informatics discovery of polymer and lipopolymer nanoparticle libraries[19-26] for nucleic acid and small molecule delivery (Collaborator: Prof. Curt Breneman, RPI).
  2. Hydrogel libraries for generation of 3D organoids[27, 28].

The foundational tools and the discovery platform developed in this thrust will lead to rapid identification of effective drug carriers in skin, GI and neural tissue repair.

References

  1. Huang, H.C., Yang, Y., Nanda, A., Koria, P., and Rege, K., Synergistic administration of photothermal therapy and chemotherapy to cancer cells using polypeptide-based degradable plasmonic matrices. Nanomedicine (Lond), 2011. 6(3): p. 459-73.
  2. Huang, H.C., Walker, C.R., Nanda, A., and Rege, K., Laser welding of ruptured intestinal tissue using plasmonic polypeptide nanocomposite solders. ACS Nano, 2013. 7(4): p. 2988-98.
  3. Urie, R., Quraishi, S., Jaffe, M., and Rege, K., Gold Nanorod-Collagen Nanocomposites as Photothermal Nanosolders for Laser Welding of Ruptured Porcine Intestines. ACS Biomaterials Science & Engineering, 2015. 1(9): p. 805-815.
  4. Mushaben, M., Urie, R., Flake, T., Jaffe, M., Rege, K., and Heys, J., Spatiotemporal modeling of laser tissue soldering using photothermal nanocomposites. Lasers in Surgery and Medicine, 2018. 50(2): p. 143-152.
  5. Urie, R., Guo, C., Ghosh, D., Thelakkaden, M., Wong, V., Lee, J.K., Kilbourne, J., Yarger, J., and Rege, K., Rapid Soft Tissue Approximation and Repair Using Laser-Activated Silk Nanosealants. Advanced Functional Materials, 2018. 28(42): p. 1802874.
  6. Ghosh, D., Urie, R., Chang, A., Nitiyanandan, R., Lee, J.K., Kilbourne, J., and Rege, K., Light-Activated Tissue-Integrating Sutures as Surgical Nanodevices. Advanced Healthcare Materials, 2019. 0(0): p. 1900084.
  7. Ghosh, D., Godeshala, S., Nitiyanandan, R., Islam, M.S., Yaron, J.R., DiCaudo, D., Kilbourne, J., and Rege, K., Copper-Eluting Fibers for Enhanced Tissue Sealing and Repair. ACS Appl Mater Interfaces, 2020. 12(25): p. 27951-27960.
  8. Urie, R., et al., Antimicrobial laser-activated sealants for combating surgical site infections. Biomater Sci, 2021. 9(10): p. 3791-3803.
  9. Zhang, L., Yaron, J.R., Tafoya, A.M., Wallace, S.E., Kilbourne, J., Haydel, S., Rege, K., McFadden, G., and Lucas, A.R., A Virus-Derived Immune Modulating Serpin Accelerates Wound Closure with Improved Collagen Remodeling. Journal of Clinical Medicine, 2019. 8(10): p. 1626.
  10. Guillou, P.J., Quirke, P., Thorpe, H., Walker, J., Jayne, D.G., Smith, A.M.H., Heath, R.M., and Brown, J.M., Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet, 2005. 365(9472): p. 1718-1726.
  11. Smith, R.L., Bohl, J.K., McElearney, S.T., Friel, C.M., Barclay, M.M., Sawyer, R.G., and Foley, E.F., Wound infection after elective colorectal resection. Annals of Surgery, 2004. 239(5): p. 599-605.
  12. Karanjia, N.D., Corder, A.P., Bearn, P., and Heald, R.J., Leakage from Stapled Low Anastomosis after Total Mesorectal Excision for Carcinoma of the Rectum. British Journal of Surgery, 1994. 81(8): p. 1224-1226.
  13. Isbister, W.H., Anastomotic leak in colorectal surgery: A single surgeon’s experience. Anz Journal of Surgery, 2001. 71(9): p. 516-520.
  14. Park, I.J., Influence of Anastomotic Leakage on Oncological Outcome in Patients with Rectal Cancer. Journal of Gastrointestinal Surgery. 14(7): p. 1190-1196.
  15. Thomson, G.A., An investigation of leakage tracts along stressed suture lines in phantom tissue. Medical Engineering & Physics, 2007. 29(9): p. 1030-1034.
  16. Shogan, B.D., Carlisle, E.M., Alverdy, J.C., and Umanskiy, K., Do We Really Know Why Colorectal Anastomoses Leak? J Gastrointest Surg, 2013.
  17. Anderson, R.H., Endoscopic laser surgery handbook (Science and practice of surgery series, vol. 10). International journal of cardiology, 1988. 20(1): p. 157.
  18. Ashammakhi, N., Kim, H.J., Ehsanipour, A., Bierman, R.D., Kaarela, O., Xue, C., Khademhosseini, A., and Seidlits, S.K., Regenerative Therapies for Spinal Cord Injury. Tissue Eng Part B Rev, 2019. 25(6): p. 471-491.
  19. Potta, T., Zhen, Z., Grandhi, T.S., Christensen, M.D., Ramos, J., Breneman, C.M., and Rege, K., Discovery of antibiotics-derived polymers for gene delivery using combinatorial synthesis and cheminformatics modeling. Biomaterials, 2014. 35(6): p. 1977-88.
  20. Miryala, B., Feng, Y., Omer, A., Potta, T., and Rege, K., Quaternization enhances the transgene expression efficacy of aminoglycoside-derived polymers. International Journal of Pharmaceutics, 2015. 489(1–2): p. 18-29.
  21. Miryala, B., Zhen, Z., Potta, T., Breneman, C.M., and Rege, K., Parallel Synthesis and Quantitative Structure–Activity Relationship (QSAR) Modeling of Aminoglycoside-Derived Lipopolymers for Transgene Expression. ACS Biomaterials Science & Engineering, 2015. 1(8): p. 656-668.
  22. Zhen, Z., Potta, T., Lanzillo, N.A., Rege, K., and Breneman, C.M., Development of a Web-Enabled SVR-Based Machine Learning Platform and its Application on Modeling Transgene Expression Activity of Aminoglycoside-Derived Polycations. Comb Chem High Throughput Screen, 2017. 20(1): p. 41-55.
  23. Zhen, Z., Potta, T., Christensen, M.D., Narayanan, E., Kanagal, K.A., Breneman, C.M., and Rege, K., Accelerated Materials Discovery Using Chemical Informatics Investigation of Polymer Physicochemical Properties and Transgene Expression Efficacy. ACS Biomaterials Science & Engineering, 2018.
  24. Goklany, S., Lu, P., Godeshala, S., Hall, A., Garrett-Mayer, E., Voelkel-Johnson, C., and Rege, K., Delivery of TRAIL-expressing plasmid DNA to cancer cells in vitro and in vivo using aminoglycoside-derived polymers. J Mater Chem B, 2019. 7(44): p. 7014-7025.
  25. Godeshala, S., Miryala, B., Dutta, S., Christensen, M.D., Nandi, P., Chiu, P.L., and Rege, K., A library of aminoglycoside-derived lipopolymer nanoparticles for delivery of small molecules and nucleic acids. J Mater Chem B, 2020. 8(37): p. 8558-8572.
  26. Miryala, B., Godeshala, S., Grandhi, T.S., Christensen, M.D., Tian, Y., and Rege, K., Aminoglycoside-derived amphiphilic nanoparticles for molecular delivery. Colloids Surf B Biointerfaces, 2016. 146: p. 924-37.
  27. Pavan Grandhi, T.S., Potta, T., Nitiyanandan, R., Deshpande, I., and Rege, K., Chemomechanically engineered 3D organotypic platforms of bladder cancer dormancy and reactivation. Biomaterials, 2017. 142: p. 171-185.
  28. Candiello, J., et al., 3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform. Biomaterials, 2018. 177: p. 27-39.