uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Kootala, Sujit, ResearcherORCID iD iconorcid.org/I-9004-2014
Biography [eng]

I am currently a postdoctoral researcher with the dept. of chemistry/polymer chem. at Uppsala University, Sweden. My research line focuses on the development and biological evaluation of materials for drug delivery, tissue engineering and regenerative medicine. I purify materials from raw materials and transform the functionality of these materials via the action of cross-linking molecules, generating valuable biomaterials without altering the natural biological affinity and functions of these molecules. Using simple synthetic tools, I develop macro and nanoscale materials to entrap (physically or chemically) active molecules such as growth
factors, drugs and inorganic molecules for therapeutic applications. Examples of such applications include hydrogels, microgels and nanoparticles. Briefly, my research themes are:
- Development of marine, bacterial and mammalian sourced biomaterials for regenerative, preventive and therapeutic medical applications
- Biomimetic approaches in tissue engineering and functional materials to tailor cell fate and tissue behaviour
- Study of the hierarchical structure-function relationship and bioactivity of biomaterials

Publications (10 of 16) Show all publications
Zhou, B., Gao, M., Feng, X., Huang, L., Huang, Q., Kootala, S., . . . Bowden, T. (2020). Carbazate modified dextrans as scavengers for carbonylated proteins. Carbohydrate Polymers, 232, Article ID 115802.
Open this publication in new window or tab >>Carbazate modified dextrans as scavengers for carbonylated proteins
Show others...
2020 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 232, article id 115802Article in journal (Refereed) Published
Abstract [en]

A series of biocompatible and non- toxic polysaccharide molecules have been successfully fabricated and explored their potential application for scavenging the carbonyl species in vitro. These macromolecules were dextrans with different hydrazide substitution ratios determined by TNBS assay, NMR and FTIR characterization. The colorimetric assay had demonstrated that these macromolecules could effectively scavenge acrolein, oxidized bovine serum albumin (BSA) in buffer solutions as well as carbonyl proteins from serum. The scavengers could achieve twice more scavenging effects for modified dextrans with high molecular weight (Mw=100,000) than those of low ones (Mw=40,000) with the same substitution ratio. Protein gel electrophoresis confirmed that the formation of the complex between carbonyls and modified dextrans resulted in appearance of slower bands. It also revealed that such macromolecules could protect cultured cells against the toxicity of acrolein or its derivatives. The proposed macromolecules indicated a very promising capability as scavengers for oxidative stress plus its derivatives without side effects.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2020
Keywords
Oxidative stress, Protein carbonyl groups, Human blood serum, Hydrazide-carbonyl click chemistry, Protein gel electrophoresis, Carbonyl scavengers
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-405335 (URN)10.1016/j.carbpol.2019.115802 (DOI)000507231800005 ()31952601 (PubMedID)
Available from: 2020-03-04 Created: 2020-03-04 Last updated: 2020-03-04Bibliographically approved
Kootala, S., Filho, L., Srivastava, V., Linderberg, V., Moussa, A., David, L., . . . Crouzier, T. (2018). Reinforcing Mucus Barrier Properties with Low Molar Mass Chitosans. Biomacromolecules, 19(3), 872-882
Open this publication in new window or tab >>Reinforcing Mucus Barrier Properties with Low Molar Mass Chitosans
Show others...
2018 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 3, p. 872-882Article in journal (Refereed) Published
Abstract [en]

The mucus gel covers the wet epithelia that forms the inner lining of the body. It constitutes our first line of defense protecting the body from infections and other deleterious molecules. Failure of the mucus barrier can lead to the inflammation of the mucosa such as in inflammatory bowel diseases. Unfortunately, there are no effective strategies that reinforce the mucus barrier properties to recover or enhance its ability to protect the epithelium. Herein, we describe a mucus engineering approach that addresses this issue where we physically cross-link the mucus gel with low molar mass chitosan variants to reinforce its barrier functions. We tested the effect of these chitosans on mucus using in-lab purified porcine gastric mucins, which mimic the native properties of mucus, and on mucus-secreting HT29-MTX epithelial cell cultures. We found that the lowest molar mass chitosan variant (degree of polymerization of 8) diffuses deep into the mucus gels while physically cross-linking the mucin polymers, whereas the higher molar mass chitosan variants (degree of polymerization of 52 and 100) interact only superficially. The complexation resulted in a tighter mucin polymer mesh that slowed the diffusion of dextran polymers and of the cholera toxin B subunit protein through the mucus gels. These results uncover a new use for low molar mass mucoadhesive polymers such as chitosans as noncytotoxic mucosal barrier enhancers that could be valuable in the prevention and treatment of mucosal diseases.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Physical Chemistry Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-351093 (URN)10.1021/acs.biomac.7b01670 (DOI)000427539600017 ()29451983 (PubMedID)
Funder
Swedish Research Council, 2014-6203]
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-05Bibliographically approved
Kootala, S., Tokunaga, M., Hilborn, J. & Iwasaki, Y. (2015). Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts. Macromolecular Bioscience, 15(12), 1634-1640
Open this publication in new window or tab >>Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts
2015 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 15, no 12, p. 1634-1640Article in journal (Refereed) Published
Keywords
osteoclasts, osteoblasts, osteoporosis, poly(ethylene sodium phosphate)
National Category
Natural Sciences Chemical Sciences
Research subject
Chemistry with specialization in Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-259078 (URN)10.1002/mabi.201500166 (DOI)000368456500001 ()26222677 (PubMedID)
Funder
Swedish Research Council, 2014-6009
Available from: 2015-07-27 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Kootala, S., Ossipov, D., van den Beucken, J., Leeuwenburgh, S. & Hilborn, J. (2015). Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis. Biomaterials Science, 3, 1197-1207
Open this publication in new window or tab >>Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis
Show others...
2015 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, p. 1197-1207Article in journal (Refereed) Published
Abstract [en]

Current treatments for osteoporosis involve the administration of high doses of bisphosphonates (BPs) over a number of years. However, the efficiency of the absorption of these drugs and specificity towards targeted osteoclastic cells is still suboptimal. In this study, we have exploited the natural affinity of high (H) and low (L) molecular-weight hyaluronic acid (HA) towards a cluster of differentiation 44 (CD44) receptors on osteoclasts to use it as a biodegradable targeting vehicle. We covalently bonded BP to functionalised HA (HA–BP) and found that HA–BP conjugates were highly specific to osteoclastic cells and reduced mature osteoclast numbers significantly more than free BP. To study the uptake of HA–BP, we fluorescently derivatised the polymer–drug with fluorescein B isothiocyanate (FITC) and found that L-HA–BP could seamlessly enter osteoclastic cells. Alternatively, we tested polyvinyl alcohol (PVA) as a synthetic polymer delivery vehicle using similar chemistry to link BP and found that osteoclast numbers did not reduce in the same way. These findings could pave the way for biodegradable polymers to be used as vehicles for targeted delivery of anti-osteoporotic drugs.

Place, publisher, year, edition, pages
United Kingdom: , 2015
Keywords
Bisphosphonates, Osteoporosis, Hyaluronic acid, Osteoclasts, Osteoblasts, Bone
National Category
Materials Chemistry
Research subject
Chemistry with specialization in Materials Chemistry; Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-258090 (URN)10.1039/C5BM00096C (DOI)000357937400003 ()26222035 (PubMedID)
Projects
MultiTERM
Funder
EU, European Research Council
Note

Erratum in Biomaterials Science 2015:3, issue 10, doi: 10.1039/c5bm90034d

Available from: 2015-07-10 Created: 2015-07-10 Last updated: 2017-12-04Bibliographically approved
Kootala, S. (2015). Evaluation of Functionalized Biopolymers as a Step Toward Targeted Therapy of Osteoporosis. (Doctoral dissertation). Uppsala: Uppsala universitet
Open this publication in new window or tab >>Evaluation of Functionalized Biopolymers as a Step Toward Targeted Therapy of Osteoporosis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented in this thesis focuses on the development of strategies and smart bioactive materials for the treatment of osteoporosis. High and low molecular weight soluble hyaluronic acid-bisphosphonate (HA-BP) derivatives were investigated for their ability to inhibit osteoclasts. Low molecular weight HA-BP (L-HA-BP) was most effective in inhibiting active resorption of both murine and human osteoclasts (without affecting osteoblasts) compared to free bisphosphonate (BP). Precursor monocytes were unaffected, suggesting the specificity of HA-BP towards osteoclasts. This new class of functionalized hyaluronic acid could lead to rapid development of tailor-made pro-drugs for targeted treatment of osteoporosis.

Polyphosphoesters (PEP) have been widely studied for their pro-osteoblast effects, primarily due to their involvement in cellular energy production pathway leading to the formation of inorganic phosphates that contribute to mineralized bone. Given that the effect of PEP on human osteoclasts is little studied, this work on poly(ethylene sodium phosphate) (PEP.Na) explores the potential to use PEP.Na as an inhibitor of osteoclast activity for the first time. PEP.Na exposure led to a dose-dependent toxicity of osteoclasts with reduction in their capacity to form resorption pits over 24h.

Currently, there is a dearth of in vitro cell-culture systems that can study osteoclast-related resorption and osteoblast-related mineralization in a single co-culture system, and to simultaneously quantify the effects of soluble factors on these processes. Described here, is the development of a novel and simple two-sided co-culture system that can overcome these limitations with reliable and quantifiable readouts. In comparison with traditional one-sided co-culture systems, the two-sided co-culture was able to generate similar readouts for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) markers. There is also the advantage of distinctly separate and quantifiable readouts for mineralization and resorption, which has been demonstrated using Pamidronate.

Finally, HA-BP was synthesized with pre-determined amounts of BP groups. The BP groups attached to HA allowed the tunable incorporation of BMP-2 in hydrogels. The charge-based affinity of BMP-2 and BP allowed stable incorporation of specific amounts of BMP-2, which could be tuned by the ratio of BP groups. 125I-labelled BMP-2 was loaded into hydrogels and their release was studied. Radioactive measurements revealed the tunable sequestration and controlled release of protein over time. This result was corroborated by ALP measurements of cells exposed to released BMP-2. ALP production was found to be almost 5-fold higher in HA-BP hydrogels loaded with BMP-2 which suggested that the sequestered BMP-2 is not only available to cells but also remains highly potent, even in entrapped form, The release of BMP-2 is dependent upon the rate of diffusion, swelling in hydrogels and degradation pattern of the gels and may assist in the long-term and rapid regeneration of osteoblasts in vitro.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2015. p. 78
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1267
Keywords
Osteoporosis, Bone regeneration, Biomaterials, Hyaluronic acid, Bisphosphonates, Osteoclasts, Osteoblasts, Growth factors
National Category
Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry; Chemistry with specialization in Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-259386 (URN)978-91-554-9287-8 (ISBN)
Public defence
2015-09-24, Häggsalen, Ångström Laboratory, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-08-28 Created: 2015-08-01 Last updated: 2015-10-01
Yi, Z., Zhang, Y., Kootala, S., Hilborn, J. & Ossipov, D. A. (2015). Hydrogel Patterning by Diffusion through the Matrix and Subsequent Light-Triggered Chemical Immobilization. ACS Applied Materials and Interfaces, 7(2), 1194-1206
Open this publication in new window or tab >>Hydrogel Patterning by Diffusion through the Matrix and Subsequent Light-Triggered Chemical Immobilization
Show others...
2015 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 7, no 2, p. 1194-1206Article in journal (Refereed) Published
Abstract [en]

A novel approach to hyaluronic acid (HA) hydrogel with a chemical gradient of the matrix-linked bisphosphonate (BP) groups is presented. The method consists of two steps, including initial generation of physical gradient patterns of BPs by diffusion of BP acrylamide reagent into HA matrix carrying thiol groups and subsequent chemical immobilization of the BP groups by UV light-triggered thiolene addition reaction. This gradient hydrogel permits spatial three-dimensional regulation of secondary interactions of different molecules with the polymer matrix. In particular, graded amounts of cytochrome c (cyt c) were reversibly absorbed in the hydrogel, thus enabling the subsequent spatially controlled release of the therapeutic protein. The obtained patterned hydrogel acts also as a unique reactor in which peroxidase-catalyzed oxidation of a substrate is determined by spatial position of the enzyme (cyt c) in the matrix resulting in a range of product concentrations. As an example, matrix template-assisted oxidation of 3,3',5,5'-tetarmethylbenzydine (TMB) in the presence of H2O2 occurs simultaneously at different rates within the gradient hydrogel. Moreover, calcium binding to the gradient HABP hydrogel reflects the pattern of immobilized BP groups eventually leading to the graded biomineralization of the matrix. This approach opens new possibilities for use of hydrogels as dynamic models for biologic three-dimensional structures such as extracellular matrix.

Keywords
hydrogel, chemical gradient, template synthesis, orthogonal reactions, hyaluronic acid
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-247160 (URN)10.1021/am506926w (DOI)000348332700020 ()25575380 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-13 Last updated: 2017-12-04Bibliographically approved
Kootala, S., Hilborn, J., Ossipov, D. & Zhang, Y. (2014). Hyaluronic acid linked bisphosphonates as a step towards targeted therapy for osteoporosis. Journal of Tissue Engineering and Regenerative Medicine, 8, 420-421
Open this publication in new window or tab >>Hyaluronic acid linked bisphosphonates as a step towards targeted therapy for osteoporosis
2014 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, p. 420-421Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-229380 (URN)000337612601061 ()
Available from: 2014-08-06 Created: 2014-08-06 Last updated: 2017-12-05Bibliographically approved
Schizas, N., Rojas, R., Kootala, S., Andersson, B., Pettersson, J., Hilborn, J. & Hailer, N. P. (2014). Hyaluronic acid-based hydrogel enhances neuronal survival in spinal cord slice cultures from postnatal mice. Journal of biomaterials applications, 28(6), 825-836
Open this publication in new window or tab >>Hyaluronic acid-based hydrogel enhances neuronal survival in spinal cord slice cultures from postnatal mice
Show others...
2014 (English)In: Journal of biomaterials applications, ISSN 0885-3282, E-ISSN 1530-8022, Vol. 28, no 6, p. 825-836Article in journal (Refereed) Published
Abstract [en]

Numerous biomaterials based on extracellular matrix-components have been developed. It was our aim to investigate whether a hyaluronic acid-based hydrogel improves neuronal survival and tissue preservation in organotypic spinal cord slice cultures. Organotypic spinal cord slice cultures were cultured for 4 days in vitro (div), either on hyaluronic acid-based hydrogel (hyaluronic acid-gel group), collagen gel (collagen group), directly on polyethylene terephthalate membrane inserts (control group), or in the presence of soluble hyaluronic acid (soluble hyaluronic acid group). Cultures were immunohistochemically stained against neuronal antigen NeuN and analyzed by confocal laser scanning microscopy. Histochemistry for choline acetyltransferance, glial fibrillary acidic protein, and Griffonia simplicifolia isolectin B4 followed by quantitative analysis was performed to assess motorneurons and different glial populations. Confocal microscopic analysis showed a 4-fold increase in the number of NeuN-positive neurons in the hyaluronic acid-gel group compared to both collagen (p < 0.001) and control groups (p < 0.001). Compared to controls, organotypic spinal cord slice cultures maintained on hyaluronic acid-based hydrogel showed 5.9-fold increased survival of choline acetyltransferance-positive motorneurons (p = 0.008), 2-fold more numerous resting microglial cells in the white matter (p = 0.031), and a 61.4% reduction in the number of activated microglial cells within the grey matter (p = 0.05). Hyaluronic acid-based hydrogel had a shear modulus (G') of ≈1200 Pascals (Pa), which was considerably higher than the ≈25 Pa measured for collagen gel. Soluble hyaluronic acid failed to improve tissue preservation. In conclusion, hyaluronic acid-based hydrogel improves neuronal and - most notably - motorneuron survival in organotypic spinal cord slice cultures and microglial activation is limited. The positive effects of hyaluronic acid-based hydrogel may at least in part be due to its mechanical properties.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-216218 (URN)10.1177/0885328213483636 (DOI)000329317100003 ()23674184 (PubMedID)
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2017-12-06Bibliographically approved
Yang, X., Yi, S., Kootala, S., Hilborn, J., Heerschap, A. & Ossipov, D. (2014). Injectable hyaluronic acid hydrogel for F-19 magnetic resonance imaging. Carbohydrate Polymers, 110, 95-99
Open this publication in new window or tab >>Injectable hyaluronic acid hydrogel for F-19 magnetic resonance imaging
Show others...
2014 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 110, p. 95-99Article in journal (Refereed) Published
Abstract [en]

We report on a19F labeled injectable hyaluronic acid (HA) hydrogel that can be monitored by both 1H and 19F MR imaging. The HA based hydrogel formed via carbazone reaction can be obtained within a minute by simple mixing of HA-carbazate and HA-aldehyde derivatized polymers. 19F contrast agent was linked to with carbazate and thiol dually functionalized HA via orthogonal Michael addition reaction which afforded cross-linkable and 19F labeled HA. The 19F labeling of HA polymer did not affect the mechanical properties of the formed hydrogel. As a result, the shape of a hydrogel sample could be imaged very well by both 1H MRI and high resolution19F MRI. This hydrogel has high potential in clinical applications since it is injectable, biocompatible, and can be tracked in a minimally invasive manner. The present approach can be applied in preparation of injectable 19F labeled hydrogel biomaterials from other natural biomacromolecules.

National Category
Polymer Chemistry Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-224259 (URN)10.1016/j.carbpol.2014.03.070 (DOI)000338005000013 ()
Note

Injectable hyaluronic acid hydrogel for 19F magnetic resonance imaging

Available from: 2014-05-09 Created: 2014-05-07 Last updated: 2017-12-05Bibliographically approved
Yang, X., Dogan, I., Pannala, V. R., Kootala, S., Hilborn, J. & Ossipov, D. (2013). A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer. POLYM CHEM-UK, 4(17), 4621-4630
Open this publication in new window or tab >>A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer
Show others...
2013 (English)In: POLYM CHEM-UK, ISSN 1759-9954, Vol. 4, no 17, p. 4621-4630Article in journal (Refereed) Published
Abstract [en]

We have developed a nanoprodrug that enables the uptake by cancer cells and the subsequent intracellular activation. The nanoprodrug is composed of a cancer cell-targeting biopolymer, hyaluronic acid (HA), and an anti-cancer drug, camptothecin (CPT). The chemical linkage between the polymer and the drug is stable outside the cells, thus maintaining the drug in an "off" state. The specific uptake of the nanoprodrug by cancer cells should then lead to an environmental change that results in the cleavage of the linkage, liberating the drug and thus entering the "on" state. The natural cancer-targeting biopolymer HA was modified with aldehyde "click" groups. This "clickable" HA was then conjugated to CPT modified with a hydrazide linker using a mild hydrazone-coupling reaction. The linker consists of a thiol-activated self-immolative dithioethoxycarbonyl spacer, which is stable in PBS buffer but should be rapidly cleaved in the reductive cytosolic environment of cancer cells. The resulting HA-CPT nanoprodrug released CPT only at low levels in PBS buffer. However, the drug was efficiently cleaved after the addition of dithiothreitol (DTT). Consistent with these data, the HA-CPT nanoprodrug showed a 3-fold greater cytotoxicity to cancer cells compared to free CPT. Fluorescence microscopy confirmed the rapid and efficient uptake of the HA-CPT nanoprodrug by the cancer cells.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-207489 (URN)10.1039/c3py00402c (DOI)000323361300013 ()
Available from: 2013-09-17 Created: 2013-09-16 Last updated: 2014-06-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/I-9004-2014

Search in DiVA

Show all publications