Library · Materials, chemistry & fabrication
What Chemical Functionalization & Crosslinking got wrong, from 48 theses
Summary written by a model from the records below: Chemical functionalization and crosslinking strategies frequently encounter failures stemming from inappropriate network density, material instability, and cytotoxic reagents. In addition, covalent chemical modifications often compromise the electronic integrity of carbon nanomaterials or sterically impede biological activity and molecular transport. These records come from graduate theses, 2021 to 2026, each labeled with its degree where the repository states it, and each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Plus 8 problems the authors left open, listed at the end.
Failure modes, by theses reporting them
Select a mode to jump to its records.
Insufficient crosslinking density leads to mechanical collapse, rapid dissolution, or premature degradation
Hydrogels fabricated with inadequate crosslinker concentration or lacking covalent network stabilization fail to maintain structural integrity and exhibit mechanical failure under load. These weakly crosslinked networks readily dissolve in aqueous media or degrade prematurely under physiological and hydrolytic conditions.
Tried and failed
multivalent cation crosslinking of biopolymer hydrogels applied to hydrogel bead synthesis. Outcome: unstable. Reason: insufficient polymer or crosslinker concentration failed to form stable gel network
The Valorization of Agricultural by Products for the Removal of Inorganic Phosphate from Water · University of Windsor · PhD
Tried and failed
uncrosslinked high molecular weight hyaluronic acid applied to cell delivery and viability. Outcome: worse than baseline. Reason: lack of crosslinking structure led to poor cytocompatibility and cell viability below buffer controls
A Biomaterial-based Stem Cell Therapy for Retinal Regeneration · MIT · PhD
Tried and failed
photopolymerization with low precursor or initiator concentration applied to hydrogel fabrication. Reason: insufficient crosslinking led to hydrogels that were too mechanically weak to handle
POLYMERIZATION AND VOLUMETRIC PRINTING OF SOFT COMPOSITES · Cornell · PhD
Tried and failed
hydrogel with low crosslinker ratio applied to microneedle skin insertion. Outcome: unstable. Reason: insufficient crosslinking led to poor mechanical strength causing mechanical failure during insertion
Engineered Microneedle Patches for Biomarker Quantification and Interstitial Fluid Collection · Georgia Tech · PhD
Tried and failed
hydrogel without covalent enzymatic crosslinking applied to cell outgrowth in tissue engineering scaffolds. Reason: lack of enzymatic covalent stabilization failed to support cell outgrowth
ENGINEERING HYDROGEL MICROSTRUCTURE TO PROMOTE MENISCUS REPAIR · Penn · PhD
Tried and failed
low-concentration thiol-ene photocrosslinked hybrid hydrogels applied to in vitro cell culture scaffolds. Outcome: unstable. Reason: insufficient network crosslinking density led to premature hydrolytic or enzymatic degradation within days
An engineered biosynthetic hydrogel for 3D neural tissue interfaces · Imperial · PhD
Tried and failed
multivalent cation crosslinking applied to chitosan hydrogels. Outcome: unstable. Reason: cation hydrolysis reduced pH causing polymer dissolution instead of stable network crosslinking
Fracture of Complex Hydrogels: Dynamic and Microstructural Effects · Harvard · PhD
Tried and failed
low-concentration dialdehyde crosslinking of biopolymer-clay composites applied to hydrogels for aqueous separation. Outcome: unstable. Reason: insufficient crosslinking density allowed hydrogel matrix to dissolve in water within days
Precise Ion Separation by Engineered Polymer Composites for Phosphorous Recovery · Georgia Tech · PhD
Chemical crosslinkers and initiation conditions induce cytotoxicity, physiological instability, or off-target reactivity
Reactive chemical crosslinkers and free radical photoinitiators generate toxic environments that diminish cell viability and cause cell detachment. In addition, chemically crosslinked matrices can degrade unexpectedly fast under physiological conditions or trigger cross-reactivity with encapsulated proteins and functional groups.
Tried and failed
Vinyl sulfone and acrylate hydrogel crosslinking applied to primary cell and lymphoma cell encapsulation. Reason: Cytotoxicity and slow gelation kinetics prevented cell survival in the hydrogel
Immune Organoids to Study Antigen Presentation · Cornell · PhD
Tried and failed
Ester-linked synthetic polymer hydrogel crosslinking applied to in vivo cell delivery scaffolds. Outcome: unstable. Reason: In vivo enzymatic or physiological conditions accelerated hydrolytic degradation far faster than in vitro predictions
Synthetic Hydrogels for the Maturation and Engraftment of Stem Cell-Derived Beta Cells · Georgia Tech · PhD
Tried and failed
cryogel scaffolding with chemical crosslinking initiators applied to stem cell culture and maintenance. Reason: toxic residual crosslinking initiators and cell-induced matrix shrinkage reduced cell viability over time
Biomaterials for acellular dental tissue regeneration · Imperial · PhD
Tried and failed
in situ secondary photocrosslinking for dynamic stiffening applied to cell-laden hydrogel culture. Reason: radical generation during secondary UV photoinitiation caused severe cytotoxicity and cell detachment
Developing a hydrogel model to study the role of environmental factors on pulmonary fibroblasts · UT Austin · PhD
Considered and rejected
Considered and rejected: UV-crosslinking hydrogels were rejected for dynamic stiffening due to UV- and crosslinker-induced DNA damage, cell toxicity, and cytoskeletal artifacts.
Passive nuclear uptake dynamics of small molecules in cancer · UT Austin · PhD
Considered and rejected
Considered and rejected: Rejected covalent hydrogel crosslinking due to potential lack of biological inertness and cross-reactivity with encapsulated proteins and cells.
Synthesis and evaluation of polymer mosaics as highly tunable biomaterials for biomedical applications · Boston University · PhD
Considered and rejected
Considered and rejected: Rejected using DTT or TCEP reducing agents to prevent polysaccharide disulfide crosslinking because they oxidize/crosslink vinyl sulfone and maleimide acceptor groups during hydrogelation.
Entwicklung Polysaccharid-basierter Materialien für biomedizinische Anwendungen · Leibniz Universität Hannover · PhD
Membrane crosslinking procedures cause oxidative linkage damage, pore collapse, or diffusion limitations
Thermal crosslinking under unsuitable atmospheres causes oxidative degradation of polymer linkages or structural collapse of intersegmental free volume. Furthermore, large crosslinker molecules suffer from diffusion limitations during post-functionalization, causing incomplete reactions and non-uniform gelation.
Tried and failed
covalent crosslinking of low molecular weight polymer membranes applied to organic solvent nanofiltration membranes. Outcome: unstable. Reason: insufficient chain entanglement caused membrane densification and continuous permeance decline in polar aprotic solvents
Organic solvent stable membranes for defined sequence polymer synthesis · Imperial · PhD
Tried and failed
thermal crosslinking under oxidative atmosphere applied to crosslinked polymer gas separation membranes. Outcome: worse than baseline. Reason: excess oxygen caused oxidative degradation of amide and urea linkages, reducing permeability without improving selectivity
Post-Synthetic Chemical and Morphological Modifications of Polymer Membranes for Gas Separations · MIT · PhD
Tried and failed
equimolar post-functionalization crosslinking of polymer membranes applied to composite polymer membranes. Reason: diffusion transport limitations of large crosslinker molecules prevented consistent reaction completion
Understanding and enabling organic solvent separations with molecularly mixed composite membranes · Georgia Tech · PhD
Tried and failed
thermal deprotection without crosslinking atmosphere applied to microporous polymer membranes. Outcome: worse than baseline. Reason: intersegmental spacing collapsed from hydrogen bonding and chain relaxation lacking oxidative crosslinks
Post-Synthetic Chemical and Morphological Modifications of Polymer Membranes for Gas Separations · MIT · PhD
Tried and failed
thermal crosslinking under inert atmosphere applied to microporous polymer membranes. Outcome: worse than baseline. Reason: failed to crosslink and caused free volume collapse and penetrant immobilization
Design, Synthesis and Applications of Versatile Porous Poly(arylene ether)s · MIT · PhD
Tried and failed
carbodiimide covalent crosslinking of porous composite membranes applied to metal-organic framework polymer composites. Outcome: unstable. Reason: framework partially lost its crystallinity during the chemical crosslinking and subsequent drying steps
Microporous Polymer-Metal Organic Framework (MOF) Hybrid Materials for Separations · MIT · PhD
Tried and failed
increasing viscosity via polysaccharide blending before crosslinking applied to porous hydrogel networks. Outcome: worse than baseline. Reason: excessive viscosity hindered uniform crosslinker diffusion, causing inhomogeneous gelation and impaired transport properties
Materials design and surface engineering of functional hydrogels for solar desalination and water purification · UT Austin · PhD
Considered and rejected
Considered and rejected: Rejected chemical crosslinking using diamines for bulk membranes due to heavy use of hazardous solvents and poor degree of control across morphologies.
Designing Organic Solvent Reverse Osmosis Membranes for The Separation of Liquid Hydrocarbons · Georgia Tech · PhD
Excessive crosslinking density causes severe matrix embrittlement, pore contraction, and transport reduction
High crosslinking densities contract matrix pores and over-densify networks, which suppresses mass transport, reduces permeance to background levels, and limits cellular spreading. Over-crosslinking also causes embrittlement, gel cracking, and mechanical failure under perfusion.
Tried and failed
glutaraldehyde chemical fixation before hydrogel embedding applied to expansion microscopy of cellular samples. Reason: excessive protein crosslinking caused gel cracking and prevented isotropic expansion
Toward Ultra-Resolution Biomolecular Mapping in Cells with Expansion Microscopy · MIT · PhD
Tried and failed
increased crosslinking and chemical post-treatment of hydrogels applied to perfused microfluidic tissue scaffolds. Outcome: unstable. Reason: extended crosslinking or genipin treatment caused scaffold leakage and complete endothelial cell detachment during perfusion
Integrating 3D Bioprinting and Cortical Organoids to Create a Tunable Platform for Modeling Human Neurodevelopment · Georgia Tech · PhD
Tried and failed
high-density photocrosslinked hydrogel encapsulation applied to 3D vascular cell culture. Reason: excessive crosslinking density restricted matrix porosity and prevented cell spreading and elongation
VASCULARIZATION OF BIOENGINEERED FAT WITH TUNABLE MATRIX PROPERTIES FOR MACRO-PERFUSION AND SOFT TISSUE RECONSTRUCTION · Cornell · PhD
Tried and failed
post-synthetic functionalization and crosslinking of microporous polymers applied to organic solvent nanofiltration membranes. Reason: excessive densification and pore contraction reduced permeance down to the background leak rate
MICROPOROUS SPIROCYCLIC POLYMERS FOR MEMBRANE SEPARATIONS OF CRUDE OIL MIXTURES · Georgia Tech · PhD
Tried and failed
increasing plasticizer concentration in crosslinked polymer gel applied to gel polymer electrolytes. Outcome: worse than baseline. Reason: excessive crosslinking increased storage modulus and reduced ionic conductivity
ENGINEERING EFFICIENT ELECTROLYTES FOR HIGH-PERFORMANCE LITHIUM SULFUR BATTERIES · Cornell · PhD
Considered and rejected
Considered and rejected: Rejected PVDF crosslinking beyond 3 h because excessive crosslinking caused severe membrane embrittlement (elasticity dropping to <1%) and enlarged pore sizes (>140 nm).
Nanostructured solvent-stable membranes for solvent permeation and pharmaceutical separation · Imperial · PhD
Considered and rejected
Considered and rejected: Ignored polymer resin compositions with PEGDA crosslinker >60 wt% because excessive chain crosslinking diminished monomer-specific property contributions.
Tandem Development of Novel Materials and Manufacturing Techniques for Direct Ink Write 3D Printing · Georgia Tech · PhD
Steric hindrance and structural distortion from functionalization compromise binding and catalytic activity
Bulky ligands, dense conjugations, and prolonged crosslinker exposure crowd surfaces and block substrate or antibody access through steric hindrance. Similarly, chemical crosslinking or proximal mutations can disrupt essential tertiary enzyme structures and restrict catalytic hinge motions.
Tried and failed
mutating active-site-proximal residues to prevent modification applied to enzyme activity retention after chemical conjugation. Outcome: worse than baseline. Reason: mutations near the active site or subunit interface impaired or eliminated catalytic activity
Enzyme-mediated methylthioadenosine depletion as a novel immune checkpoint therapy · UT Austin · PhD
Tried and failed
sterically hindered ortho-substituted substrate relay metathesis applied to catalytic polymer functionalization. Outcome: worse than baseline. Reason: steric hindrance impeded ligand re-association, destabilizing active catalytic intermediates and lowering conversion
The design and application of functional enyne reagents in metathesis polymerization · Georgia Tech · PhD
Lost to a baseline
Conjugation of quinidine into poly(acrylic acid) backbone resulted in a modest loss of in vitro P-gp inhibitory potency compared to free quinidine due to steric hindrance.
Multimodal Engineering Approaches to Circumvent P-glycoprotein-Mediated Multidrug Resistance in Cancer · Cornell · PhD
Considered and rejected
Considered and rejected: Glutaraldehyde crosslinking of adsorbed enzymes on nanoflowers was rejected due to risk of distorting tertiary/quaternary enzyme structure and blocking substrate/product diffusion.
ENZYME IMMOBILIZATION ON HIERARCHICAL MATERIALS FOR THE VALORIZATION OF FOOD BYPRODUCTS · Cornell · PhD
Considered and rejected
Considered and rejected: Rejected C-terminal domain disulfide crosslinking (αQ399C/βQ441C) because it restricted essential catalytic hinge motions and abolished enzymatic activity.
Strategies for covalent stabilization of F1-ATPase to enhance its usability as a nanomotor. · Texas Tech · PhD
Tried and failed
bulky aromatic group post-synthetic functionalization applied to porous framework gas adsorbents. Outcome: worse than baseline. Reason: bulky functional groups sterically blocked accessible pore space, significantly reducing target molecule adsorption capacity
Influence Of Water Vapor on the Adsorption of Exhaled Breath-Borne VOC Biomarkers for COVID-19 · Georgia Tech · PhD
Covalent functionalization disrupts conjugated sp2 networks and degrades electronic properties
Covalent attachment and diazonium modification convert sp2 carbon networks into sp3 hybridized defects that act as scattering sites. These structural disruptions degrade electrical conductivity, carrier mobility, and redox currents across carbon nanomaterials.
Tried and failed
prolonged chemical functionalization applied to graphene electrodes. Outcome: worse than baseline. Reason: extended exposure to functionalization solution caused surface damage, severely degrading redox current
Thin-film transistor : characterization, scaling studies, and applications in electrochemical charge sensing · UT Austin · PhD
Tried and failed
covalent functionalization with diazonium salts applied to graphene field-effect transistors. Outcome: worse than baseline. Reason: sp2 to sp3 rehybridization creates scattering sites, degrading carrier mobility and electrical conductivity
Graphene field effect transistor biosensor platform for detection of disease biomarkers in physiological solutions · Imperial · PhD
Tried and failed
extended incubation of pyrene ester crosslinkers applied to graphene surface functionalization. Reason: prolonged incubation causes ester hydrolysis and structural defect formation, reducing active functionalization sites
Graphene field effect transistor biosensor platform for detection of disease biomarkers in physiological solutions · Imperial · PhD
Considered and rejected
Considered and rejected: Rejected covalent functionalization in favor of noncovalent π-π stacking to avoid disrupting graphene's sp2 network and degrading electrical conductivity.
Graphene as an active material for sensors and other devices · Politecnico di Torino · PhD
Considered and rejected
Considered and rejected: Rejected covalent functionalization/acid oxidation routes for GNPs because disruption of sp2 hybridization damages electrical and thermal conductivity.
Structure-Property Relationships of Graphene Nanoplatelets and their Functionalization to Enable Applications in Composites and Supercapacitors · Queen's University · PhD
Surface functionalization and homobifunctional crosslinkers trigger colloidal aggregation and particle instability
Dense ligand modification or unsuitable functionalization chemistry can cause irreversible nanoparticle aggregation and rapid sedimentation. Homobifunctional crosslinkers and incompatible surface interactions promote inter-particle crosslinking and repulsive agglomeration.
Tried and failed
single-ligand surface functionalization applied to nanoparticles in high-salinity brine. Outcome: unstable. Reason: insufficient electrostatic/steric screening caused rapid aggregation and sedimentation under high ionic strength
Tried and failed
dense ligand functionalization via click chemistry applied to protein nanoparticle surfaces. Outcome: unstable. Reason: high ligand density caused irreversible particle aggregation
Protein Nanoparticles For Applications In Chemical Biology And Immunology · Georgia Tech · PhD
Considered and rejected
Considered and rejected: Exclusion of cation-containing reducing agents (such as sodium borohydride) during nanoparticle synthesis to prevent undesired aggregation and simplify conjugation.
Development of Au-Pt Nanoflowers as Nanoenzyme for Highly Sensitive Immunoassay: Application to the Detection of Melioidosis Biomarker · University of Nevada, Reno · Master's
Considered and rejected
Considered and rejected: Decided against DTSSP homobifunctional crosslinking for nanoparticle surface coating in favor of heterobifunctional SDAD to prevent soluble coat antigen self-aggregation and inter-particle crosslinking.
Development and Immunological Evaluation of Protein-Based Nanoparticle Vaccines · Georgia Tech · PhD
Considered and rejected
Considered and rejected: Rejected pristine graphene without functionalization/spacers because smooth surfaces cause severe van der Waals agglomeration and poor interfacial bonding.
High Thermal Conductivity Epoxy Composites In The Application Of 3D Semiconductor Packaging · Georgia Tech · PhD
Non-covalent physical functionalization fails due to weak binding affinity and interfacial detachment
Non-covalent adsorption methods suffer from reversible detachment when exposed to buffers, surfactants, or dynamic environments. Because physical interactions lack the stability and adhesion energy of covalent networks, non-covalent functionalization fails to provide durable coatings.
Considered and rejected
Considered and rejected: Physical crosslinking methods (such as ionic crosslinking and thermogelation) for polysaccharide-protein conjugate synthesis rejected due to instability compared to covalent linkages.
Synthesis of Polysaccharide-based Biomaterials for Drug Delivery · Virginia Tech · Doctorate
Tried and failed
non-covalent physical adsorption of targeting proteins applied to nanoparticle surface functionalization. Outcome: unstable. Reason: adsorption failed to provide stable coatings and did not enhance cellular uptake
Engineering Biomaterial - Protein Corona Interactions to Mediate Biological Responses · Georgia Tech · PhD
Tried and failed
incorporating reversible non-covalent crosslinkers applied to polymer network adhesion. Outcome: worse than baseline. Reason: decreases adhesion free energy compared to covalent networks at identical crosslinking density
In Silico study of hydrogel adhesives · Imperial · PhD
Tried and failed
passive electrostatic adsorption for protein immobilization applied to biosensor surface functionalization. Outcome: unstable. Reason: random molecular orientation and detachment caused by buffers and surfactants led to poor adhesion and low signal
Capillary-driven Microfluidic Biosensing Platforms for Digital Biomolecule Detection · Texas Tech · PhD
Left open by the authors
Problems the authors named and did not get to.
Left open
Develop secondary crosslinking or mechanical restraint methods to stabilize dynamic hydrogels against dissolution during long-term cell culture. Blocker: Requires a wet lab, chemical synthesis, hydrogel fabrication, and cell culture facilities
Investigating the stimuli responsiveness of reversible thia-conjugate addition crosslinked hydrogels · UT Austin · PhD
Left open
Synthesize advanced hydrogel biomaterials that independently decouple crosslinking density and mesh size from stiffness. Blocker: Requires chemical synthesis and wet-lab material characterization facilities
Biomaterial-driven lymphangiogenesis using click-crosslinked gelatin hydrogels · Imperial · PhD
Left open
Mechanistically distinguish cation-mediated crosslinking stiffening from Hofmeister ion-specific salting out in nucleopeptide hydrogels. Blocker: Requires wet-lab synthesis, buffer preparation, and biophysical/rheological characterization experiments
Biological buffer-mediated self-assembly of modular nucleo-peptide hydrogels for tissue engineering applications · UT Austin · PhD
Left open
Develop surface functionalization and capping strategies for plasmonic metal nitride nanoparticles to improve colloidal stability and solvent dispersion. Blocker: Requires wet-lab chemical synthesis, specialized reagents, and experimental characterization apparatus.
SYNTHESIS, CHARACTERIZATION, AND PHOTOTHERMAL PROPERTIES OF PLASMONIC METAL NITRIDE NANOPARTICLES · Dalhousie · PhD
Left open
Functionalize silicalite-1 zeolite nanoparticles to reduce toxicity and improve colloidal stability for in vivo clinical use. Blocker: Requires wet lab chemical synthesis, nanoparticle surface functionalization, and in vivo biomedical/toxicological testing apparatus.
Using zeolites to create microporous water with high gas carrying capacities · Harvard · PhD
Left open
Optimize reaction solvents, incubation times, and reagent concentrations to maximize drug and aptamer grafting efficiency on multi-functionalized harmonic nanoparticles. Blocker: Requires a wet chemistry lab to synthesize nanoparticles, perform functionalization reactions, and measure grafting efficiency.
Functionalization of Harmonic Nanoparticles for Active Cancer Targeting · EPFL · PhD
Left open
Reoptimize PPSMI nanoparticle functionalization protocols using cyclopentadiene chemistry in place of amine-silanes. Blocker: Requires a wet chemistry laboratory to synthesize and functionalize silica nanoparticles.
Left open
Enhance particle coating stability on polymer optical fibers using post-crosslinking, covalent attachment without aggregation, or in-situ particle growth. Blocker: Requires a chemistry wet lab, synthesis of nanoparticles, plasma treatment apparatus, and optical fiber functionalization materials.
Functionalization of polymer optical fibers for medical application · EPFL · PhD
Who has worked on this
Authors of the public theses cited on this page, most-cited first.
- Taigyu Joo · MIT · PhD · 2024
Post-Synthetic Chemical and Morphological Modifications of Polymer Membranes for Gas Separations - Tianyi Yin · Imperial · PhD · 2024
Graphene field effect transistor biosensor platform for detection of disease biomarkers in physiological solutions - Hang Yang · Harvard · PhD · 2026
Fracture of Complex Hydrogels: Dynamic and Microstructural Effects - Boyuan Hao · Imperial · PhD · 2026
Nanostructured solvent-stable membranes for solvent permeation and pharmaceutical separation - Alessandra Spada · EPFL · PhD · 2026
Functionalization of Harmonic Nanoparticles for Active Cancer Targeting - Vaidik Shah · Cornell · PhD · 2025
ENGINEERING EFFICIENT ELECTROLYTES FOR HIGH-PERFORMANCE LITHIUM SULFUR BATTERIES - Cara Robertus · Cornell · PhD · 2025
Multimodal Engineering Approaches to Circumvent P-glycoprotein-Mediated Multidrug Resistance in Cancer - Elizabet Moreno Reyes · Cornell · PhD · 2025
ENZYME IMMOBILIZATION ON HIERARCHICAL MATERIALS FOR THE VALORIZATION OF FOOD BYPRODUCTS - Melissa Andrea Cadena · Georgia Tech · PhD · 2025
Integrating 3D Bioprinting and Cortical Organoids to Create a Tunable Platform for Modeling Human Neurodevelopment - Mallika Kumar · Texas Tech · PhD · 2025
Strategies for covalent stabilization of F1-ATPase to enhance its usability as a nanomotor. - Ojuolape Olawunmi Oghenetega · Georgia Tech · PhD · 2024
Influence Of Water Vapor on the Adsorption of Exhaled Breath-Borne VOC Biomarkers for COVID-19 - Yi Ren · Georgia Tech · PhD · 2024
Designing Organic Solvent Reverse Osmosis Membranes for The Separation of Liquid Hydrocarbons
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