Design & Characterization of Tribologically Enhanced Hydrogels for Biomedical Applications

A Thesis Submitted in Partial Fulfillment of theRequirements of the Renée Crown University Honors Program at

Syracuse University

Katherine Lindsley

Candidate for Bachelor of Science Degreeand Renée Crown University Honors

Spring 2020

Honors Thesis in Your Major

Thesis Advisor: _______________________ Dr. Michelle Blum, Associate Teaching Professor

Thesis Reader: _______________________ Dr. Jackie Anderson, Assistant Teaching Professor

Honors Director: _______________________ Dr. Danielle Smith, Director

Abstract

Osteoarthritis is a disease that involves the degradation of articular cartilage until bones are in contact with each other. Bone on bone contact in joints produces pain that often limits mobility of those suffering with it. Articular cartilage does not easily heal on its own, therefore leaving treatment options limited. The most common is an invasive and painful surgery that partially or fully replaces the joint which causes long recovery periods with limited implant life spans. Here lies the need for a material with comparable friction and wear properties as articular cartilage. This project includes the use of tribologically enhanced hydrogels and the addition of lubrication to determine its effects on the coefficient of friction and resistance to wear seen in these hydrogels. The hydrogels are fabricated with polyvinyl alcohol (PVA) crosslinked during freeze thaw cycles to maintain their structure. Lubrication, PMEDSAH and PMPC (brush only), is either added before the crosslinking stage, or is grafted on top of the hydrogel after swelling. The coefficient of friction (COF) of each sample is determined through loading into a rheometer and spun against a petri dish at different angular velocities at a load of 40 Newtons. The wear is determined through running a pin over the surface of the hydrogel for 10,000 cycles then imaged with the HIROX microscope to determine the degree of wear. Results indicate that PMPC brush gels reduce the COF of friction the most. Individually, the low and medium blends of PMEDSAH have the lowest COF of blend gels. The blends also exhibit a repulsive interaction whereas the plain hydrogels exhibit an adhesive interaction. The wear results indicate that weight percentages of 70% and above of PVA experience little to no wear at all. Weight percentages below 70% were inconclusive due to positioning error within the tribometer. The positioning drifted during testing causing for the gels to pop out of the holder and causing for the gels to puncture prematurely. The results of this research indicate inclusion of lubrication of any kind decreases the COF for the hydrogels. The most effective lubrication is the PMPC brush hydrogel and is not dependent on the type of bath it is submerged in. With continued testing of different compositions along with determining proper wear, will help develop a material with comparable tribological characteristics to articular cartilage.

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Executive Summary

This project includes the development of a material that can replace articular cartilage

within the human body. Articular cartilage is the most common type of cartilage in weight

bearing joints and often wears away over time. Once defects are found in the cartilage, it is hard

for it to selfheal since there is no direct blood supply to the cartilage. This usually means that

once damage has been done, there is little that can be done to repair it. The degradation of

cartilage leading to bone on bone contact is known as osteoarthritis. Patients with Osteoarthritis

can develop symptoms such as pain, swelling, and limited mobility within the joints. Current

treatment options are limited and often invasive with long recovery periods. The most common

treatment is a partial or total joint replacement. This surgery is not only invasive, but it includes

long recovery periods and the implants often has short life spans. This treatment is less than ideal

especially for younger patients that want to resume high impact physical activity after surgery.

Because of these poor treatment options, there exists a need for a material with

comparable qualities to articular cartilage that can be transplanted to preserve the original joints.

The material must reduce friction between surfaces as well as being able to withstand large loads

over long periods of time such that mimics human activity. The material being studied in this

project is hydrogels. Hydrogels are a biocompatible material that is created from a polymer that

is swelled in water. Specifically, the polymer used is polyvinyl alcohol (PVA). The addition of

lubrication in the composition of the hydrogels should help reduce the friction experienced from

the material but may hinder how much wear the hydrogel can withstand before breaking.

The hydrogels are created by measuring out PVA and mixing with deionized water to

create a solution. This solution is repeatedly frozen and thawed to create the structure that the

hydrogel needs. The samples are then swelled in water to create the gel like texture. Lubrication

can be added in two ways. Lubrication can be added in various concentrations to the solution

before freezing and thawing or after the hydrogel is swollen by grafting the lubricant on the

surface. Two different polymers were used as lubricants, PMEDSAH and PMPC. The

PMEDSAH was used for both blend and brush gel testing, but PMPC was only used in the brush

hydrogel testing.

Once samples are created, they are put through two types of testing. The first type is to

determine the friction experienced by the hydrogel. The hydrogels are placed into a machine

called a rheometer which takes the hydrogels and forces them to spin against a petri dish filled

with water. The forces recorded by the rheometer help to calculate the coefficient of friction

which determines the friction experienced by the material loaded. The wear test takes each

hydrogel and puts a pin on top and moves it back and forth across the surface 10,000 times. This

test determines how much the surface wears away after continual usage. The hydrogels are then

imaged to determine exactly how much wear occurred.

This project is significant because it aims to develop a material to replace articular

cartilage. The development of this material would allow people suffering from arthritis caused by

cartilage degradation to have a treatment that is less invasive than total joint replacement. This

also would allow patients to preserve their own joints along with being able to return to an active

lifestyle without having to worry about the life span of their implants. This material could

revolutionize the treatment for conditions such as Osteoarthritiseasing the pain of the patients

who live with it every day.

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Table of Contents

Abstract……………………………………….……………….………….. iiExecutive Summary………………………….……………….………….. iv

Chapter 1: Introduction ……………………………………………… 1

Chapter 2: Methods ……………………………………………………… 4

Chapter 3: Results and Discussion ……………………………………… 9

Chapter 4: Conclusions ……………………………………………… 12

Chapter 5: Future Work ……………………………………………… 14

Works Cited.……………………………………………………………… 19

1

Chapter 1

Introduction

Throughout its lifetime, the body is subjected to repeated and varying loads, even through

the smallest of activities. This repeated loading places high levels of stress on various structures,

including joints. These joints are meant to connect various bones that allow for humans to move

and perform activities. Since joints are subject to repeated motion and stresses, connective and

protective tissues are positioned in joints to smooth and distribute stress between opposing

surfaces of the bone.

The most common type of joint in the body is known as a synovial joint [1]. This joint is

meant to support a wide variety of motions and forces from loads that can be as high as several

times a person’s own body weight.

Synovial joints contain a variety of functions necessary for fluid movement and weight

bearing. The structure that is particularly of interest for this research project is articular cartilage.

Figure 1: (a) Illustration of the six primary joints found in humans. (b) Illustration of the primary structures found in the knee joint. This joint behaves like a complex hinge.

2

Articular cartilage plays a role in reducing friction and distributing stress between bone surfaces.

This tissue is smooth and white and helps create the fluidity of motion necessary for proper

function. This tissue is also characteristically soft with a high-water content, about 60 to 80% [2].

The solid portion of the tissue is mostly composed of several types of collagen, which creates the

structure needed for bearing weight.

Like any material that is subjected to dynamic loading at various intensities, the cartilage

in joints is prone to degradation, especially in people who perform high impact exercises

regularly. Focusing specifically on the knee, these high impact exercises can include jogging,

jumping, dancing, hiking, and more. Since the structure of articular cartilage lacks high cell

density and is not associated with blood vessels, self-repair does not occur often or efficiently

[2,3]. This means that the smallest of tears, about 2-4 nm, do not usually heal, and degrade

surrounding tissue quickly causing bone on bone contact [4]. Cartilage is meant to reduce

friction and distribute stress along the bone surfaces, so once there is no protection against bone

interaction. This is often associated with Osteoarthritis, which can cause pain and stiffness in

joints [5]. These symptoms are often chronic and severely limits mobility of those who are

diagnosed.

There are few treatment options, but often they are quite invasive. Treatments that try to

preserve the original joint include a transplant of healthy cartilage. This procedure requires

cartilage from a lower weight bearing joint that is transplanted into the affected area [6-8]. This

treatment is usually reserved for young patients, those under the age of 50 [9]. This surgery

allows for preservation of the original joint, but it directly impairs another joint for its own

repair. Also, the success widely depends on the age of the patient and the ability to locate enough

tissue for transplantation. Since this option is severely limited, patients often require a partial or

3

total replacement of the joint [10-12]. Even though this alleviates the original problem, there are

several drawbacks to this treatment method as well. The surgery itself is invasive and requires a

long recovery period with lots of physical therapy. Coupled with the short life span of these

implants, this treatment option is less than ideal, especially for younger patients.

Transplantation would be a superior option, but the lack of healthy cartilage that can be

used without the severe impairment of other joints reduces the viability of this procedure.

Transplantation, though, could be revolutionized with the introduction of a synthetic material

that can be transplanted into the joint without impairing others. However, there currently is no

known man-made material with sufficient enough properties to those of articular cartilage

[13,14].

The goal of this research is to investigate known synthetic materials to determine and

enhance properties focusing on finding materials that could possibly replace articular cartilage.

Finding a replacement for this cartilage would allow less invasive treatment options such as the

transplantation of a synthetic material without impairing other joints. This also would alleviate

the need for partial and total joint replacements. Without the need for such invasive surgeries,

patients can find relief without the long and intense healing process especially for younger

patients.

The study of such synthetic materials, articulating, and their properties is known as

tribology [15]. Tribology is an expansive field that studies the friction and wear behavior of

articulating surfaces of mechanical systems. The theories based on chemistry, material science,

and solid and fluid mechanics can be applied to other less conventional surfaces such as joints

within the human body [15,16]. The study of tribology along with the addition of a material

called hydrogels allowed for the development of tribologically enhanced hydrogels.

4

Hydrogels are a type of polymer that is widely used for biomedical applications.

Hydrogels are crosslinked polymers that are swelled in water to create a gel like texture. The

crosslinked polymers allow for these gels to retain their shape despite their submersion in water.

Varying stiffnesses of these structures can be manipulated based on how much polymer is added.

Hydrogels have a wide range of applications in biomedical technology, but due to their poor

tribological properties they are not ideal for the use in load bearing applications such as the

replacement of articular cartilage [17-19]. However, through the changing in composition of the

polymers, their tribological properties can be enhanced. This investigation specifically focuses

on the reduction of the coefficient of friction (COF) of Poly-vinyl Alcohol (PVA) hydrogels as

well as determining the amount of wear that each hydrogel can withstand.

5

Chapter 2

Method

This research focuses on reducing the coefficients of friction of PVA hydrogels by the

addition of lubricants. The lubrication is added in two forms, a blend and a brush. The blends

have the lubricant added during fabrication while the brush gels have a structure grafted on top

of the hydrogel surface to create lubrication.

The fabrication of PVA hydrogels without lubrication is described below. A solvent is

created with PVA and deionized (DI) water so that 40% by weight consisted of the PVA. The

mixture was heated to 90 degrees Celsius in an isothermal oven for six hours to create a viscous

solution. Note that the solution was not stirred in order to prevent bubbles from forming within

the gels. The solution then undergoes four cycles of freezing and thawing. Freezing occurs at -80

degrees Celsius for 30 minutes, and thawing occurs directly after at room temperature for 30

minutes. The freeze thaw cycles allow for the polymers to crosslink, which creates the crystalline

structure. The samples were then submerged in DI water for 48 hours to allow for swelling. The

final samples are 12mm in diameter and have a thickness of 5mm.

For wear testing only, hydrogels were made using the same method as described above,

but with varying weight percentages of PVA. The varying weight percentages is to determine if

wear properties can be enhanced by varying the chain length of the base polymer used.

6

In order to fabricate the blend hydrogels, a zwitterionic polymer PMEDSAH was added

to the solution before the freeze thaw cycles. The polymer was prepared through a free radical

polymerization of MEDSAH. This reaction was performed for six hours at 65 degrees Celsius.

The aqueous PMEDSAH was then added to the PVA solution in varying molecular weights. The

molecular weights of the final samples varied from 50% to 80% in intervals of 10% PMEDSAH.

Once the blend solution was completed, the samples follow the same procedure as described

previously.

Figure 2: Schematic of hydrogel fabrication procedure: (a) Structure of PVA and a cartoon depiction of PMEDSAH, (b) Illustration of heating PVA-PMEDSAH solution, (c) Hydrogel crosslinking and (d) Final product.

7

In order to fabricate the brush hydrogels, the procedure varies slightly. Since the

lubrication is grafted on top of the hydrogel,

a plain PVA hydrogel must be fabricated

first. Unlike the blend hydrogels, two

different zwitterionic polymers were grafted

to the surface of the hydrogels. These

polymers include both PMEDSAH and

PMPC. The brush gels were fabricated

using atom transfer radical polymerization.

Grafting consists of two steps, initiator

functionalization, and surface-initiated polymerization using the technique above. Brush

hydrogels were fabricated for each polymer to include low, medium, and high concentrations of

lubrication grafted to the surface. Once grafting was completed the hydrogels are then swelled in

DI water.

8

All sample types, blends with different molecular weights, and brush gels with different

grafted polymers were stored submerged in DI water to ensure swelling equilibrium. Hydrogels

were only out of DI water when transferring them to holders for testing.

In order to simulate joint conditions, two different tests were conducted, friction and

wear. The purpose of these tests is to determine which sample provides comparable qualities to

articular cartilage.

To determine the friction experienced by each gel, a rheometer was used. Three of the

same hydrogels were placed into a holder, careful to release any air underneath the gels. The

holder was then loaded into the rheometer. Using the program for this device, the gels are

Figure 3: Brush hydrogel fabrication method

9

lowered into a bath of DI water in a petri dish. The gels are lowered until they touch the bottom

of the dish and is loaded to 40 Newtons. The gels are then brought back out of the water for the

start of the run. During the run the samples are lowered, loaded to a constant 40 Newtons, and

are rotated on the bottom of the petri dish at different angular velocities as specified in the code

setup. The angular velocities are randomized for independent results. This procedure is repeated

for all hydrogel compositions. The brush gels repeat the same procedure twice but replacing the

DI water with a .2 Moles NaCl bath during the second run. This is only for the brush gels to

determine if a saltwater solution reduces friction further. All raw data from the friction testing

was exported and compiled to calculate coefficients of frictions (COF) for each test ran. The

COF was calculated using the torque and normal force measurements from raw data from the

rheometer.

The second test simulates wear that hydrogels would encounter due to movement. This

test consists of a loaded pin travelling across the hydrogel for 10,000 cycles to determine the

wear patterns for each PVA weight percentage. One hydrogel is placed into the base of the

tribometer at a time, again escaping any air bubbles that may have been ttapped during insertion

into the holder. The base is then filled with DI water to ensure the gel does not dry out. The top

portion of the tribometer is put into place and the pin is manually shifted to the center of the

hydrogel. Centering the pin ensures that the wear track does not extend beyond the hydrogel. The

10

wear track is 5mm forward and 5mm backwards from the center of the hydrogel so that the entire

track is 10mm. Only the plain PVA samples with varying compositions were used. The enhanced

hydrogels with added lubrication were not used for the wear testing. The samples ran about

10,000 cycles without extra weight added.

At the conclusion of the wear test, each hydrogel was imaged with the HIROX

microscope to determine wear patterns and calculate the severity of degradation. If the hydrogel

was not ripped apart, the same procedure was repeated on a new hydrogel of the same weight

percentage, this time with additional weights loaded on the tribometer to simulate increased

loading during movement.

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Chapter 3

Results and Discussion

Friction testing had varying results based on the type of lubricant used. The figure below

shows the results for the blend hydrogels. The blend hydrogels included low, medium, and high

molecular weights of added PMEDSAH.

Figure 6: Average Coefficient of Friction vs Angular velocity for blend hydrogels

The figure as seen above shows the average coefficient of friction vs the angular velocity

of the sample. The neat PVA represents a plain hydrogel for comparison between the low,

12

medium, and high blends of PMEDSAH. As can be seen, lower blends of PMEDSAH have

lower COF than the high PMEDSAH blend at all angular velocities. This suggests that with

higher molecular weights of PMEDSAH, the stiffer the hydrogels and the more friction seen

between the gel and the surface. The low and medium blends also have lower COF than the Neat

PVA sample, except for the highest angular velocity. It should also be noted that the average

COF of the low and medium blends are very close in value despite the difference in lubrication.

As also seen from the figure above, all PMEDSAH blends have a positive relationship. This

means that the average COF increases as angular velocity increases. However, this is not the case

for the Neat PVA sample. This sample’s average COF increases dramatically until about 1 rad/s,

and then decreases significantly to the highest angular velocity of 5 rad/s. This may be attributed

to theories based in fluid mechanics and polymer physics [20]. A widely accepted repulsion

absorption model proposed by Gong and Sada describes friction of hydrogels against solid

substrates [21]. This theory involves repulsive and attractive cases. Repulsive cases involve

viscous flow of solvent which dictates the friction force magnitude [22]. The attractive case

notes that the friction force is attributed to the elastic force associated with the stretching

absorbed polymer chains during motion [23]. The figure above represents that the Neat PVA

displays an adhesive interaction whereas, the blends display a repulsive profile.

13

Figure 7: Average Coefficient of Friction for brush hydrogels in both DI and 0.2 M NaCl bath solutions

The figure above represents the average COF versus the different brush hydrogels in both

the DI and saltwater baths. As can be seen, the lowest COF is the PMPC PVA brush hydrogel,

whereas the PMEDSAH brush hydrogel has the highest coefficient of friction. Specifically, the

PMEDSAH brush hydrogels display a 63% increase in COF in the DI water. However, there is a

40% reversible change in COF when the PMEDSAH hydrogel is tested in the 0.2 M NaCl

solution. This behavior may be due to interchain association of the grafted surface. The grafted

brush act like hairs on the hydrogel surface, and the ions in the saltwater solution could act as a

detangling agent in the hairs to reduce friction. As can be seen in the graph, the PMEDSAH

hydrogel is the only sample significantly affected by the change in the bath confirming the

assumption of “detangling” with the presence of the NaCl solution. The PMPC brush

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functionalized hydrogel does not show a dependence in solvent, but also displays a 60%

reduction in COF.

Wear testing included hydrogels with 40-80% molecular weights varying by 10%. The 70

and 80 weight percent hydrogels only had surface scratches without weight added for 10,000

cycles. The other weight percentage of hydrogels were torn in half during the wear testing. The

tearing occurred at the edge of the hydrogels which should not have happened if the starting

position was correct. The 60 wt% hydrogel was tested repeatedly to ensure that the starting

position was directly center, so the pin did not go further than the bounds of the gel. Even with

correct positioning, the hydrogels were still being ripped on the sides which signified an issue.

The 60 wt% was run one more time, but the test was checked every half hour. It was determined

that throughout the duration of the wear testing, the tribometer was drifting from the center

position. The drifting caused for the pin to go past the boundary of the hydrogel. Since the top

portion of the tribometer is held in place through gravity, the pin dropped off the surface of the

hydrogel. When changing directions to go back across the gel, the pin wedged the hydrogel out

of its holder causing for the sides of the gel to be exposed. The pin continued its wear track

throughout the duration of the test causing for the pin to be dragged through the sides of the

hydrogel creating significant tearing. The drifting appeared to get worse through the duration of

the test, and since the lower wt% were less stiff, they were more likely to be evacuated from their

holder. The hydrogels were not imaged due to the inaccuracies of the wear results.

15

Chapter 4

Conclusions

The results from this project indicate varying degrees of conclusively towards finding a

replacement material for articular cartilage. Friction results suggest that any sort of lubrication

decreases the coefficient of friction. The most effective blend hydrogel at reducing the average

COF was the blend gel, with either a low or medium blend of PMEDSAH. The most effective

brush gel by far was the high concentration of PMPC polymers. However, it is important to note

the PMEDSAH brush gels COF reduced once the hydrogel was submerged into the NaCl

indicates that the average COF can be reduced depending on type of solution it is submerged in.

Overall, the most effective hydrogel composition was the low/medium PMEDSAH blend with

the highest COF seen of being around 0.10.

The wear testing results were less conclusive since the hydrogels were being wedged out

of their holder during testing. The initial tests show that the higher the molecular weight

percentage of PVA used, the more resistant to wear that hydrogel becomes. The degree of the

degradation of samples below 70% is not known, due to the positioning issue. However, from the

friction results, the higher wt% is added to the gel, the higher the coefficient of friction. This

proposes that the stiffer gels though have better wear qualities, may have significantly higher

COF than those less resistant to wear.

Unfortunately, this hypothesis cannot be tested yet due to inaccuracy of positioning in the

tribometer. The pin travelling past the boundaries of the hydrogel suggests that the degree of

accuracy of the positioning system is not enough to return the pin to the same origin every time.

16

This creates a small horizonal shift after each cycle, which eventually causes for the pin to fall

off the surface of the hydrogel, puncturing the hydrogel prematurely. The inaccuracy of method

needs to be addressed before reliable data can be collected about wear properties of each

hydrogel composition.

The addition of lubrication helps reduce the coefficient of friction, when compared to a

plain sample. This result is encouraging towards developing a tribologically enhanced material

that reduces friction comparable to articular cartilage. Further testing needs to be done to

determine if the addition of these friction reducing lubricants affects the wear properties of the

hydrogels. These tests will help to determine optimal properties from both friction, and wear

tests to determine a composition that would optimize both wear and friction properties in

hydrogels.

The need for more research still exists to find an optimal material comparable to articular

cartilage. With this research and others, steps are being made towards finding an adequate

replacement for those suffering with cartilage loss. The continuation of this research is working

to provide noninvasive treatments to Osteoarthritis and other painful conditions associated with

cartilage degradation. With continued advancements, a material can be developed that reduces

friction effectively, withstand loads experienced by typical movement, is a less invasive

treatment than knee replacements, and is a more attractive treatment for younger patients who

will not have to experience long recovery times or limited life spans of implants.

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Chapter 5

Future Work

Extensive discovery still needs to occur to develop a comparable material to articular

cartilage. The most important step in allowing for continued progress is the correction of the

translational error in the tribometer. Future work includes determining where this error lies. The

accuracy issue could either be through coding that is too broad or a component within the

tribometer that does not provide the necessary resolution for the precise movement needing

during wear testing.

Once this issue is resolved, wear testing can continue to determine the proper wear

patterns of different weight percentages of PVA. These results would help determine how much

load the hydrogels can withstand before puncturing over a prolonged period. The other hydrogel

compositions would also be included in the wear testing allowing to see how the addition of

lubrication effects the wear properties in each hydrogel.

Proper imaging will also be documented to calculate the degree of degradation and wear

after each test. These images and computational degree of wear will help to classify how well the

hydrogel performs in comparison to other compositions. The imaging techniques using the

HIROX microscope will also need to be refined. Since the hydrogels are transparent, the

refraction makes it challenging to properly image the wear patterns. So far, the procedure

involves reducing surrounding light as much as possible and taking pictures of sections of the

hydrogel instead of all at once. The goal is to be able to photograph the entire wear profile

without having to merge multiple photos.

18

Future work with friction testing includes varying the weight percent of PVA with the

different boundary lubrications to see how the added stiffness affects the coefficients of friction,

and if the PMPC brush hydrogel remains superior to hydrogel blends.

Much of the future work and progress towards the development of a comparable material,

is finding superior independent qualities and trying to merge them together. This involves

making different blends and continually performing the same experiments in order to optimize

all qualities.

19

Works Cited

[1] Wojnar R. Bone and cartilage–its structure and physical properties. 2010;:1-75.

[2] Mansour JM. Biomechanics of cartilage. 2003;:66-79.

[3] Ethier CR, Simmons CA. Introductory biomechanics: from cells to organisms. : Cambridge

University Press, 2007.

[4] Reinholz G, Lu L, Saris D, Yaszemski MJ, O’driscoll S. Animal models for cartilage

reconstruction. Biomaterials 2004;25:1511-1521.

[5] Buckwalter JA, Mow VC, Ratcliffe A. Restoration of injured or degenerated articular

cellular and mechanical inhomogeneity. 2009;15:2315-2324.

[6] Beresford WA. Chondroid bone, secondary cartilage, and metaplasia. : Urban &

Schwarzenberg, 1981.

[7] Lexer E. Substitution of whole or half joints from freshly amputated extremities by free

plastic operation. 1908;6:601-607.

[8] Axhausen G. Die histologischen und klinischen Gesetze der freien Osteoplastik auf Grund

von Tierversuchen. 1909;88:23-145.

[9] Zheng H, Martin JA, Duwayri Y, Falcon G, Buckwalter JA. Impact of aging on rat bone

marrow-derived stem cell chondrogenesis. 2007;62:136-148.

[10] Hunziker EB, Lippuner K, Keel M, Shintani N. An educational review of cartilage repair:

precepts & practice–myths & misconceptions–progress & prospects. 2015;23:334-350.

[11] Musumeci G, Castrogiovanni P, Leonardi R, Trovato FM, Szychlinska MA, Di Giunta A,

Loreto C, et al. New perspectives for articular cartilage repair treatment through tissue

engineering: A contemporary review. World J Orthop 2014;5:80-88.

[12] Minas T. A primer in cartilage repair. J Bone Joint Surg Br 2012;94:141-146.

20

[13] Seror J, Zhu L, Goldberg R, Day AJ, Klein J. Supramolecular synergy in the boundary

lubrication of synovial joints. Nat Commun 2015;6:6497.

[14] Klein J. Hydration lubrication. 2013;1:1-23.

[15] Bhushan B. Principles and applications of tribology. : John Wiley & Sons, 2013.

[16] Dowson D. Bio-tribology. Faraday Discuss 2012;156:9-30.

[17] Freeman ME, Furey MJ, Love BJ, Hampton JM. Friction, wear, and lubrication of

hydrogels as synthetic articular cartilage. Wear 2000;241:129-135.

[18] Yarimitsu S, Sasaki S, Murakami T, Suzuki A. Evaluation of lubrication properties of

hydrogel artificial cartilage materials for joint prosthesis. 2016;2:40-47.

[19] Blum MM, Ovaert TC. Investigation of friction and surface degradation of innovative

boundary lubricant functionalized hydrogel material for use as artificial articular cartilage. Wear

2013;301:201-209.

[20] Bonnevie, E. D., et al.  45.6 (2012): 1036-1041.

[21] Angelini, Thomas E., and W. Gregory Sawyer. (2015).

[22] Gong, Jian Ping. Soft matter 2.7 (2006): 544-552.

[23] Gong, Jianping, and Yoshihito Osada.  The Journal of chemical physics 109.18 (1998):

8062-8068.