Allogeneic MCSs to make Cartilage for Knee Function

Allogeneic MCSs to make Cartilage for Knee Function INTRODUCTION: 1.1 What is Osteoarthritis? Articular cartilage is a highly resilient hyaline tissue composed of chondrocytes and surrounded by extracellular matrix present in a joint which act as shock absorber, protects the bones from the friction and wear and helps in smooth movement of the joint (Bhumiratana et al. 2014). Osteoarthritis is a disease of joint where lack of cartilage causes musculoskeletal pain and restriction of the movement or disability of the joint for the patient. (Ahmed and Hincke, 2010) (Duthey, 2015). Reasons for cartilage damage are: The impact / blow caused during sport activities or accident Wear and tear because of overuse of a joint (Observed in elderly people) Lack of movement (Medical News Today, 2017) Figure No.1. Osteoarthritis Affected Region Image Source: www.osteoosteoOsteoarthritisresearchuk.org Osteoarthritis can affect any joint present in the body. As the knee-joint Osteoarthritis is the most common type of Osteoarthritis, in this report, we will discuss about knee-joint Osteoarthritis only. Tibiofemoral and patellofemoral are the two articular surfaces that the knee consists of. As it can be seen in the below image, the damaged cartilage, reduces the gap between joint and friction is generated between the bones which ultimately results in bone erosion and causes muscle pain or inflammation or restriction to the movement. Figure No.2. Osteoarthritis affected Knee Image Source: http://www.bupa.co.uk/health-information/directory/o/Osteoarthritis Osteoarthritis is estimated to affect 250 million people worldwide. Osteoarthritis sufferers include men and women, children and adults. And according to World Health Organization, 30% of men and women over the age of 65 have Osteoarthritis (Woolf and Pfleger, 2003). Worldwide, 9.6% of men and 18.0% of women over the age of 60 years have symptomatic Osteoarthritis. Approximately 80% of those with Osteoarthritis will have limitations in movement, and 25% cannot perform their major activities of daily life (Duthey, 2015). Figure No.3. Prevalence of Osteoarthritis of Knee Image Source: Burden of major musculoskeletal conditions, Bulletin of the WHO 2003 1.2 Treatments available for Osteoarthritis: There are various ways to cure Osteoarthritis when it is at the initial level, such as: Exercise and weight loss Bracing Medication Viscosupplementation Nutritional supplements (Duthey, 2015). But when it becomes incurable by exercise and medication, surgical operations must be performed. Surgical procedures include: Debridement i.e. Smoothening of the cartilage using surgical instruments Marrow Stimulation, a treatment which helps in regrowth of cartilage in the joint (but this process is less reliable) (Treatment Options for Osteoarthritis in the Knee, 2017). Mosaicplasty, a process where the cartilage from some other joint of body is used. But this process has size limitations (Medical News Today, 2017). Autologous Chondrocyte Implantation, a treatment in which a small part of no-load bearing cartilage is removed from the joint of the patient by Arthroscopy, regrown and multiplied in the laboratory and then implanted back in the body by a procedure called arthrotomy. (Cartilage Repair, 2017) (Ahmed and Hincke, 2010) (Duthey, 2015). Even though the Autologous Chondrocyte Implantation seems effective and easy, it has many disadvantages such as: The patients cartilage sample must be removed by a medical procedure, marked/tagged and treated separately just like blood sample. This treatment requires big Logistics and Supply Chain. It requires a lot of time (approximately 6 weeks) for cells to multiply. Hence, till then the patient will suffer from pain (Peretti et al. 2000). 1.3 Proposed Treatment for Osteoarthritis: All these problems can be solved by Allogeneic Human Mesenchymal Stem Cell. For autologous transplant donor and receiver are same, whereas for allogeneic transplant, the donor and the receiver are different. The selection of the donor must be done carefully cause if the tissue type, i.e. HLA (Human Leukocyte Antigens) doesnt match, the patients body will treat the transplanted organ or tissue as a foreign body. It might result in GVHD i.e. Graft Vs Host Disease. It is a fatal immune system response against stem cell transplant (Si et al. 2011). Selection of donor for allogeneic transplant: Syngeneic (i.e. Twins) It is the perfect HLA match, but very few people have a twin. HLA- matched relative (sibling) It is the second preferred option as HLA will be closely matched. HLA-matched unrelated donor, it can be possible to find a donor whose HLA matches to the patient. HLA-mismatched family member, even though the HLA doesnt match, it has great chance that patients body may accept it. Umbilical cord blood, stem cells retrieved during birth of the patient and preserved in a cell bank. It will be safest of all but stem cells must be available (Flomenberg et al. 2004). Hence, allogeneic implant will make sure that the patient wont have to undergo two medical procedures, as seen in autologous chondrocyte implantation. 1.4 What are HMSCs? HMSC means Human Mesenchymal Stem Cells. They are multipotent cells, which have the ability to transform into bone, muscle, fat or cartilage, etc. upon the proper simulation of providing environmental conditions in the laboratory. They have potential for regeneration (Si et al. 2011) (Li, LHeureux and Elisseeff, 2011) (Wei, 2013). Figure No.4. Potential of MSCs Image Source: http://www.medicalnewstoday.com/articles/241215.php Figure No.5. Mesenchymal Stem Cells Image Source: http://www.cytopeutics.com/IntroductionOfStemCells.html For knee restoration, cartilage cells are needed. Hence, the MSCs will be simulated for cartilage development. MSCs exists in almost all tissues. These cells can be easily obtained from bone marrow, adipose tissue, cord cells and molar cells, fetal liver, muscle, and lung (Ahmed and Hincke, 2014) (Si et al. 2011). 1.5 Product delivery to the Patient: For blood transfusion, the blood group and presence of Rh factor is checked and the matching blood is introduced into the body. Similarly, after checking the tissue (HLA) match, the best matching cells are chosen and regrown exponentially in the controlled environment of a laboratory. When the required number of cells, shape, and size is achieved, the cartilage is implanted into the patient via an open joint surgery named arthrotomy. This implanted cartilage will function exactly as that of the original cartilage. This cartilage will function properly for approximately 10 years (Ahmed and Hincke, 2010). 1.7 Functioning of the product in the patients body: Since, the HLA was matched, and the cartilage is manufactured using MSCs which has the same functional properties and characteristics that of the original cartilage, the function of the joint will return to normal. There wont be any complication after the treatment and that graft will be accepted by the body as a part of it, it wont be treated as a foreign body. MANUFACTURING FEASIBILITY REVIEW: 2.1 Current Manufacturing Technology and Scope for Future: Currently, the knee restoration is done via other surgical procedures. But because of those procedures have many limitations and they give only temporary relief, allogeneic Mesenchymal Stem Cell therapy will replace them in the coming time. Mesenchymal Stem Cell therapy is currently under development. Various tests are being performed on them in the laboratory (Ahmed and Hincke, 2010). First, the bone marrow or adipose tissue or cord sample is collected from the donor. Then the mesenchymal stem cells are separated out from other cells, such as fat or muscle by centrifugation or apheresis. These two density separation processes are feasible only for liquid. For the extraction from solid tissues, the slices of tissue are digested by the enzymes such as trypsin or collagenase. It breaks the bonding of cells i.e. the extracellular matrix (ECM) that holds the cells. Hence, the cell line is found (Li, LHeureux and Elisseeff, 2011). Then the cells are harvested. During the cell culture process, there are various parameters that need to be monitored, little inconsistency will result in subnormal product or it might be just a waste of product. Temperature, humidity, oxygen, pH level of the cell culture reagent, nutrient supply and waste removal are the physical parameters and cell count and cell viability are the biological parameters that need to be monitored (Schwamb, Puskeiler and Wiedemann, 2015). Once the desired number of cells is achieved, boundary for CMB (Condensed Mesenchymal Cell Bodies) is set. Then the cells are condensed to increase the seeding density as the cartilage requires higher seeding density. Then the fusion of the CMB happens. Now this fused CMB is pressurized against a porous decellularized bone matrix to create dense cellular region i.e. cartilage (Bhumiratana et al. 2014). As the knee joint is a mechanical tissue, physical stimulation is needed for its development. However, excessive stimulation can lead to cartilage damage (Ahmed and Hincke, 2010). Cartilage then sticks to the surface of that bone matrix and takes its shape while growing around it. Then it is removed from the bone matrix to implant into the knee joint of the patient (Bhumiratana et al. 2014). Figure No.6. Condensed Mesenchymal Cell Bodies Fusion Image Source: http://www.pnas.org/content/111/19/6940.abstract Currently, only culture plates and culture flasks are being used for allogeneic Mesenchymal Stem Cells as it is still in testing phase (Schwamb, Puskeiler, and Wiedemann, 2015). Figure No.7. Culture flasks and plates Image Source: https://www.shutterstock.com But monitoring all these parameters becomes very hard when using flasks and plates. And the cells need to be shifted into bigger containers frequently. Also, flasks and plates are not useful for mass production because of size limitation and economic consideration. Hence, a device named bioreactor can replace them and still perform all those tasks efficiently. Figure No.8. Bioreactor for mass Cell Culture Image Source: http://www.bioc.rice.edu/bios576/nih_bioreactor/NDL_Bioreactor%20Page.html It is a container which is feasible for both aerobic and anaerobic cell culture and can be used for suspended as well as immobilized cells (Sandhya Anand, 2017). It can be operated in batch, fed batch and continuous mode. As MSCs are surface anchorage dependent, the extra agitation or stirring might result in damage to the tissue. And the MSCs require oxygen to grow, so it will be an aerobic, immobilized, batch production bioreactor. (Martin, Wendt and Heberer, 2004) (Oragui, Nannaparaju and Khan, 2011). 2.2 Challenges in mass production of MSCs: Large scale in vitro expansion of MSCs is very complex because maintaining cells quality attributes such as identity, potency, purity and safety is extremely hard. It is hard to monitor that the cells are not undergoing any quality changes while expansion and harvesting. Another challenge is obtaining required no of cells and their recovery. MSCs are not suspension type, but anchorage dependent therefore the surface area for anchorage and proliferation must be taken into account. As allogeneic treatments are supposed to be for a lot of people, hence the required no of cells must be extremely large. There are 3 major and 3 minor types of HLAs in MHC Class I and 3 major and 2 minor types of HLAs in MHC Class II. So, there are lots of variants to manufacture and maintain for the cartilage manufacturer. 2.3 Clinical Demand for Dosage: Even though there are 250 million people suffering from Osteoarthritis and 3.6% of them are suffering from knee Osteoarthritis i.e. 9 million people. More than 600,000 knee replacements are performed each year in the United States alone (A Nation in Motion, 2017). In UK 160,000 knee replacement surgeries are performed every year (Joint replacement statistics, 2017). As the cartilage manufactured in the laboratory exhibit almost similar properties that to the natural cartilage, it is expected to last approximately 50-60 years (i.e. Average human life) if there are no unexpected tragedies. Hence, once treated properly, the patient wont have to worry about the joint in his life again. 2.4 Supply Chain for Product: Figure No.9. Formation of Master Cell Bank First the cell line is chosen for culturing, it can be a well-known cell line or a newly found cell line. After certain passages, when the desired number of cells is achieved, the Master Cell Bank will be established. In this case, many Master Cell Banks are needed as there are many types of tissues. Then one portion of master cell bank will be used for research purpose, i.e. the working cell bank and the rest will be cryopreserved for future use. Good manufacturing practice protocol should be followed during cell culturing. Figure No.10. Clinical Process for Cell Culturing The working cell bank will be used for manufacturing of cells for mass production after testing is performed. Several production runs (i.e. Passages) will be performed to obtain the required number of cells. Then the cells will be cryopreserved in central storage and distributed via local channels until there is a patient who needs them. 2.5 Risk Assessment: The main aim of risk assessment is to prevent transmission of diseases, and avoid harm to individuals and the environment. In many countries, the performance of risk assessment is a legal requirement. (University of Manitoba) Risk Impact Probability of Occurrence Mitigation Strategy Tissue/cell origin Rejection of Cells Low Thorough testing of cell line Lack of Donor History Transmission of Disease Low Choosing a donor carefully Mismatch of HLA Graft vs Host Disease Intermediate Careful matching of HLA Environmental Changes Change in cell Quality High Close monitoring of environmental conditions Plasma Derived Material Cell line contamination with unwanted cells High Proper filtration of MSCs (Herberts, Kwa and Hermsen, 2011) 2.6 Biosafety Measure: Depending upon the as the product is human derived, Biosafety Level 2 practices, equipment and facilities are chosen. It is most suitable for clinical, diagnostic and teaching purposes. Laboratory personnel must maintain hygiene while entering and exiting the lab. Decontaminated of potentially infectious material must be done before disposal, either by a disinfectant, or by autoclaving. Personal protective equipment is only required when there is a possibility of exposure to hazardous material. The laboratory must be isolated from the general building. Laboratory personnel must be trained in handling pathogenic agents. Access to the laboratory should be limited during the work. Certain procedures in which infectious aerosols or splashes may be created biological safety cabinets or other physical containment equipment should be used and the rest can be performedÂÂ   on the open bench. Biosafety level 2 is suitable for indigenous moderate-risk agents. This includes various microbes that cause mild disease to humans, or are difficult to contract via aerosol in a lab setting, human derived blood, body fluid, tissues, or primary cell lines (Inc, 2017). PROCESS MAP AND CELL GROWTH ANALYSIS: 3.1 Process Map: Figure No.11. Process Map for HMSC Therapy Process Description: Cell lines are created/chosen for each type of tissue (HLA). Shipping of the tissue sample to cell therapy processing facility. HMSC isolation and culturing in culture chambers (manual production using culture flask or culture plate) or bioreactor is performed. Fresh HMSCs are then tested for various parameters such as identity, potency, purity and safety, the modifications are done. Aliquoting of HMSC samples (i.e. Master Cell Bank) is done. Freezing and storage at -196 ÂÂ °C in Vapor Liquid Nitrogen (i.e. Cryopreservation) for future reference and use is done (Inc, 2017). Cells are thawed i.e. their temperature is brought up to normal room temperature and further increased to 37 ÂÂ °C (Normal Body Temperature) for best cell growth result (Inc, 2017). Cell characterization per release Criteria for Thawed HMSCs Expansion of thawed HMSCs using an incubator and/or bioreactor for production. Activation of HMSCs into final cell therapy product. Shipping of final product to medical treatment centre. Implantation of the cartilage into the patient by open joint surgery, i.e. arthrotomy (Harel, 2013). Cell Growth Analysis: As there are many types of tissues (HLA), testing for all of them must be performed and validated. Hence, the whole process will be repeated several times for each type of cells. Input Data: Desired seeding density= 1 million/ml Duration of Passage= 72 hours Doubling Time= 36 hours Efficiency= 80% (Average efficiency) Input Vial contains= 1.00E+09 cells Dose per Patient= 1.00E+09 cells =1 vial of dose Growth Rate= Ln (2) /Doubling Time= 0.019254 Seeding Density 1,000,000 Passage Duration 72 Doubling Time 36 Efficiency 0.8 Input Vial 1.00E+09 Growth Rate 0.019254 Phase 1 15 Patients Flask Dose Per Patient 1.00E+09 T25 MCB Creation Real SA Input Ideal SA Output Note T75 Thaw 1.00E+09 800.00 8.00E+08 All Flask of Same Size T175 Passage 1 700 6.40E+08 2560.00 2.56E+09 4*T175 T500 Passage 2 2500 2.05E+09 8192.00 8.19E+09 5*T500 T650 Passage 3 7800 6.55E+09 26214.40 2.62E+10 6*T1300 T1300 Passage 4 26000 2.10E+10 83886.08 8.39E+10 1*T26000 T3250 T6500 T26000 MCBs Created 21.51 Equivalent Vials 83.89 Cells Per 5-Layer flask 3.90E+09 Phase 1 Real SA Input Ideal SA Output Note Thaw 3.99E+09 3195.66 3.20E+09 Passage 1 3000 2.56E+09 10226.11 1.02E+10 6*T500 Passage 2 9100 8.18E+09 32723.56 3.27E+10 7*T1300 Dosages 3.27E+01 2.62E+01 For Phase 1 Testing 21 Master Cell Banks will be created in a 5-layer flask (T3250). It would be equivalent to the size of 83.89 input vials after 4 passages. From those 21 cell banks, 1 will be thawed and the rest will be cryopreserved. That 1 cell bank will be chosen as working cell bank and will be harvested for production. During Phase 1, treating 30 patients will be the target. Hence, 30 vials of doses should be manufactured during phase one. Every time 20% loss of cells is considered while changing the flask. And During passages, exponential growth will take place. Formula for Exponential Growth is: The Ideal surface area is calculated by: Flask size was kept uniform during every passage. And Actual Surface Area was always chosen less than Ideal Surface Area to maintain the desired density and environment. Flask of capacity 5-Layer was chosen for MCB creation. Calculations for MCB, Number of doses, After successful testing of phase 1, phase 2 will begin where 300 patients will be treated. So, 300 vials of cells will be required. PHASE 2 Real SA Input Ideal SA Output Note Thaw 3.99E+09 3195.66 3.20E+09 Passage 1 3000 2.56E+09 10226.11 1.02E+10 6*T500 Passage 2 9100 8.18E+09 32723.56 3.27E+10 7*T1300 Passage 3 32500 2.62E+10 104715.39 1.05E+11 5*T6500 Passage 4 104000 8.38E+10 335089.26 3.35E+11 4*T26000 Dosages 3.35E+02 For Phase 2 Testing After successful testing of phase 1 and phase 2, phase 3 will begin when mass production will start and 100s of 1000s of people will be treated with allogeneic HMSC derived cartilage. PHASE 3 Real SA Input Ideal SA Output Note Thaw 3.99E+09 3195.66 3.20E+09 Passage 1 3000 2.56E+09 10226.11 1.02E+10 6*T500 Passage 2 9100 8.18E+09 32723.56 3.27E+10 7*T1300 Passage 3 32500 2.62E+10 104715.39 1.05E+11 5*T6500 Passage 4 104000 8.38E+10 335089.26 3.35E+11 4*T26000 Passage 5 312000 2.68E+11 1072285.63 1.07E+12 12*T26000 Passage 6 1066000 8.58E+11 3431314.00 3.43E+12 41*T26000 Passage 7 3406000 2.75E+12 10980204.81 1.10E+13 131*T26000 Dosages 1.10E+04 For Phase 3 Since, there are 7 passages the process to manufacture 11000 vials will require approximately 25 (considered an extra time for changing flask) days. And at that rate 15 batches will be produced per year and approximately 165000 patients can be treated per year. As there are 6 types of tissues (HLA) total number of patients treated will be 990000 approximately. It will be equivalent to 11% of global demand. Using Bioreactor for Phase 3: Instead of using Culture flasks or plates, a bioreactor can be used for cell culturing. To check which of these two techniques will be more efficient, all the parameters are kept same. And total time of 7 passages will be considered as one passage time for bioreactor. Passage Duration 504 Doubling Time 36 PHASE

Chipotle Satire

In the early 2010’s fast food, with health twists was popular. The population was becoming more worried and conscience about what they fed themselves and their families, and this, combined with the always-busy, modern-day society in need of quick meals, gives an opening for fast-food restaurants like Taco Time, Chipotle, and Taco Del Mar to spot light their greasy-burger-free, and sometimes organic, menus.In 2010 Chipotle released a commercial called â€Å"Scarecrow† showing an animated scarecrow witnessing the cruelness and fraud and of big food corporations, and then starting his own organic restaurant, which the audience assumes is Chipotle; all to the tune of â€Å"Pure Imagination† covered by Fiona Apple. Funny or Die, a well known comedy web site, made a satire of Chipotle’s â€Å"Scarecrow†, called â€Å"Honest Scarecrow†, which changed the lyrics and added other words, images, and sounds in order to mock Chipotle’s, and other r estaurants’, emotional and exaggerated way of advertising.â€Å"Honest Scarecrow† by Funny or Die, released in 2013, convinces fast-food consumers, to not let ads determine where we eat, because ads can be misleading and can play on emotions. Funny or Die uses ridicule to point out how hyperbolic and fooling the animation is in the Chipotle commercial. For example, in the original commercial, the animated scarecrow happily chops up some peppers, and makes a Chipotle bowl for a customer. The audience finds this cute, and begins to see Chipotle as a nicer and healthier institution.Anyone that knows of Chipotle knows they use meat, yet vegetables have a healthier image to the consumer. The audience will laugh, yet deep down they’ll feel Chipotle, and other fast food restaurants have attempted to delude them. This will make them feel a kind of mistrust towards food ads, accomplishing Funny or Dies goal of making the audience not choose their food just because of ads . Funny or Die also uses sounds and imagery that are associated with brain washing in horror films to persuade fast food consumers who have seen the original â€Å"Scarecrow† ad to base their decision of where to eat not only on ads.In the original commercial Chipotle shows the scarecrow grabbing a pepper, to connect the beginning of the scarecrow’s healthy restaurant to their logo, also a pepper, in the audience’s subconscious. Funny or die edits the ad by adding in screeching guitar noises, and has the Chipotle logo flash on screen occasionally. The sounds and imagery combine makes this seem like something straight out of a horror movie, from a scene where the TV scarily goes haywire. This creates a relatable humor, yet it also seriously points out what Chipotle is actually doing.Another tactic used by Funny or Die to persuade fast-food consumers who have seen the original commercial to not let ad’s control where you eat, is hyperbole of the (already hy perbolized) emotional images in â€Å"Scarecrow† with words and lyrics. In the original commercial, the scarecrow peeks behind an ad for the evil â€Å"Crow Foods† company, and sees an adorable and innocent little cow, strapped up to a merciless milking machine, looking up at him with un wavering puppy dog eyes. Funny or die takes this and exaggerates Chipotle’s attempt to get sympathy and sadness from the audience.The audience, again feels like the victim of a giant corporation trying to fool them, or even brainwash them, and definitely wont let ads decide where they eat. In 2013, Funny or Die released a video called â€Å"Honest scarecrow† ( a satire of â€Å"Scarecrow† by Chipotle) to sway fast-food consumers, who have seen the original commercial to not let ads determine where we eat, because ads can be misleading and can play on emotions, with ridicule, hyperbole, sounds, words, and lyrics.

Power of Context Essay Essay

The power of context, written by Malcolm Gladwell, discuss’ many different social change theories such as the â€Å"Broken Windows Theory†, â€Å"Tipping Points† and the â€Å"Power of Context theory†. All of these theories were researched and studies performed to prove that we are influenced by the features of our immediate social and physical world, these shaping who we are and how we act. These theories have been seen in every part of town, Graffiti painted buildings and broken windows in vacant houses. Where there are news paper articles written about the few that have taken the initiative to turn their neighborhood around. Where neighbors rally to paint over graffiti, fix broken windows, make a park where once was a gang hangout. Where as sad as it may seem, most of the children fit into the description of the four youths who attempted to mug Goetz December 22 ,1984. Where Goetz was dubbed the â€Å"Subway Vigilante† after fighting back against he would be muggers, shooting them in the subway and later being acquitted on charges of assault and attempted murder. Goetz’ case has become a symbol of a particular, dark moment in New York City history, the moment when the city’s crime problem reached epidemic proportions or the â€Å"Tipping Point†. The â€Å"Tipping Point† where in epidemiology the â€Å"tipping point† is the moment when a virus reaches critical mass. Gladwell links these would have been muggers and the shooting to another theory, one that would change the atmosphere and quite possibly the culture of the neighborhood the thugs came from. The â€Å"Broken Window Theory† was the brainchild of the criminalogistics James Q Wilson and George Kelling. Wilson and Kelling argued that â€Å"crime is the inevitable result of disorder. If a window is broken and left unrepaired, people walking by will conclude that no one cares and no one is in charge. Soon, more windows will be broken, and the sense of anarchy will spread from the building to the street on which it faces, sending a signal that anything goes. In a city, relatively minor problems like graffiti, public disorder, and aggressive panhandling, they write, are all the equivalent of broken windows, invitations to more serious crimes.† (Gladwell, 237) The â€Å"Power of Context† theory that Gladwell writes about and the â€Å"Broken Windows Theory† are one and the same We have all heard the saying, â€Å"You are what you eat†. The same would be true in you are what you surround yourself with. I feel that the â€Å"Power of Context† is true in the context that if you live in a home you are proud of, you will be more confident in your self worth. If you surround yourself with people more intelligent than yourself, you will increase your mental aptitude. Those that set goals and stick to them seem to achieve more than those who never set goals. I feel that Gladwell did a great job in personifying the theories and arguing their relevance. Works Cited Gladwell, Malcolm. Gladwell, Malcolm. The Power of Context. Boston: Houghton Mifflin Harcourt and Publishing Company, 2009. View as multi-pages

Comparing the Teotihucans and the Sumerians Essay

Comparing the Teotihucans and the Sumerians Written language was an important milestone in human history. It enabled the recording of history, dreams and tragedy. It allowed for commercial and historical record keeping. It allowed human beings to imprint thoughts on paper, for sharing, later review or just for fun. What about societies that never developed a written language? Could such a society rival one with that has? When advances of Sumerian city-states are compared to that of Teotihuacan there are a few instances where the Mesoamerican city appears to be more advanced. However, if ranked these appearances do not place Teotihuacan ahead of any one of Sumers Mesopotamian city-states. The formations of Sumerian city-states†¦show more content†¦Within these huge stepped cities within cities (49). an entire workforce was busy with the affairs of civilization (49). Field workers would farm temple lands to provide for the massive amounts of food that was distributed. In Lagash for example, food was prepared for 1200 people on a daily basis (49). Though the Pyramids of the Sun and Moon in Teotihuacan were not as elaborate as Sumerian Ziggurats, each civilization shared a Cosmo- magical characteristic. In Sumer, royal burial sites were so elaborate, that only specialized artisans could possibly have constructed them. According to the text, arches, vaults and domes were new levels of architecture found in burial tombs of the elite. In addition, elaborate funeral objects of gold and silver were also found with the dead. Sumerian arts and inventions flourished. The wheel itself, which led to the potters wheel and wagon wheels, were apparently invented in Sumer. (49). This lent sophistication to pottery and increased efficiency to farming. The Bronze Age found its origins in Sumerian civilization, which put metal tips on hoes, axes, arrowheads, daggers and many other tools. In Teotihuacan however, the economy thrived on agriculture, craftwork, and trade in ceramics and quarried obsidian. (98) There was no evidence in the text or lecture notes that they had achieved the amenities of the Bronze age. However,