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حماة | |
---|---|
Clockwise from top: Hama skyline, Azem Palace, Al-Hassanein Mosque, Nur al-Din Mosque, Khan Rustem Pasha, Norias of Hama | |
Nicknames: | |
Location in Syria | |
Coordinates: 35°08′N36°45′E / 35.133°N 36.750°ECoordinates: 35°08′N36°45′E / 35.133°N 36.750°E | |
Country | Syria |
Governorate | Hama |
District | Hama |
Subdistrict | Hama |
Government | |
• Governor | Abdul Razzaq al-Qutaini |
Elevation | 305 m (1,001 ft) |
Population | |
• Total | 312,994[1] |
• Ethnicities | Syrians |
• Religions | Sunni Islam Syriac Orthodox Church Greek Orthodox Church |
Demonym(s) | Arabic: حموي, romanized: Ḥamwi |
Time zone | UTC+2 (EET) |
• Summer (DST) | UTC+3 (EEST) |
Area code(s) | 33 |
Geocode | C2987 |
Climate | BSh |
Website | www.ehama.sy |
Hama (Arabic: حماة Ḥamāh, [ħaˈmaː]; Syriac: ܚܡܬ Ḥmṭ, 'fortress'; Biblical Hebrew: חֲמָתḤamāth) is a city on the banks of the Orontes River in west-central Syria. It is located 213 km (132 mi) north of Damascus and 46 kilometres (29 mi) north of Homs. It is the provincial capital of the Hama Governorate. With a population of 854,000 (2009 census), Hama is the fourth-largest city in Syria after Damascus, Aleppo and Homs.[2][3]
The city is renowned for its seventeen norias used for watering the gardens, which are locally claimed to date back to 1100 BC. Though historically used for purpose of irrigation, the norias exist today as an almost entirely aesthetic traditional show.
- 1History
- 1.1Ancient era
- 3Demographics
History[edit]
Ancient era[edit]
An alley in Old Hama
The ancient settlement of Hamath was occupied from the early Neolithic to the Iron Age. Remains from the Chalcolithic have been uncovered by Danish archaeologists on the mount on which the former citadel once stood.[4] The excavation took place between 1931 and 1938 under the direction of Harald Ingholt. The stratigraphy is very generalized, which makes detailed comparison to other sites difficult. Level M (6 m or 20 ft thick) contained both white ware (lime-plaster) and true pottery. It may be contemporary with Ras Shamra V (6000–5000 BC). The overlying level L dates to the Chalcolithic Halaf culture.
Amorite period and the Mittanni[edit]
Although the town appears to be unmentioned in cuneiform sources before the first millennium BC,[5] the site appears to have been prosperous around 1500 BC, when it was presumably an Amorite dependency of Mitanni, an empire along the Euphrates in northeastern Syria.[4] Mitanni was subsequently overthrown by the Hittites, who controlled all of northern Syria following the famous Battle of Kadesh against Ancient Egypt under Ramesses II near Homs in 1285 BC.
In early 19th century, Johann Ludwig Burckhardt was the first to discover Hittite or Luwian hieroglyphic script at Hama.[6]
The site also shows signs of Assyrian and Aramaean settlement.[4]
Neo-Hittites[edit]
By the turn of the millennium, the centralized old Hittite Empire had fallen, and Hama is attested as the capital of one of the prosperous Syro-Hittite states known from the Hebrew Bible as Hamath (Aramaic: Ḥmt; Hittite: Amatuwana;[5]Hebrew: חֲמָת Ḥəmåṯ), which traded extensively, particularly with Israel and Judah.[7]
Assyrian inscriptions[edit]
When the Assyrian king Shalmaneser III (858–824 BC) conquered the north of Aramea, he reached Hamath (Assyrian: Amat or Hamata)[5] in 835 BC; this marks the beginning of Assyrian inscriptions relating to the kingdom.[8]Irhuleni of Hamath and Hadadezer of Aram-Damascus (biblical 'Bar-Hadad') led a coalition of Aramean cities against the encroaching Assyrian armies. According to Assyrian sources, they were confronted by 4,000 chariots, 2,000 horsemen, 62,000 foot-soldiers and 1,000 Arab camel-riders in the Battle of Qarqar. The Assyrian victory seems to have been more of a draw, although Shalmaneser III continued on to the shore and even took a ship to open sea. In the following years, Shalmaneser III failed to conquer Hamath or Aram-Damascus. After the death of Shalmaneser III, the former allies Hamath and Aram-Damascus fell out, and Aram-Damascus seems to have taken over some of Hamath's territory.
An Aramaic inscription of Zakkur, dual king of Hamath and Luhuti, tells of an attack by a coalition including Sam'al under Ben-Hadad III, son of Hazael, king of Aram-Damascus. Zakir was besieged in his fortress of Hazrak, but saved by intervention of the God Baalshamin. Later on, the state of Sam'al came to rule both Hamath and Aram.[citation needed]
In 743 BC, Tiglath-Pileser III took a number of towns in the territory of Hamath, distributed the territories among his generals, and forcibly removed 1,223 selected inhabitants to the valley of the Upper Tigris; he exacted tribute from Hamath's king, Eni-Ilu (Eniel).
In 738 BC, Hamath is listed among the cities again conquered by Assyrian troops. Over 30,000 natives were deported to Ullaba and replaced with captives from the Zagros Mountains.[5]
Destruction under Sargon II[edit]
After the fall of the northern kingdom of Israel, Hamath's king Ilu-Bi'di (Jau-Bi'di) led a failed revolt of the newly organized Assyrian provinces of Arpad, Simirra, Damascus, and Samara.
Styling himself the 'Destroyer of Hamath,' Sargon II razed the city c. 720 BC,[9] recolonized it with 6,300 Assyrians, and removed its king to be flayed alive in Assyria.[5] He also carried off to Nimrud the ivory-adorned furnishings of its kings.[10]
Hamath in the Bible[edit]
The few Biblical reports state that Hamath was the capital of a Canaanite kingdom (Genesis 10:18; 2 Kings 23:33; 25:21), whose king congratulated King David on his victory over Hadadezer, king of Zobah (2 Samuel 8:9-11; 1 Chronicles 18:9-11). In God's instructions to Moses, Hamath is specified as part of the northern border of the land that will fall to the children of Israel as an inheritance when they enter the land of Canaan.[11]Solomon, it would seem, took possession of Hamath and its territory and built store cities.[12] 1 Kings 8:65 names the 'entrance of Hamath', or Lebo-Hamath, as the northern border of Israel at the time of the dedication of the first temple in Jerusalem. The area was subsequently lost to the Syrians, but Jeroboam II, king of Israel, is said to have 'restored the territory of Israel from the entrance of Hamath to the Sea of the Arabah (the Dead Sea)'.[13]
Assyria's defeat of Hamath made a profound impression on Isaiah.[14] The prophet Amos also named the town 'Hamath the Great'.[15] Indeed, the name appears to stem from Phoeniciankhamat, 'fort.'[16]
Hellenistic and Roman history[edit]
Aqueduct in Epiphania (= Hama).
In the second half of the 4th century BC the modern region of Syria came under the influence of Greco-Roman culture, following long lasting semitic and Persian cultures. Alexander the Great's campaign from 334 to 323 BC brought Syria under Hellenic rule. Since the country lay on the trade routes from Asia to Greece, Hama and many other Syrian cities again grew rich through trade. After the death of Alexander the Great his Near East conquests were divided between his generals, and Seleucus Nicator became ruler of Syria and the founder of the Seleucid dynasty. Under the Seleucids there was a revival in the fortunes of Hama. The Aramaeans were allowed to return to the city, which was renamed Epiphaneia[5] (in Greek: Επιφανεία), after the Seleucid Emperor Antiochus IV Epiphanes. Seleucid rule began to decline, however, in the next two centuries, and Arab dynasties began to gain control of cities in this part of Syria, including Hama.[17]
The Romans took over original settlements such as Hama and made them their own. They met little resistance when they invaded Syria under Pompey and annexed it in 64 BC, whereupon Hama became part of the Roman province of Syria, ruled from Rome by a proconsul. Hama was an important city during the Greek and Roman periods, but very little archaeological evidence remains.[17]
In AD 330, the capital of the Roman Empire was moved to Byzantium, and the city continued to prosper. In Byzantine days Hama was known as Emath or Emathoùs (Εμαθούς in Greek). Roman rule from Byzantium meant the Christian religion was strengthened throughout the Near East, and churches were built in Hama and other cities. The Byzantine historian John of Epiphania was born in Hama in the 6th century.[17]
Muslim rule[edit]
During the Muslim conquest of Syria in the 7th century, Hama was conquered by Abu Ubaidah ibn al-Jarrah in 638 or 639 and the town regained its ancient name, and has since retained it. Following its capture, it came under the administration of Jund Hims and remained so throughout the rule of Umayyads until the 9th century.[18]
Arab geographer al-Muqaddasi writes Hama became a part of Jund Qinnasrin during Abbasid rule.[19] Although the city's history is obscure at this time period, it is known that Hama was a walled market town with a ring of outlying cities. It came under the control of the Hamdanid rulers of Aleppo in the 10th century and was consequently drawn into the orbit of that city where it remained until the 12th century.[18] These were considered the 'dark years' of Hama as the local rulers of northern and southern Syria struggled for dominance in the region. The Byzantines under emperor Nicephorus Phocas raided the town in 968 and burned the Great Mosque. By the 11th century, the Fatimids gained suzerainty over northern Syria and during this period, the Mirdasids sacked Hama.[18]Persian geographer Nasir Khusraw noted in 1047 that Hama was 'well populated' and stood on the banks of the Orontes River.[20]
Tancred, Prince of Galilee, took it in 1108, but in 1114 the Crusaders lost it definitively to the Seljuks. The governor of Hama in the early 12th century was Ali Kurd, and his sons, Nasir and Kurdanshah became vassals of Toghtekin.[21] In 1157 an earthquake shattered the city.[22] For the next sixty years, Hama was battled for by competing rulers. Nur al-Din, the Zengid sultan, erected a mosque with a tall, square minaret in the city in 1172.[23] In 1175, Hama was taken from the Zengids by Saladin. He granted the city to his nephew, al-Muzaffar Umar, four years later, putting it under the rule of his Ayyubid family. This ushered in an era of stability and prosperity in Hama as the Ayyubids ruled it almost continuously until 1342.[18] Geographer Yaqut al-Hamawi, who was born in Hama, described it in 1225 as a large town surrounded by a strongly built wall.[24] Hama was sacked by the Mongols in 1260, as were most other Syrian cities, but the Mongols were defeated that same year and then again in 1303 by the Mamluks who succeeded the Ayyubids as rulers of the region.[17] Hama briefly passed to Mamluk control in 1299 after the death of governor al-Mansur Mahmoud II. However, unlike other former Ayyubid cities, the Mamluks reinstated Ayyubid rule in Hama by making Abu al-Fida, the historian and geographer, governor of the city and he reigned from 1310 to 1332.[18] He described his city as 'very ancient... mentioned in the book of the Israelites. It is one of the pleasantest places in Syria.'[25] After his death, he was succeeded by his son al-Afdal Muhammad who eventually lost Mamluk favor and was deposed. Thus, Hama came under direct Mamluk control.[18]
Hama grew prosperous during the Ayyubid period, as well as the Mamluk period. It gradually expanded to both banks of the Orontes River, with the suburb on the right bank being connected to the town proper by a newly built bridge. The town on the left bank was divided into upper and lower parts, each of which was surrounded by a wall. The city was filled with palaces, markets, mosques, madrasas, and a hospital, and over thirty different sized norias (water-wheels). In addition, there stood a massive citadel in Hama.[18] Moreover, a special aqueduct brought drinking water to Hama from the neighboring town of Salamiyah.[18]
Ibn Battuta visited Hama in 1335 and remarked that the Orontes River made the city 'pleasant to live in, with its many gardens full of trees and fruits.' He also speaks of a large suburb called al-Mansuriyyah (named after an Ayyubid emir) that contained 'a fine market, a mosque, and bathes.'[25] In 1400, Timurlane took Hama, along with nearby Homs and Baalbek.[26]
Ottoman rule[edit]
The Azem Palace in Hama was built in 1742
The prosperous period of Mamluk rule came to an end in 1516, when the Ottoman Turks conquered Syria from the Mamluks after defeating them at the Battle of Marj Dabiq near Aleppo. Hama, and the rest of Syria, came under Ottoman rule from Constantinople.[27] Under the Ottomans, Hama gradually became more important in the administrative structure of the region. It was first made capital of one of the liwas ('districts') of the vilayet ('province') of Tripoli.[18] Hama once again became an important center for trade routes running east from the Mediterranean coast into Asia. A number of khans ('caravansaries's) were built in the city, like Khan Rustum Pasha which dates from 1556. Syria was later divided into three governorships and Hama was ruled by the governorship based at Aleppo.[27]
Then in the 18th century, it became a part of the holdings of the governor of Damascus.[18] The governors of Damascus at this time were the Azems, who also ruled other parts of Syria, for the Ottomans. They erected sumptuous residences in Hama, including the Azem Palace and Khan As'ad Pasha which were built by As'ad Pasha al-Azem, who governed Hama for a number of years until 1742.[27] By then, there were 14 caravansaries in the city, mostly used for the storage and distribution of seeds, cotton, wool, and other commodities.[28] After the passing of the Vilayet Law in 1864, Hama became the capital of the Sanjak of Hama (gaining the city more administrative powers), part of the larger vilayet of Sham.[18]
Modern history[edit]
General view
The clock tower of Hama
Ottoman rule ended in 1918, after their defeat in World War I to the Allied Forces. Hama was made part of the French Mandate of Syria. By then, Hama had developed into what it has remained: a medium-sized provincial town, important as the market for an agricultural area abundant in cereals, but also cotton and sugar beets. It gained notoriety as the center of large estates worked by peasants and dominated by a few magnate families. The 1925 Hama uprising occurred in the city during the Great Syrian Revolt against the French.
During the French Mandate, the district of Hama contained within its bounds the municipality of Hama and 114 villages. By an estimate in 1930, only four of these villages were owned outright by local cultivators, while sharing ownership of two villages with a notable family. Thus, the hinterland was owned by landowning elites.[29] Starting in the late 1940s, significant class conflict erupted as agricultural workers sought reform in Hama.
Syria gained full independence from France in 1946. Akram al-Hawrani, a member of an impoverished notable family in Hama, began to agitate for land reform and better social conditions. He made Hama the base of his Arab Socialist Party, which later merged with another socialist party, the Ba'ath. This party's ascent to power in 1963 signaled the end of power for the landowning elite.
Political insurgency by Sunni Islamic groups, particularly the Muslim Brotherhood, occurred in the city, which was reputed as a stronghold of conservative Sunni Islam. As early as the spring of 1964, Hama became the epicenter of an uprising by conservative forces, encouraged by speeches from mosque preachers, denouncing the policies of the Ba'ath. The Syrian government sent tanks and troops into the quarters of Hama's old city to put down the insurrection.[29]
In the early 1980s, Hama had emerged as a major source of opposition to the Ba'ath government during the Sunni armed Islamist uprising, which had begun in 1976. The city was a focal point for bloody events in the 1981 massacre and the most notable 1982 Hama massacre.[30] The most serious insurrection of the Syrian Islamic uprising happened in Hama during February 1982, when Government forces, led by the president's brother, Rifaat al-Assad, quelled the revolt in Hama with very harsh means.[31] Tanks and artillery shelled the neighbourhoods held by the insurgents indiscriminately, and government forces are alleged to have executed thousands of prisoners and civilian residents after subduing the revolt, which became known as the Hama massacre. The story is suppressed and regarded as highly sensitive in Syria.[32] The Hama Massacre led to the military term 'Hama Rules' meaning the complete large-scale destruction of a military objective or target. The city was the site of conflict between the Syrian military and opposition forces as one of the main arenas of the Syrian civil war during the 2011 siege of Hama.
Climate[edit]
Its climate is classified as semi-arid (BSk) in Köppen-Geiger system.[33] Hama's inland location ensures that it receives no softening coastal influences and breezes from the Mediterranean Sea. As a result, the city has a much hotter and drier climate than nearby Homs.
Climate data for Hama (1961–1990, extremes 1956–2004) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Month | Jan | Feb | Mar | Apr | May | Jun | Jul | Aug | Sep | Oct | Nov | Dec | Year |
Record high °C (°F) | 20.0 (68.0) | 23.1 (73.6) | 28.0 (82.4) | 36.2 (97.2) | 41.0 (105.8) | 42.0 (107.6) | 45.2 (113.4) | 45.0 (113.0) | 42.2 (108.0) | 37.6 (99.7) | 31.0 (87.8) | 25.2 (77.4) | 45.2 (113.4) |
Average high °C (°F) | 11.4 (52.5) | 13.8 (56.8) | 17.9 (64.2) | 23.1 (73.6) | 29.3 (84.7) | 33.8 (92.8) | 36.2 (97.2) | 36.2 (97.2) | 33.8 (92.8) | 27.6 (81.7) | 19.7 (67.5) | 13.1 (55.6) | 24.7 (76.5) |
Daily mean °C (°F) | 6.6 (43.9) | 8.3 (46.9) | 11.6 (52.9) | 15.9 (60.6) | 21.1 (70.0) | 25.8 (78.4) | 28.2 (82.8) | 27.9 (82.2) | 25.3 (77.5) | 19.3 (66.7) | 12.7 (54.9) | 7.9 (46.2) | 17.5 (63.5) |
Average low °C (°F) | 2.9 (37.2) | 3.3 (37.9) | 5.4 (41.7) | 8.8 (47.8) | 12.9 (55.2) | 17.4 (63.3) | 20.2 (68.4) | 20.1 (68.2) | 17.1 (62.8) | 12.4 (54.3) | 6.6 (43.9) | 3.7 (38.7) | 10.9 (51.6) |
Record low °C (°F) | −8.3 (17.1) | −7.3 (18.9) | −3.0 (26.6) | −0.5 (31.1) | 5.9 (42.6) | 10.6 (51.1) | 14.7 (58.5) | 14.0 (57.2) | 9.5 (49.1) | 2.2 (36.0) | −3.7 (25.3) | −5.5 (22.1) | −8.3 (17.1) |
Average precipitation mm (inches) | 72.5 (2.85) | 54.3 (2.14) | 49.3 (1.94) | 32.3 (1.27) | 10.3 (0.41) | 3.8 (0.15) | 0.4 (0.02) | 0.1 (0.00) | 1.8 (0.07) | 21.4 (0.84) | 40.0 (1.57) | 66.5 (2.62) | 352.7 (13.89) |
Average precipitation days (≥ 1.0 mm) | 9.9 | 8.1 | 7.4 | 4.5 | 1.8 | 0.3 | 0.0 | 0.0 | 0.3 | 2.8 | 5.1 | 9.0 | 49.2 |
Average relative humidity (%) | 81 | 75 | 69 | 61 | 49 | 40 | 39 | 42 | 43 | 51 | 69 | 83 | 58 |
Mean monthly sunshine hours | 127.1 | 151.2 | 217.0 | 249.0 | 325.5 | 366.0 | 387.5 | 356.5 | 312.0 | 257.3 | 192.0 | 130.2 | 3,071.3 |
Mean daily sunshine hours | 4.1 | 5.4 | 7.0 | 8.3 | 10.5 | 12.2 | 12.5 | 11.5 | 10.4 | 8.3 | 6.4 | 4.2 | 8.4 |
Source #1: NOAA[34] | |||||||||||||
Source #2: Deutscher Wetterdienst (extremes 1956–2004, and humidity 1973–1993)[35] |
Demographics[edit]
A Greek Orthodox church.
According to Josiah C. Russel, during the 12th century, Hama had a population of 6,750.[36] James Reilly accounts the historical population as: 1812– 30,000 (Burckhardt) 1830– 20,000 (Robinson) 1839– 30–44,000 (Bowring) 1850– 30,000 (Porter) 1862– 10–12,000 (Guys) 1880– 27,656 (Parliamentary Papers) 1901– 60,000 (Parliamentary Papers) 1902–1907 80,000 (Trade Reports) 1906– 40,000 (al-Sabuni) 1909– 60,000 (Trade Reports)[37]In 1932, while Hama was under the French Mandate, there were approximately 50,000 residents. In the 1960 census, there were 110,000 inhabitants. The population continued to rise, reaching 180,000 in 1978 and 273,000 in 1994.[38] The infant mortality rate per 1,000 live births in the Hama Governorate was 99.4.[39] A 2005 estimate had Hama's population at around 325,000 inhabitants.[40]
Most of the residents are Sunni Muslims (including mostly Arabs, Kurds, and Turkmen), although some districts of the city are exclusively Christian.[40] Hama is reputed to be the most conservative Sunni Muslim city in Syria since French Mandate times. During that period there was an old saying reflecting this characteristic: 'In Damascus, it takes only three men to make a political demonstration, while in Hama it takes only three men to get the town to pray.'[29] The Christian population mostly adheres to the Greek Orthodox Church or the Syriac Orthodox Church.[41]
Ecclesiastical status[edit]
The Greek Orthodox Church has a prelacy in Hama under the Patriarch of Antioch.[41] Hama is still a Roman Catholic titular see (referred to as 'Hamath' or Amath'), suffragan of Apamea. It is as 'Epiphania' that it is best known in ecclesiastical documents. Lequien mentions nine Greek bishops of Epiphania.[42] The first of them, whom he calls Mauritius, is the Manikeios whose signature appears in the First Council of Nicaea.[43] Currently, it has two Catholic archbishops, a Greek Melkite and a Syrian, the former residing at Labroud, the latter at Homs, reuniting the titles of Homs (Emesus) and Hamah.[44]
Main sights[edit]
The Orontes River and Norias of Hama
Hama's most famous attractions are the 17 Norias of Hama (Arabic: نواعير حماة), dating back to the Byzantine times. Fed by the Orontes river, they are up to 20 metres (66 ft) in diameter. The largest norias are the al-Mamunye (1453) and the al-Muhammediye (14th century). Originally they were used to route water into aqueducts, which led into the town and the neighbouring agricultural areas.
Other sights include:
- the museum, housed in an 18th-century Ottoman governor residence (Azem Palace). Remains in the exhibition include a precious Roman mosaic from the nearby village of Maryamin (4th century AD)
- al-Nuri mosque, finished in 1163 by Nur ad-Din after the earthquake of 1157. Notable is the minaret.
- The small Mamluk al-Izzi mosque (15th century)
- The mosque and Mausoleum of Abu al-Fida, a celebrated Ayyubid historian who was also governor of the city.
- al-Hasanain mosque, also rebuilt by Nur ad-Din after the aforementioned earthquake.
- The Great Mosque. Destroyed in the 1982 bombardment, it has been rebuilt in its original forms. It has elements dating from the ancient and Christian structures existing in the same location. It has two minarets, and is preceded by a portico with an elevated treasury.
See also[edit]
Sound of a noria | |
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References[edit]
- ^'2004 official census'(PDF). cbss. Archived from the original(PDF) on 10 March 2013. Retrieved 4 November 2013.
- ^Updated: Your Cheat Sheet to the Syrian Conflict. PBS.
- ^'Hamah (Syria)'. Encyclopædia Britannica. Retrieved 3 June 2013.
- ^ abcRing, 1996, p.315.
- ^ abcdefHawkins, J.D. 'Hamath.' Reallexikon der Assyriologie und Vorderasiatischen Archäologie, Vol. 4. Walter de Gruyter, 1975.
- ^The Decipherment of Hittite James Norman (Schmidt), Ancestral Voices: Decoding Ancient Languages, Four Winds Press, New York, 1975.
- ^'Hamath'. Jewish Encyclopedia. Jewishencyclopedia.com. Retrieved 4 February 2013.
- ^Hamath's history from the inscriptions was encapsulated by George L. Robinson, 'The Entrance of Hamath' The Biblical World32.1 (July 1908:7–18), in discussing the topography evoked by the Biblical phrase 'the entrance of Hamath'.
- ^'Hamath Wrecked to Terrify Small Opponents of Assyria' The Science News-Letter. 39:13 (29 March 1941:205–206.)
- ^The ivories were found there by Layard. One of the ivory panels found at 'Fort Shalmaneser' is inscribed 'Hamath.' (R. D. Barnett, 'Hamath and Nimrud: Shell Fragments from Hamath and the Provenance of the Nimrud Ivories.' Iraq. 25:1. [Spring 1963:81–85.])
- ^Numbers 34.1–9
- ^1 Kings 4:21–24; 2 Chronicles 8:4
- ^2 Kings 14:25: NKJV translation; cf. NIV translation, which refers to the Dead Sea
- ^Isaiah 10:9
- ^Amos 6:2
- ^Room, Adrian. Placenames of the World. London: MacFarland and Company, Inc., 1997.
- ^ abcdRing, 1996, p.317.
- ^ abcdefghijkDumper, Stanley, and Abu-Lughod, 2007, p.163.
- ^le Strange, 1890, p.39.
- ^le Strange, 1890, p.357.
- ^Chaliand, Gerard (1993). A People Without a Country: The Kurds and Kurdistan. London: Interlink Books.
- ^Robinson 1908:9.
- ^Nur al-Din MosqueArchived 3 July 2013 at the Wayback Machine. Archnet Digital Library.
- ^le Strange, 1890, p.359.
- ^ able Strange, 1890, p.360.
- ^le Strange, 1890, p.xxiii.
- ^ abcRing, 1996, p.318.
- ^Reilly, 2002, p.72.
- ^ abcDumper, Stanley, and Abu-Lughod, 2007, p. 164.
- ^Larbi Sadiki. 'In Syria, the government is the real rebel – Opinion'. Al Jazeera English. Retrieved 31 July 2011.
- ^[1][dead link]
- ^'English.alarabiya.net'. English.alarabiya.net. 9 July 2011. Archived from the original on 14 July 2011. Retrieved 31 July 2011.
- ^M. Kottek; J. Grieser; C. Beck; B. Rudolf; F. Rubel (2006). 'World Map of the Köppen-Geiger climate classification updated'. Meteorol. Z. 15: 259–263. doi:10.1127/0941-2948/2006/0130. Retrieved 1 August 2013.
- ^'Hama Climate Normals 1961–1990'. National Oceanic and Atmospheric Administration. Retrieved 26 April 2017.
- ^'Klimatafel von Hama / Syrien'(PDF). Baseline climate means (1961–1990) from stations all over the world (in German). Deutscher Wetterdienst. Retrieved 26 April 2017.
- ^Shatzmiller, 1994, p.59.
- ^James Reilly, A Small Town in Syria, Ottoman Hama in the 18th and 19th Centuries, p73. Peter Lang Publishing (2002)
- ^Wincler, 1998, p.72.
- ^Wincler, 1998, p.44.
- ^ abDumper, Stanley, and Abu-Lughod, 2007, p.162.
- ^ abSchaff and Herzog, 1911, p.232.
- ^Oriens Christianus, II, pp.915–918.
- ^Gelzer, Heinrich, Patrum Nicaenorum Nomina. p.lxi.
- ^Missiones Catholicae. pp.781–804.
Bibliography[edit]
- This article incorporates text from a publication now in the public domain: Herbermann, Charles, ed. (1913). 'article name needed'. Catholic Encyclopedia. New York: Robert Appleton.[2]
- Dumper, Michael; Stanley, Bruce E.; Abu-Lughod, Janet L. (2007), Cities of the Middle East and North Africa: A Historical Encyclopedia, ABC-CLIO, ISBN9781576079195.
- Herzog, Johann Jakob; Schaff, Phillip (1911), The new Schaff-Herzog encyclopedia of religious knowledge: embracing Biblical, historical, doctrinal, and practical theology and Biblical, theological, and ecclesiastical biography from the earliest times to the present day, Funk and Wagnalls Company.
- Reilly, James (2002), A small town in Syria: Ottoman Hama in the eighteenth and nineteenth centuries, P. Lang, ISBN9783906766904.
- Ring, Trudy; Berney, K.A.; Salkin, Robert M.; La Boda, Sharon; Watson, Noelle; Schellinger, Paul (1996), International Dictionary of Historic Places: Middle East and Africa, Routledge, ISBN1-884964-03-6.
- Shatzmiller, Maya (1994), Labour in the medieval Islamic world, BRILL, ISBN9789004098961.
- le Strange, Guy (1890), Palestine Under the Moslems: A Description of Syria and the Holy Land from A.D. 650 to 1500, Committee of the Palestine Exploration Fund.
- Winckler, Onn (1998), Demographic developments and population policies in Baʻathist Syria, Sussex Academic Press, ISBN1-902210-16-6.
Further reading[edit]
- P. J. Riis/V. Poulsen, Hama: fouilles et recherches 1931–1938 (Copenhagen 1957).
External links[edit]
Wikimedia Commons has media related to Hama. |
Wikivoyage has a travel guide for Hama. |
- The Official City's Group on facebook(in Arabic) – (in English)
- e.sy Governmental online services
- Official site of Hama governorate(in Arabic)
- Hama city community on the net(in Arabic)
- Ancient Hama king list historyfiles.co.uk
Retrieved from 'https://en.wikipedia.org/w/index.php?title=Hama&oldid=917099817'
Published online 2012 Jul 17. doi: 10.1364/BOE.3.001880
PMID: 22876351
This article has been cited by other articles in PMC.
Abstract
Iatrogenic nerve damage is a leading cause of morbidity associated with many common surgical procedures. Complications arising from these injuries may result in loss of function and/or sensation, muscle atrophy, and chronic neuropathy. Fluorescence image-guided surgery offers a potential solution for avoiding intraoperative nerve damage by highlighting nerves that are otherwise difficult to visualize. In this work we present the development of a single camera, dual-mode laparoscope that provides near simultaneous display of white-light and fluorescence images of nerves. The capability of the instrumentation is demonstrated through imaging several types of in situ rat nerves via a nerve specific contrast agent. Full color white light and high brightness fluorescence images and video of nerves as small as 100 µm in diameter are presented.
OCIS codes: (170.3880) Medical and biological imaging, (170.2150) Endoscopic imaging, (300.2530) Fluorescence, laser-induced
1. Introduction
Iatrogenic nerve damage is a leading cause of morbidity associated with surgical procedures, including prostatectomy [,], coronary artery bypass graft [,], thyroidectomy [,], lumpectomy and mastectomy [,]. Complications arising from these injuries are dependent on the severity and location of the nerve injury but may result in loss of function and/or sensation, muscle atrophy, and chronic neuropathy [9]. The exact cause of nerve injury during laparoscopic and open surgical procedures is highly variable. However, inadvertent surgical damage due to poor visibility of nerves in comparison to surrounding tissue, or simply the unfortunate necessity due to proximity of the nerve to target structures remains a risk. Currently employed nerve sparing techniques rely primarily upon anatomical landmark identification or use of intraoperative nerve electrical stimulation devices to verify stimulation of innervated muscles or organs [,]. Surgical procedures are typically performed without any form of image guidance as the available technologies lack specificity needed to provide nerve-specific imaging [].
Optical imaging allows for both microscopic [–] and macroscopic [–] visualization of nerves during surgery. One method for intraoperatively identifying nerves and other critical structures is through the use of fluorescence image guided surgery (FIGS), which in recent years has undergone substantial growth leading to clinical translation [–] and commercialization. The surgical technique consists of optical contrast agents coupled with optical imaging hardware to provide visualization and increased contrast of otherwise indistinguishable anatomical features [–]. A range of targeted contrast agents have been used for tumor margin delineation [] and visualization of nerves [–], while non-specific agents such as ICG have been used for sentinel lymph node mapping [21,] and for vascular imaging [,].
Presently, optical imaging hardware for FIGS is undergoing rapid development in functionality and miniaturization [–]. Minimally invasive surgery (MIS) is gaining prevalence because it offers the benefits of small incisions, less pain, faster recovery, and fewer post-operative complications. Until recently laparoscopic surgeries were performed using white light illumination and color digital cameras, but have recently been enhanced with the capability of fluorescence imaging. Conventional laparoscopes have been outfitted with filtered illumination and filtered cameras to provide fluorescence guidance in pre-clinical [,] and clinical procedures [,]. Additionally, commercial MIS systems are becoming available with integrated fluorescence imaging capabilities (e.g., Karl Storz D-Light, O2view Artemis, and Intuitive Surgical Firefly [,]).
Standard laparoscopes (10 mm or 5 mm diameter) have a large field of view (70-135 degrees) and small collection aperture (typically F/8 to F/12). FIGS imaging with laparoscopes faces specific challenges due to low collection efficiencies and the requirement for compact and lightweight equipment. The need for a lightweight system precludes the use of sensitive, scientific grade cameras which typically include large detectors and cooling circuitry, or the use of two simultaneous cameras split with a dichroic beam splitter or similar methods [,]. However a recent approach used an image-preserving fiber bundle to relay the laparoscope output image onto a sensitive electron-multiplying CCD [], rather than mounting the detector directly on the laparoscope. In open surgical procedures, where the surgeon can directly view the surgical area, a single channel fluorescence-only FIGS system may be sufficient. However in MIS, obtaining white light video is a requisite feature of any laparoscopic system. Therefore, MIS FIGS should ideally perform dual-mode imaging with a single camera. Presently, dual-mode laparoscopic imaging is typically achieved by manual switching between a white light and fluorescence image [,] or by allowing partial leakage of the white light through the emission filter []. Several hybrid approaches to simultaneous multi-spectral imaging have been demonstrated for surgical imaging, incorporating multiple cameras and dichroic mirrors [], hybrid color cameras with custom filter mosaics [], fast liquid crystal tunable filters [] and modulated light sources coupled to the camera acquisition []. Thus far these have been restricted to reflected light only.
In this work we present a simple, low-cost, and lightweight system that provides near simultaneous acquisition of white-light and fluorescence video via time multiplexing. The system uses a single camera which allows for easy registration of the two channels for optional overlay and is compatible with any standard laparoscope. A custom built illumination module is electronically synchronized to a color camera that captures alternating white light and fluorescence images at 30 frames per second (fps). This architecture allows for the maximum display frame rate and adaptability of the system to any camera for dual mode imaging. The capability of the system is demonstrated in a rodent model by imaging several types of nerves in situ, via a nerve-specific fluorophore, GE3082, previously described [].
2. Methods
2.1. Instrumentation
The imaging system (Fig. 1) consists of three primary modules: laparoscope, illumination, and control and acquisition. The laparoscope module comprises a standard 10 mm zero degree surgical laparoscope with 70 degree field of view (T1000 Linvatec, Largo, FL), a 4 mm diameter, 1800 mm long laparoscope light guide (Medit Inc., Winnipeg, Canada), a 35 mm video coupler (MVC-35 Medit Inc.), a compact 90 gram, 659x494 pixel GigE color camera (acA640-90gc Basler, Ahrensburg, Germany), and a 405 nm blocking filter (BLP01-405R Semrock, Rochester, NY), which has >97% transmission from 420 to 800 nm. The 1/3” format sensor provides high sensitivity with 7.4 µm pixel size and adequate field of view (40 degrees out of 70 degrees passed by the laparoscope). The video coupler interfaces with the eyepiece of the laparoscope providing an interchangeable set up for different types of laparoscopes. The 405 nm filter is secured directly in front of the image sensor with a c-mount retaining ring. The camera threads onto the video coupler directly. The illumination light guide connects directly to each laparoscope with the appropriate mechanical coupler.
Single camera, dual-mode laparoscopic FIGS instrument. (a) Photograph of the laparoscope, coupler, camera with filter, and light guide. (b) Schematic of the illumination path. The LED and 405 nm laser are collimated and coupled into the light guide with aspheric lenses and combined with a dichroic mirror. A longpass filter in the LED path filters the white light spectrum below 450 nm.
Illumination for white light and fluorescence imaging is coupled into a single light guide using conventional optics. The light coupling module (Fig. 1(b)) consists of two 32 mm aspheric lenses (ACL4532, Thorlabs, Newton, NJ) to collimate a white light LED (XPGWHT-L1-0000-00H53, Cree Inc., Durham, NC) and a 500 mW, 405 nm blue laser diode coupled into a multimode fiber with 400 μm diameter (Shanghai Laser & Optics Century Co., Ltd., China). The LED spectrum is filtered with a 450 nm long pass filter (NT49-819, Edmund Optics, Barrington, NJ) to minimize excitation of the fluorescent agent, while maintaining the white light color spectrum. The LED and laser are combined with a 425 nm dichroic mirror (DMLP425R, Thorlabs). The combined illumination is coupled into the light guide with a third 32 mm aspheric lens (ACL4532, Thorlabs). The maximum irradiance from the LED and 405 nm laser are 2.0 mW/cm2 and 7.3 mW/cm2, respectively, at 25 mm from the tip of the laparoscope. These laser powers represent class 3B operation when compared to the ANSI and IEC laser safety standards (ANZI Z136.1-2007, IEC 60825-1 2007) when eye exposure occurs at the laparoscope tip. When accidentally viewed from over 0.5 m, the diverging illumination hazard is well within class 1.
Electronic synchronization between the camera and illumination sources provides nearly simultaneous display of white light and fluorescence frames. Synchronization is achieved by triggering a 4 channel digital pulse generator (DG535, Stanford Research Systems, Inc., Sunnyvale, CA) with the output line of the GigE camera, which generates a 5V signal when the camera exposure is active. The camera acquisition is stopped and started from the PC; thus the illumination is automatically synchronized. The exposure active pulse is used to synchronize TTL pulses with pre-set delay and pulse width from the digital pulse generator, as shown in Fig. 2. The stop and start time of each pulse is precisely aligned to ensure no bleed through to the opposing frames.
Timing diagrams indicating synchronization of the camera and light sources. The camera sync output (black) is used to drive the laser (red) and LED (blue) modulation via a digital pulse generator. All waveforms are 5V in amplitude.
The LED driver (D1B, Thorlabs) accommodates TTL input and provides LED illumination power control. The 405 nm laser is modulated by a TTL input and power controlled by the laser driver. Raw interleaved camera frames are acquired using a work station (Hewlett-Packard, xw8400, Palo Alto, CA) with custom image acquisition software written in C++. Images were adjusted for contrast and brightness in ImageJ (National Institutes of Health, Bethesda, MD). Since the images are obtained with a color camera, both channels represent true-color images of light reflected or emitted from the sample. This in contrast to conventional imaging, where fluorescence images are typically rendered using a false-color intensity display.
2.2. Fluorescent contrast agent
Detailed optical characterization, in vivo dosing and kinetics studies for GE3082 has been previously published []. However, the optical properties of GE3082 were reevaluated here in various solvents to prevent inconsistencies due to instrumentation (Table 1). Briefly, a 10 mM stock solution of GE3082 was prepared in anhydrous dimethylsulfoxide (DMSO) to ensure complete dissolution of the fluorophore. Subsequent aliquots of the stock solution were taken to prepare 10 μM solutions of GE3082 in the following solvents: DMSO, water, methanol, and a selected intravenous (IV) formulation (35% propylene glycol, 35% polyethylene glycol-300, 18% 2-hydroxypropyl-β-cyclodextrin, 11.5% distilled water, and 0.5% DMSO).
Table 1
Solvent | ε (M−1 cm−1) | Exc (nm) | Em (nm) | QY (%) |
---|---|---|---|---|
DMSO | 37200 | 417 | 623 | 1.7 |
MeOH | 41900 | 395 | 592 | 1.0 |
Water | 19356 | 380 | 578 | 0.8 |
IV formulation* | 32898 | 396 | 594 | 1.5 |
*Contained 35% propylene glycol, 35% polyethylene glycol-300, 18% 2-hydroxypropyl-β-cyclodextrin, 11.5% distilled water, and 0.5% DMSO; ε = molar extinction coefficient; Exc = excitation maximum wavelength; Em = emission peak wavelength; QY = quantum yield.
Absorbance spectra were taken using a Lambda 20 UV/Vis spectrometer (Perkin Elmer, Waltham, MA). The wavelength of maximum absorbance was then used as the excitation wavelength for the collection of the fluorescence emission spectra on a steady state spectrofluorometer (Photon Technology International, Birmingham, NJ). The molar extinction coefficient (ε) for GE3082 was calculated at the maximum excitation wavelength corresponding to each solvent, using Beer-Lambert’s law. The quantum yield (QY) of GE3082 in each solvent was measured in comparison to the fluorescence emission of a known standard (Coumarin-6; QY = 78%)) [43] using the single-point method [44]. An enhancement of fluorescence emission was observed upon binding to purified native myelin basic protein (MBP), a constituent of myelinated nerves (Fig. 3). Here, 10 μM of GE3082 was diluted in CHAPS (3[(3-cholamidopropyl)dimethylammonio]-propanesulfonic acid) buffer. Fluorescence emission spectra (405 nm excitation) were measured from the solution before and after the addition of 1.6 μM of MBP, resulting in an average enhancement factor of 17 across the spectrum, upon introduction of the protein.
Fluorescence spectra of the contrast agent GE3082 taken before (blue) and after (red) addition of native myelin basic protein (MBP), its biological target. The agent demonstrates increased fluorescence intensity upon binding to MBP. The average of the enhancement factor (green triangles) across this spectral range is 17.0 ± 0.72 for the specified concentrations of agent (10 μM) and protein (1.6 μM).
2.3. Animal preparation and surgical imaging
All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at GE Global Research. Male Sprague-Dawley rats ranging in body weight from 250 to 300 g were purchased from Charles River Laboratories (Wilmington, MA) and housed at 22-23°C on a 12-hour light/dark cycle. Rats were maintained on rodent chow (LabDiet 5001, Framingham, MA) and water ad libitum. On the day of the experiment, rats were anesthetized using 2-4% isofluorane and given a single tail vein injection of either GE3082 (11 mg/kg) in formulation buffer (35% propylene glycol, 35% polyethylene glycol 300, 18% 2-hydroxypropyl β-cyclodextrin, 11.5% sterile water, 0.5% dimethylsulfoxide) or formulation buffer alone as a control. The rats were then returned to the home cage until the designated time point for imaging. Four hours post-injection, the rats were euthanized using compressed CO2 gas, and major nerves were exposed and imaged. In addition, a small incision was made below the sternum allowing for passage of the laparoscope into the closed thoracic cavity for phrenic nerve imaging. Five different locations were imaged in the experimental rat. The range of locations demonstrates the extent of nerve labeling, taking into account nerves of differing sizes and myelination, and thus the overall imaging capability. Only the sciatic nerve was imaged in the control animal, since it is heavily myelinated. After the procedure was complete, the same locations were imaged using a fluorescence microscope (SteREO Lumar, Carl Zeiss, Thornwood, NJ) to measure the physical dimensions of each nerve.
3. Results
To test the imaging properties of the laparoscope, a USAF resolution target (Edmund Optics, NT38-710) was first used as a sample to characterize the spatial resolution of the assembled laparoscope. A white light external lamp was used to avoid specular reflection from the target protective lamination. On axis and edge images where acquired as shown in Fig. 4. At a working distance of 25 mm from the tip of the laparoscope, 7.13 lp/mm (line pairs per mm) were resolved on axis and at the edge of the FOV. At 50 mm working distance, 5.04 lp/mm were resolved. These correspond to a spatial resolution of ~70 μm and ~100 μm respectively.
Image of USAF resolution chart taken on axis at a working distance of 25 mm, demonstrating the spatial resolution of the instrument. Group number 2, element 6 can be easily resolved, corresponding to 7.13 lp/mm, or ~70 μm.
During imaging, ambient room lighting was minimized in order to prevent light leakage. The camera gain, laparoscope focus, and power of the LED and laser were adjusted to maximize image quality. Several myelinated nerves, such as the sciatic, brachial, median, vagus, and phrenic nerves were imaged using white light and fluorescence, as shown in Fig. 5. The identity of each nerve was verified under white light conditions. Fluorescence was clearly visible in all nerves imaged, allowing for easy visualization of major nerve trunks and their branches. Fluorescence was also observed in adipose tissue, while the surrounding muscle tissue was dark. In Fig. 5(b) the major trunk of the brachial plexus nerve spans the length of the image. Fluorescence signal from smaller nerves such as the suprascapular (horizontal arrow in Fig. 5(b)) and branches of the phrenic, radial, ulnar, and median nerves are also visible (yellow arrow in Fig. 5(b)). Moreover, distinct borders of the nerves were clearly distinguishable from adjacent tissue and blood vessels in the fluorescence images. For example, in Fig. 5(d), the vagus nerve runs parallel to the carotid artery and nearby trachea. In this white light image, the borders of the vagus were not easily defined along the entire length of the nerve in comparison to other adjacent tissue types. In contrast, the borders of the vagus are readily seen against the adjacent carotid artery and nearby trachea and thyroid gland in the corresponding fluorescence image, Fig. 5(d).
Laparoscopic surgery of fluorescently labeled nerves in rodent model, shown under white light (left column) and fluorescence (right column) obtained with the single camera, dual-mode laparoscopic instrument. Both channels are displayed in true color. All scale bars = 1 mm. Red arrows indicate the primary nerves imaged, which include the (a) sciatic, (b) brachial, (c) median, (d) vagus, and (e) phrenic nerves. The yellow arrow (b) shows a branch of the phrenic nerve, with ~100 µm diameter, and branches of the radial, ulnar, and median nerves in close proximity.
Similar findings were observed when imaging the phrenic nerve through a small incision in a closed thoracic cavity, more closely mimicking a minimally invasive surgery. In Fig. 5(e) the phrenic nerve is obscured under white light by attached parietal pleura. However, in the corresponding fluorescence image, distinct fluorescence of the phrenic nerve could be clearly seen along its entire length, regardless of the obscuring tissue seen in the white light image. Overall, these findings demonstrate visualization of nerves as small as 100 µm in diameter with high fidelity both in open and minimally invasive conditions.
The composite image acquisition rate was 30 fps, resulting in an effective frame rate of 15 fps per channel, which is high enough for motion-artifact and blur-free imaging. A video sequence of the phrenic nerve (Fig. 6) shows high fidelity imaging in recorded in real-time. In the video the heart, lungs and sternum are also visible. Although there is a single frame lag between the two channels, the small delay (33 ms) is not readily apparent.
Single-frame excerpt from video recordings of simultaneous white light (left) and fluorescence (right) imaging of the rat phrenic nerve (Media 1).
The sciatic nerve of a control rat (no fluorophore administered) was imaged under the same illumination, imaging distance, and camera settings as the experimental rat, as shown in Fig. 7. A histogram of the image intensity shows no measurable signal in the fluorescence channel, indicating that autofluorescence is negligible under these measurement conditions.
Results of control experiment, highlighting the sciatic nerve under (a) white light and (b) fluorescence. The inset in (b) is the image intensity histogram, showing no signal in the fluorescence channel, in the absence of injected dye. Scale bar ~1 mm.
4. Discussion
Reduction and prevention of nerve damage in surgery is an unmet clinical need requiring innovation in contrast agents as well as imaging hardware. A novel system incorporating both a contrast agent and fluorescence imaging instrumentation has been demonstrated. The instrumentation provided simultaneous real-time display of reflected white light and fluorescence images of nerves as small as 100 µm. The use of a single color camera streamlined the design, allowed for a form factor comparable to conventional laparoscopes, and provided inherent registration between the two channels. Factors such as the excitation and emission spectra, utilization in a closed environment (as is present in minimally invasive surgery), advancement of light sources and available camera technology have made this single-camera, dual-mode imaging solution feasible using a combination of standard, low cost equipment.
The promising imaging results obtained with the system using a visible fluorophore suggest that absorption and emission in the visible spectrum may allow for high fidelity imaging in an intraoperative setting. Here the agent can be excited at the edge of the normal white spectrum (405 nm laser) and the emission can be collected over the same waveband as the white light images. The camera is only filtered by a single 405nm laser line filter, thus allowing un-compromised white light reflectance imaging using an LED. Furthermore, the high brightness of the contrast agent affords high SNR images with minimal excitation power.
Recently, several works have demonstrated the advantages of contrast agents for FIGS in the NIR spectrum, because of its separation from the visible spectrum (white light channel), reduced autofluorescence, and prospects for deeper imaging penetration [,]. However, in controlled lighting environments such as MIS or with specialized room lighting, an agent excited at the blue end of the spectrum may also be advantageous. In particular, a highly specific, targeted fluorophore with a large Stokes shift can provide a high signal-to-background ratio despite operating in the visible spectrum. Excitation at 405 nm allows for laser line rejection with minimal impact on white light image quality, and emission in the visible benefits from large detector quantum efficiency within this range. Furthermore, this approach is complementary to NIR imaging, and does not interfere with NIR fluorescence if multi-channel molecular imaging is desired [].
While many of these benefits result from the optical properties of the present fluorophore, the single-camera dual-mode design is adaptable to other contrast agents. Adaptation to other dyes requires merely changing the laser source and corresponding rejection filter to match the excitation wavelength. A notch filter can be used for laser rejection while transmitting the remainder of the visible spectrum. Multiband dichroic mirrors can be used to combine the white light and laser source without excessive loss of light.
Several fluorescent nerve-highlighting contrast agents have been described recently, including non-targeted NIR fluorophores that are injected directly at the nerve of interest [], a non-toxic fragment of tetanus toxin for labeling retrograde transport in nerves [], and peptides that bind to the connective tissue in the nerve epineurium and endoneurium []. GE3082, and a related analog we reported on previously (GE3111) [] are small molecule fluorophores capable of crossing the blood-nerve and blood-brain barriers, a key requirement for systemic administration of targeted nerve contrast agents. Small molecules are generally less costly to produce than peptides and protein fragments, and they may be modified by chemistry to confer more desirable properties, such as stronger binding to a protein target or improved in vivo pharmacokinetics.
However, most molecules that cross the blood-nerve and blood-brain barriers have high lipid solubility, resulting in non-specific partitioning to adipose tissue. GE3082 appears to exhibit higher fluorescence intensity in adipose tissue than in nerves. One possible explanation for this observation is the dependence of agent optical property in local environment. A related analog, GE3111, exhibited an increase in quantum yield when measured in a non-polar solvent, such as olive oil [].
For clinical translation of myelin-targeting FIGS, better differentiation of nerve from adipose tissue fluorescence may be necessary. Using a commercial multispectral instrument, we have previously shown that GE3082 nerve fluorescence appeared a different color than its adipose tissue fluorescence []. Moreover, nerve and adipose tissue appear quite different structurally. Therefore, future initiatives will explore multispectral detection and shape-based segmentation/image processing to better differentiate nerve from adipose tissue fluorescence.
Acknowledgments
The authors thank Stephen Zingelewicz for software support and Tiberiu Siclovan for synthesis of GE3082. This research was supported by NIH grant EB022872 from the National Institute of Biomedical Imaging and Bioengineering.
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