WHO 2016 updated classification of medulloblastomas.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"668",leadTitle:null,fullTitle:"Congenital Diaphragmatic Hernia - Prenatal to Childhood Management and Outcomes",title:"Congenital Diaphragmatic Hernia",subtitle:"Prenatal to Childhood Management and Outcomes",reviewType:"peer-reviewed",abstract:"Congenital Diaphragmatic hernia (CDH) occurs in approximately 1 in every 2,500 births and the cause is yet unknown. 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Harvey Cushing and Percival Bailey were the first who described the name medulloblastoma as “Spongioblastoma Cerebelli” in June, 1925 for posterior fossa tumors of preadolescents population. They reported 29 cerebellar vermis tumor in children and young adults. Later they renamed as “medulloblastoma” as the term “Spongioblastoma multiforme” was described by Globus and Strauss in 1925 for various adults cerebral tumors in which feature of considerable cellular differentiation was seen. This picture was found absent in tumors of cerebellar origin [1, 2]. World Health Organization (WHO) defined medulloblastoma as “invasive malignant embryonal tumor of the cerebellum with commonest manifestation seen in children”. These neuroepithelial tumors have inherent tendency to spread through the cerebrospinal fluid to cranial and spinal subarachnoid spaces [3].
\nInjuries followed by malignancy are the second leading cause of mortality among children. After leukaemia’s, brain tumors are the most common in children accounting for ‘25%’ of all malignancies in children [4]. Most common malignant CNS tumor in children is medulloblastoma (MB) constituting 20% of primary brain tumors and approximately 40% of all tumors of the posterior fossa [5]. The incidence of medulloblastoma in adults is relatively low as compared to pediatric population. This constitutes 1% of all CNS tumors and this may be the cause of scanty data available in adult MB group [6]. U.S data showed the incidence of the medulloblastoma is 1.5–2 cases/100,000 population. Three hundred and fifty new cases in the United States are seen each year. The peak incidence is seen in 1st decade of life and incidence is noted higher in the pediatric age group 3–4 years followed by 8–10 years of age.
\nCBTRUS (Central Brain Tumor Registry of the United States) showed that incidence is higher in males as compared to females (Males: 0.16 vs. Females: 0.12). But this trend is different in children who are less than one year old. There is rising trend of higher incidence (APC: 1.7, 95% CI −0.4, 4.0) and death risk (Hazard Ratio for Survival: 0.74 with p value 0.09) seen in black race compared to whites which is non-significant [7, 8].
\nThere is rapid initiation of clinical symptoms are secondary to the rapid proliferation of these cellular malignant tumors. Symptoms of medulloblastomas vary with age. Earlier age of onset is associated with behavioral changes. Other symptoms may include listlessness, moodiness or irritability, vomiting, and lack of social interactions. As medulloblastoma is rapidly growing tumor, this results in obstructive hydrocephalus which manifests as raised intracranial pressure (ICP). Children may be seen with macrocephaly, fullness of fontanelle, and delayed developmental milestones. Older children and adults have symptoms of raised intracranial pressure like headache, vomiting, especially upon awakening in the morning hours. Headache usually gets better during the day. As anatomical location of medulloblastoma is cerebellum but symptoms slightly vary within various sites of cerebellum. Truncal ataxia result from tumors located in midline of cerebellum and appendicular ataxia is associated with the hemispheric located tumors [1]. There can be stretching of sixth cranial nerve because of hydrocephalus resulting in double vision. Meningeal irritation causes tilting of head and stiffness of neck due to the tonsillar herniation. Trochlear nerve palsy related to tumor compression is another reason of head tilt. Patients with spinal metastasis had symptoms of backache, weakness of bilateral lower limb and loss of bowel and bladder control. Metastatic disease symptoms depend upon the site involvement [9]. Majority are sporadic cases but there are associated syndromes like Gorlin syndrome (nevoid basal-cell carcinoma syndrome), Blue rubber-bleb nevus syndrome, Rubinstein-Taybi syndrome and Turcot syndrome (glioma polyposis syndrome) [10].
\nAlthough radiology is good contributor of diagnosis still detailed history and physical examination remained important and has to be done before proceeding for any investigations. Alteration of child behavior, persistent symptoms and focal neurological deficit are warning signs and should be proceeded with neuroimaging for diagnosis.
\nComputed tomographic (CT) appearance of a medulloblastoma is seen as well-defined vermian cerebellar mass which is hyperattenuated with surrounding vasogenic edema and sometimes evidence of hydrocephalus is seen. Contrast enhanced images show homogeneous enhancement.
\nMRI imaging of the entire neuraxis, brain and spine is recommended for suspected cases. MRI images show “Low-to-intermediate signal intensity” on T1-weighted images and “moderately high signal intensity” on T2-weighted images, compared to cerebellar white matter. Intratumoral haemorrhage, peritumoral oedema, tonsillar herniation, hydrocephalus and calcification are other associated findings. Multivoxel MR spectroscopy (MRS) of the primary tumor can assess the tumor metabolites like ‘elevated Choline peaks and decreased Creatine and N-acetyl acetate peaks’. Even without frank necrosis, a small amount of lipid-lactate peak sometimes observed indicating an increase in metabolic activity. Due to densely packed cells within the tumor and nuclear: cytoplasm ratio is higher, MB causes restriction of diffusion. There is restriction of diffusion of water particles in the tumor. So there is high signal of the tumor in diffusion-weighted MR images [11]. As frequency of spine seeding is 35% at diagnosis, to rule out any leptomeningeal metastases, Sagittal fat-suppressed post- gadolinium contrast MRI of the spine should be performed prior to surgery (Figure 1). Guang-Yao Wu et al. published data showed that proton magnetic resonance spectroscopy (1H-MRS) and Diffusion Weighted Imaging are helpful for qualitative diagnosis of medulloblastoma [12].
\nShowing preoperative MRI. (A) T1 weighted image post- gadolinium with tumor arising from midline of cerebellum. (B) T2 FLAIR with mild hyper intensity and voxel showing the tumor area of interest for spectroscopy. (C) Drop metastasis. (D) Significantly increased choline peaks with decreased NAA and Cr peaks on Spectroscopy.
Baseline hearing status with tests like Audiometry, IQ Testing and hormonal levels with Serum TSH and GH can be tested.
\nMostly medium and large sized tumors in posterior fossa are associated with hydrocephalus. In routine practice, prior to definitive surgery, ventriculo-peritoneal (VP) shunt should generally be avoided as definitive resection of tumor efficiently relieves the obstruction by opening the CSF pathways. Ideal surgery of any tumor is complete surgical resection, but feasibility and safety is priority. In such circumstances, it is recommended to attempt maximal safe resection and residual disease can be left behind rather than aggressive surgical resection approach that can precipitate significant morbidity. Benefit to risk ratio of complete surgical removal of tumor has to be assessed preoperatively [13, 14].
\nIdeal timing of post surgery MRI imaging should be obtained immediately, within 24–48 h of tumor resection, for accurately identification of the extent of surgical resection and quantification of the status of the residual tumor. If immediate post surgery MRI imaging has not been obtained, then recommendation is to wait for at least 2–3 weeks, but no more than 4-weeks, for resolution of post surgical changes and this will further prevent false positive results. Recommendations for timing of postoperative CSF analysis for malignant cells are also same, at least 2–3 weeks post surgery to prevent errors like false positive results [15, 16].
\nClassification of most of the CNS tumors are still relying on only histopathological features but in medulloblastomas, integration of additional molecular information has updated WHO classification from 2007 to 2016. Medulloblastoma is classified now by an integrative diagnosis including a histologically as well as genetically defined compound as shown in Table 1 [17].
\nHistopathologically defined MB | \nGenetically defined MB | \n
---|---|
Medulloblastoma, classic | \n\n
| \n
Desmoplastic/nodular medulloblastoma | \n\n
| \n
Medulloblastoma of extensive nodularity | \n\n
| \n
Large cell/anaplastic medulloblastoma | \n\n
| \n
Medulloblastoma, not otherwise specified (NOS) | \n\n
| \n
WHO 2016 updated classification of medulloblastomas.
Molecular classification provides additional clinical and prognostic information which has the potential for identification of innovative strategies and research for the management of this disease (Table 2) [18, 19].
\n\n | Wingless activated (WNT) MB | \nSonic hedgehog (SHH) subgroup | \nGroup 3 | \nGroup 4 | \n
---|---|---|---|---|
Cell of origin | \nDorsal brainstem (lower rhombic lip) neuronal progenitors | \nCerebellar external granular layer, neuron precursors | \nVentricular zone neural progenitors | \nCerebellum progenitors (upper rhombic lip) | \n
Prevalence | \n10% | \n30% | \n25% | \n35% | \n
Male:female | \n1:1 | \n1:1 | \n2:1 | \n3:1 | \n
Common age | \nOlder children | \n<3 year and >16 year, adult group | \nInfants and children <16 year | \nInfants/children/adults | \n
Histopathology | \nClassic. In few case, large cell and anaplastic | \nNodular desmoplastic histology, classic, large cell and anaplastic | \nClassic, large cell and anaplastic | \nClassic, large cell and anaplastic | \n
Genetic aberrations | \nCTNNB1 DDX3X SMARCA4 | \nMYCN, GLI2, PTCH1, SUFU, MLL2, SMO, TP53, BCOR1, LDB1, GABRG1 | \nMYC, PVT1, OTX2, MLL2, SMARCA4, CHD7 | \nOTX2, DDX31, CHD7, SNCAIP, MYCN, CDK6 GFI1/GFI1B, MLL2, KDM6A, MLL3, ZMYM3 | \n
Chromosome | \n−/6 | \n3q gain, 9q loss, 10q loss | \n1q gain, 5q loss, 10q loss | \nIsochromosome 17q chr X loss, 17p loss | \n
Molecular markers | \nBeta-catenin | \nSFRP1or GAB1 | \nMYC activation in 50% of this subtype | \nUnknown | \n
Metastasis | \nRarely present | \nNot common | \nHigh | \n35–40% at presentation | \n
Recurrence | \nRarely seen | \nLocal | \nMetastasis | \nMetastasis | \n
5 year overall survival | \n95% | \n75% | \n50% | \n75% | \n
Future strategy | \nReduction in therapy | \nSHH pathway inhibitors | \nIntensified therapy, novel therapeutics | \nRobust and large data research | \n
Medulloblastoma as a group of molecularly distinct subtypes.
Medulloblastomas originally were staged only on surgical basis but “Modified Chang Staging” is the current standard and there is addition of imaging [20] explained in Figure 2.
\nModified Chang’s staging system.
Risk stratification based on clinico-radiological analysis is still widely practiced and remains valid for Radiation planning in institutions. COG and SIOP Group accepted the clinical prognostic variables [21] shown in Figure 3. Although with the inclusion of molecular sub-grouping and genetic analysis of disease, more robust information about risk stratification and outcome of disease can be concluded to some extent but this required availability of these facilities with expertise in institutions. Incomplete neuraxis staging should be classified as high risk disease.
\nThe stratifying medulloblastoma patients clinically into high risk and standard (average) risk based on variables like age, resection and metastasis.
Medulloblastoma, the embryonal tumors of the central nervous system, are highly radiosensitive tumors. After 200 cGy, the survival fraction has been reported to be 27%. Although Dargeon in 1948 stated that “medulloblastomas … have a consistently unfavourable prognosis” but later careful observation of Edith Paterson regarding pattern of disease spread brings hope to this disease. Radiating brain and spinal cord in one undivided volume principle mentioned by Edith Paterson and Farr. was based on the post-mortem findings of brain and spinal cord deposits in untreated cases. In 1953, at the Christie Hospital a five-year survival rate for children who were treated with kV irradiation reported by Paterson and Farr was 41%. Since then the practice to irradiate the entire craniospinal axis is universally adopted [22, 23].
\nAfter resection of tumor, entire craniospinal axis irradiation followed by whole posterior fossa or tumor bed boost irradiation is recommended irrespective of clinically detectable disease. Being Radiosensitive, Radiotherapy is curative up to 70% of standard risk patients. For this pediatric age group disease, linear accelerators are better than telecobalt machines and these children should preferably be referred in time to well equipped higher center with radiotherapy facility and infrastructure to prevent unnecessary side effects. As treatment delays beyond 6–7 weeks result in worse outcome, cobalt-60 therapy may be offered in those areas where linacs are not available. To prevent the adverse effects of radiotherapy in the developing nervous system, radiotherapy is avoided initially in children up to 3 years of age. CSI technique required accurate reproducibility and complex field matching techniques. Long and complex shaped target volume homogeneity is a technically challenging process.
\nTiming of radiotherapy
\nImproved survival for patients is associated with a shorter interval from surgery to the start of radiation therapy. After definitive surgery, treatment should be started within 4–7 weeks. International Society of Paediatric Oncology (SIOP) trials showed that increase in the risk of relapse is seen if radiotherapy treatment is delivered after 7 weeks [24].
\nYounger brains are much more sensitive to damage caused by radiotherapy. CT based conformal radiation therapy, 3DCRT, is standard of care exists for many years. Patient can be in the supine or prone position during CSI treatment. Over the years, prone position was used universally. Nowadays supine position is used increasingly.
\nAdvantages of supine position [25]
Target volume coverage is more easily assured and delivery more reproducible.
Patient is more comfortable due to stable position.
Technically, there is better shielding of cribriform plate and inferior temporal lobes.
For younger pediatric patients who require anaesthesia, there can be better management of airways and cardiopulmonary complications can be reduced.
Limitations of supine position
Without adequate portal imaging, setup accuracy is difficult.
Old couches contain metal inserts and beam entrance posteriorly through the head rest and treatment couch is not possible.
Advantages of prone position is the junction between the spinal and cranial fields can be better visualized.
\nFor younger children, good sedation may be required. Expert play therapist may help in treatment for radiotherapy without sedation.
\nIn 2-dimensional planning, fluoroscopic guidance two-dimensional simulation is done. Immobilization is done with thermoplastic cast and universal prone head-rest is used. CSI board with Lucite base plate having semicircular Lucite structures are available for head rest and chin rest. Various degrees of neck extensions is possible which will prevent the exit of superior border of spinal field through the oral cavity. Chest wall can be supported by thermocols.
\nThis complex 2-dimensional CSI technique fundamentals are:
Two parallel opposed lateral portals for cranium and upper cervical spinal cord.
Posterior spinal field matching with the cranial fields.
In case of adults or larger children, matching of upper posterior spinal field with the separate lower posterior spinal field.
Craniospinal junction can be placed at higher level: C1/C2 interspace or lower level C5-C7. At higher level, overdose to spinal cord is low. Shoulders are excluded from the lateral fields by keeping the craniospinal junction at lower level (C5-C7). Also the exit dose to mandible, thyroid, pharynx and larynx is lowered. Inferior edge of S2 is mostly the anatomical landmark where lower border of spinal field (SF) is set. Single Craniospinal junction is set for smaller children. If length is >36 cm, two junctions are required which are craniospinal and spinal-spinal (SS) junction. Mostly SS junction is place at L2-L3 interspace. Multi-leaf collimators or custom made lead blocks are utilized for orofacial region shielding. In order to know the divergence of spinal fields, the spinal fields are simulated first.
\nVarious techniques used for matching craniospinal junction are:
For matching the beam divergence of the lateral head portals with the superior beam edge of SF, Collimator rotation is done 7–10°.
Couch rotation 6°.
Half beam blocks
Asymmetric jaws
Penumbra trimmers
The craniospinal junction should be feathering/moving weekly during craniospinal irradiation for homogenous dose distribution and further minimizing the hot or cold spots resulted from the gap-junction or set-up errors. With each shift, spinal field can be extended superiorly, and cranial fields can be decreased inferiorly by 0.5–1 cm. Similarly LB (lower border) of “superior spinal field” and SB (superior border) of “inferior spinal” field can be shifted superiorly. This all is done for spread out of dose homogeneity. Still the contribution of human errors is seen in many studies. As there is direct visualization of the optical field light on the skin surface in prone position, verification of beam delivery of CSI is relatively simple (Figure 4A) [26, 27].
\n(A) Gap feathering during craniospinal irradiation (CSI). Junction movement across the long treatment length allows homogenous dose distribution by reducing the overlap hot spot and gapping cold spots. If field length <35 cm, 100 cm SSD is used and for field length >35 cm, 120 cm SSD is used. (B) Posterior fossa boost volume including whole infratentorial compartment.
The posterior fossa (PF) boost volume
\nDepending on the risk-stratification of the disease, volume of the posterior fossa boost is decided. Those cases which are considered low risk and standard risk medulloblastomas, posterior fossa target volume includes pre-operative tumor bed with adequate margins. Most institutions add 1–1.5 cm margin to the tumor bed. Cases of high risk and very high risk disease require irradiation of the entire posterior fossa. Posterior fossa irradiation can easily be planned based on fluoroscopic imaging in low and middle income countries where there is no availability of multileaf collimators.
\nConventional portals for PF boost
\nThe PF boost is given using two lateral opposing fields. Anterior radiotherapy borders are formed by the posterior clinoids, posteriorly by internal occipital protuberance, superiorly extended up to mid-point of foramen magnum and vertex (or 1 cm above tentorium) and inferiorly extended up to C2-C3 interspace (Figure 4B) [28].
\nIn case of pediatric patients who are potential long term survivors, critical structures are better spared by conformal techniques.
\nImmobilization is done in supine position and patient is aligned straight keeping neck in the neutral position. A 4-clamp thermoplastic immobilization cast for the head and shoulder region along with appropriate neck rest should be used. A five point orfit for immobilization along with hyperextended head and depressed both shoulders can result in optimal sparing of the upper esophagus and laryngeal structures.
\nTraditionally, axial planning images of 5 mm thickness on CT simulator from the vertex till the upper thigh region were preferred. But in this era of high precision radiotherapy where CTV accuracy is important for optimal outcome, CT slice thickness is reduced in some anatomical sites of CSI field. Slice Thickness of 1–2.5 mm from the vertex to the inferior border of third cervical vertebrae (C3) and 2–5 mm from the lower border of third cervical vertebrae (C3) to the upper anatomical region of the femur should be obtained. Skull base foramina delineation is of utmost important and for their identification, “1 mm slice thickness at the base of skull” is preferred. To improve better identification of cranial nerves dural sheaths, co-registration of planning imaging CT to MRI can be done [29]. CSF extensions within the dural reflections are better demonstrated by FIESTA (Fast Imaging Employing Steady-State Acquisition) MRI sequences [30].
\nTreatment volumes
\nDue to the risk of CSF dissemination, entire arachnoid space is included in the clinical target volume (CTV).
\nThe frontal lobe and the cribriform plate must be included in the clinical target volume. Inclusion of superior orbital tissue is must in the radiation field for the adequate coverage of the frontal lobe and cribriform plate. As per SIOPE guidelines, “the geometric edge of shielding should extend at least 0.5 cm inferiorly below the cribriform plate and at least 1 cm elsewhere below the base of the skull”.
\nDelineation of CTVcranial
Brain along with its covering meninges are contoured till second cervical vertebrae (C2). For outlining the inner table of the skull, CT bony window setting is used with window/level: 1500–2000/300–350 suggested by SIOPE group.
The most critical sites are the ‘cribriform plate’, the ‘most inferior parts of the temporal lobes’, and the ‘whole pituitary fossa’. They all to be included in the CTVcranial delineation. For cribriform plate CT window/level suggested is 3000/400.
For inclusion of CSF within the dural sheath of cranial nerves, CTVcranial is modified. For second cranial (optic) nerve, window width 350/level 40 is to be used
Foramina or canals of skull base which are significant for delineation of CTVcranial are cribriform plate, optical canal of sphenoid, superior orbital fissure, foramen ovale, internal auditory meatus (IAM), jugular foramen and hypoglossal canal. Entire components length of the optic nerves in the CTVcranial is included in most institutions where photons are used. But in those institutions where medulloblastomas are treated by protons, for prevention of any potential optical retinopathy risk, only the posterior length components of the optic nerves is included [31, 32].
\nAs CSF flows up to the posterior aspect of eyeball which is better observed in MRI images, it is better to include whole optic nerves in CTV in routine practice of photon beam based radiotherapy in these cases. The cranial nerves which are wrapped without dural cuff are the third, fourth and sixth (oculomotor, trochlear and abducens) nerves. Nobel et al. studied the flow of cerebrospinal fluid beyond the inner table of skull into the IAM (internal auditory meatus), juglar foramen (JF) and hypoglossal canal (HC). Their study (on basis of 96 FIESTA MRI sequences) concluded that the CSF extension was up to ‘16 mm’ in the internal auditory meatus which is not very far away from the cochlea. So the cochlear sparing by CSF exclusion within the internal acoustic canal should not be attempted. Their data also showed that the CSF extension was up to 11 mm in the juglar fossa from inner table of skull. There is no extension of CSF within these dural sheaths outside the outer table of the skull. It is not so easy to delineate dural sheath CSF on MRI but CT images with 1 mm thickness along the base of skull can show skull foramina and canals and they can easily be contoured on bony windows (Figure 5) [29].
CTV brain: brain and its covering meninges till lower border of C2. PTV brain: 5 mm isotropic margin around CTV brain. CTV spine: entire arachnoid space with nerve roots. PTV spine: 5–8 mm isotropic margin is recommended around the CTV-spine | \n
Showing conformal planning. (A) Cribriform plate is in close proximity to ocular structures. Shielding edge should be at least 0.5 cm below the cribriform plate and 1 cm elsewhere below base of skull to cover the temporal fossa and skull base foramina. (B) The petrous part of temporal bone showing Internal acoustic canal (IAC). (C) Various skull base foramina contoured in CTVcranial including dural cuffs of cranial nerves. (D) Cribriform plate must be in target volume. (E) Entire subarachnoid space, including nerve roots laterally must be included in CTVspinal. SFOP, French Paediatric Oncology Society; CP, cribriform plate; SOF, superior orbital fissure; FO, foramen ovale.
Issues of the cribriform plate (CP)
\nAccording to a 1982 report from MSKCC, 15% of recurrences are subfrontal in medulloblastomas [33]. Hypothesis given by Donnal et al. was that the pooling of cells secondary to gravitational effect of prone position with maximum shielding of eyes can result in the recurrences at the region of cribriform plate [34].
\nThe CTVSpinal (spinal target volume) includes the complete dural or thecal sac. Lateral extension of delineation is must to cover the intervertebral or neural foramina with their exiting nerve roots from the C2 cervical spine till the lower end of the thecal sac. Lower border of CTVSpinal is appreciated by the latest spinal MRI imaging. Children Oncology Group (ACNS0332, ACNS 0331, ACNS 0122) recommended the inferior border of CTVSpinal is ‘2 cm below the termination of the subdural space’ which is usually at bottom of second sacral vertebrae. The other SIOPE group trials recommended that the lower border of CTVSpinal must be determined by the spinal MRI imaging of the termination of the thecal or dural sac. This border should be kep. 1 cm inferior to this. Root canals in the Sacral CTVSpinal can be excluded. This recommendation is based on a MRI study conducted on ten volunteers who were healthy proved that there was no CSF around the nerve roots of sacral segments.
\nIf patients are to be treated by protons, then for skeletally immature patients, CTVSpine should include the vertebral bodies. This will decrease the risk of unequal vertebral growth. In skeletally mature patients, spinal TV should include the subarachnoid space of spine with a margin of 3–5 mm is summed up to the body of vertebrae for set up uncertainties/variation (interfraction) [29].
\nDelineation of posterior fossa boost volume
\nHigh Risk and Very High Risk disease: The clinical target volume PF (CTVPF) boost encompassed the whole PF. The boost CTVPF extends superiorly up to the tentorium cerebelli, inferiorly to the foramen magnum, and posterolaterally to the occipital bony walls and temporal fossa. BS (Brain Stem) anterior border and midbrain cover the components of the posterior fossa anteriorly. The geometric margin of 0.5 cm around the CTVPF is taken for delineation of the PTV posterior fossa (PTVPF). PTVPF is limited to the bony confines of the skull, except at the foramen magnum where it extended to the level of C1. The PTVPF contoured anteriorly up to the posterior clinoids and inferiorly to the C1-C2 junction. PTV is modified at sella and pituitary gland is excluded from anterior extension of PF boost planning.
\nFor low risk and standard risk, tumor bed, as defined on CT images, delineation with a margin of 1–2 cm is recommended. For three-dimensional planning, two lateral opposing portals with editing/shaping using the multileaf collimators (MLCs) is recommended. Finally, these craniospinal and boost plans must be summated to produce a composite treatment plan and final dose-distribution is calculated [35, 36].
\nChildren and adults are two different groups as far as radiotherapy treatment in medulloblastoma is concerned. Proliferating tissues are more in children as compared to the adults. IMRT for adult population is a used as a routine practice for numerous malignancies but for pediatric patients, IMRT has to be used with great caution in view of low dose volumes. Spinal irradiation during CSI results in increased doses delivered to anterior thoracic and abdominal structures with conventional plans. Parker et al. published data showed that the PTV and dose homogeneity was better for the medulloblastoma CSI, IMRT plans. Dosimeteric analysis showed V95% for IMRT was 100%, 3D planning was 96% and 2D planning was 98%. Also V107% for IMRT was 3%, 3D planning 38% and 2D was 37%. The IMRT plans provided better sparing of heart and liver in terms of V (10 Gy) and above. Integral Dose analysis showed the IMRT plans were superior for liver and heart and the 3D plan were better for the body contour. Tomotherapy may be helpful in reducing high dose regions in OAR, but low dose of radiation to a large volume is a concern for pediatric patients [37].
\nIMRT planning
\nIMRT for craniospinal irradiation in adult medulloblastomas is delivered after summation of PTV brain plan and PTV spine plan. Usually the spinal PTV planning is done first with ‘inverse planning technique’ using the 5 posterior fields with 0°, ±20° and ± 50°gantry angles. For the craniocaudal direction, the isocenter is kept at the “geometrical center of the PTV_spine”. For the depth and lateral position, it is usually set at the “midline and midplane” at the level of the interphase of second and third cervical vertebral body. Dose prescription and normalization is to the isocenter of the spine. For the cranial target, a separate plan is created. Cranial fields isocenter is set at the inferior most slice of the PTV brain. MLC positions can be modified for dose reduction to the nearby OARs and adequate coverage of the target volume. The geometric center of the PTV_brain is defined as the reference point for dose prescription and normalization. Final composite plan for the whole cranio-spinal axis is obtained after dosimetrically summation of spinal and cranial plans. For taller patients, for upper and lower spine, IMRT plans are created separately [38].
\nIntensity modulated radiotherapy for posterior fossa boost
\nMeenu et al. re-planned seven previously irradiated patients of MB with seven field inverse planning IMRT for whole posterior fossa boost. Equidistant gantry angles (0°, 50°, 100°, 150°, 210°, 260°, 310°) were used with step and shoot IMRT on 6MV energy LINAC. Treatment isocenter was set at the geometrical center of the planning target volume. They compared with 3DCRT plan delivered by two lateral opposing beams with multileaf collimators for shaping. Their dosimeteric results showed there were decreased mean dose to most critical organ at risk, cochlea, with IMRT compared to the three dimensional radiotherapy plans with significant p values i.e. 0.032 for the cochlea of right ear and 0.020 for the left sided cochlea (Figure 6) [35] Similar results are found in published clinical studies conducted by Huang et al. where 13% of the IMRT group had grade 3 or 4 hearing loss as compared to 64% for the conventional group [39].
\nCoursey JCRT. Meenu et al. mid-axial dose distributions with (a) 3DCRT (b) IMRT for one of the representative case of entire posterior fossa boost. Yellow represents 100%, red 95% and blue 70% of the isodose lines. IMRT is advantageous over 3DCRT for cochlear sparing. 3DCRT, three dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy.
Organ at risk
\nOAR as demarcated on axial CT images include brain, eyes, lens, optic nerves, optic chiasma, cochlea, parotids, mandible, thyroid, esophagus, lungs, heart, breasts, liver, kidneys, bowel bag, rectum, bladder, gonads (ovary or testes), vertebral bodies, uterus plus pelvis (red bone marrow).
\nBerry et al. reported a five year survival rate of 47% with lesser doses and ten year DFS of 77% once the posterior fossa doses delivered were >52 Gy [40]. Abacioglu et al. showed in adult medulloblastomas, control rate was 33% at 5 year with doses <54 Gy native to 91% in those patients on whom higher doses were delivered [41]. CSI dose reduction is feasible with the addition of chemotherapy as level 1 evidence based data released by Children’s Cancer Study Group showed that the reduction of doses from 36- to 23.4 Gy resulted in significantly higher risk of recurrences outside the posterior fossa [42].
\nRadiotherapy doses to CSI depends upon the risk stratification of the disease at presentation. If risk stratification or accurate staging is incomplete then patient can be treated as high-risk disease. Radiation therapy doses according to the risk stratification are shown in Table 3 [43]. There are different long term toxicities between the adult and children. CSI dose reduction approach is avoided for adult patients. Still big data is required to justify the addition of adjuvant chemotherapy to radiotherapy in average risk adult patients as data showed that 70–80% of these patients have no progression of disease at 5 years when RT is used as a sole modality. Also there are issues of hematological toxicities in adult patients.
\nVarious risk stratification | \nVolume and doses of radiation therapy | \nConcurrent or adjuvant chemotherapy | \n
---|---|---|
High risk and very high risk disease | \nCSI: 36 Gy/ 20 fractions, 5 days a week Boost to posterior fossa: 19.8 Gy/ 11 fractions, 5 times/week Gross metastatic deposits: Boost dose of 5.4–9 Gy/3–5 fractions | \nConcurrent carboplatin followed by adjuvant six cycles of systemic chemotherapy | \n
Standard risk | \nChildren <18 year CSI: 23.4 Gy/13 fractions, 5 days a week Boost to whole posterior fossa (or tumor bed): 30.6 Gy/17 fractions, 5 times/week Adults CSI: 36 Gy/20 fractions, 5 days a week Boost to posterior fossa: 19.8 Gy/11 fractions, 5 times/week | \nChildren <18 year Weekly vincristine followed by adjuvant six cycles of systemic chemotherapy | \n
Low risk | \nCSI: 23.4 Gy/13 fractions, 5 days a week Boost to whole posterior fossa (or tumor bed): 30.6 Gy/17 fractions, 5 times/week | \nReduced intensity chemotherapy | \n
Radiotherapy doses according to risk stratification.
Pediatric age is more sensitive to radiation induced carcinogenesis as compared to adults by a factor of at least 10 [44].
\nAs children anatomy is small so critical organs are very much close to the target volume. Also the scatter from the treatment volume is highly significant in children having small body area as compared to large body of adults. Particle beam therapy is a potential powerful tool for improving the therapeutic ratio. Goal of pediatric radiation oncologists is integral dose minimization to whole body and organs at risk. Advantage of protons over the photons is that they can modulate the dose to avoid very close OARs. For CSI, advantages of protons are because of absorption of low dose on tissue entry and the point of maximum dose deposition at the Bragg-peak. This results in the avoidance of dose deposition to anterior organs like thyroid, lungs, heart, gut, liver, esophagus, kidneys and urinary bladder. Also critical brain structures such as the lens, optic chiasma, pituitary, cochleae are better spared. In grown up children, sparing the anterior portion of the vertebral body results in minimization of bone marrow dose (Figure 7).
\nCSI Schematic Model. (A) Photons are absorbed and secondary electrons have large range in mm resulting in doses beyond the target volume. (B) Advantage of stopping of protons is due to the Bragg peak curve resulting in lower doses to OARs with proton therapy.
Consensus report from the Stockholm pediatric proton therapy conference showed that treatment of choice for medulloblastoma is proton therapy [45]. Based on the review of the existing theoretical and early clinical outcomes evidence, results showed that proton craniospinal irradiation provide similar control of tumor with potentially decreased doses to the normal structures thus reduces the risk of side effects when compared with photon existing data [46]. Spot-scanned intensity-modulated proton therapy (IMPT) is advantageous over the photon therapy in terms of all radiobiological risk estimation [47].
\nWeight changes in medulloblastoma and adaptive proton therapy are coming up but at present there is scanty data available. Patient selection is of utmost important in proton therapy. Limitations of patients with their families to travel in these centers, the proton center capacity to treat children and the availability of expertise and support structures must be evaluated by the referral physicians.
\nChemotherapy is integral part of treatment and in standard risk cases CSI doses can be reduced. Children less than 3 years, chemotherapy is recommended till the child will attain the age of 3 years. Drugs like carboplatin, cyclophosphamide and etoposide is recommended. There are various regimens recommended (Box 1). In a published database analysis of medulloblastoma children (n = 816) age 3–8 years who received adjuvant chemotherapy after surgery, overall rate of RT deferral after surgery was 15.1%. Their practice was associated was decreased overall survival in this pediatric population even in the well-established era of chemotherapy. [48] At present, recommendations of chemotherapy are:
Following RT as adjuvant settings
In Infant medulloblastoma, to defer RT, till the age of 3-years
Autologous stem-cell rescue accompanied with high-dose chemotherapy with
Concurrent chemotherapy with radiotherapy
As a salvage therapy in cases of relapsed of recurrent medulloblastoma.
Chemotherapy regimens (adjuvant) in MB children >3 years of age [49, 36].
\n\n
A detailed discussion about the chemotherapy and late effects of radiochemotherapy, management of adverse effects are outside the scope of this chapter. It is recommended and important to have multidisciplinary follow-up with pediatric radiation oncologists and endocrinologists.
\nFollow up counseling is mandatory prior to initiation of treatment. MRI brain may be performed every three months and MRI spine may be obtained every six months in standard risk category of standard risk patients for the initial two years. These two investigations can be performed every 6 months up to five years, and then repeated every year. In high-risk group, MRI of whole brain and spine may be repeated every three months for the initial two years. Thorough clinical examination with every visit is necessary. In case of pediatric or adolescence groups following radiotherapy, neuroendocrine follow-up with evaluation of serum hormonal levels should be performed every six months.
\nAuthors are grateful to Prof. Sunil Saini, Director Cancer Research Institute, Swami Rama Himalayan University for providing motivation and necessary facilities for writing this book chapter.
\nThe authors declare that this chapter was written in the absence of any commercial or financial relationships that could elucidate as a potential conflict of interest.
\nThe quest for controlled drug release emanating from side effects associated with the application and delivery of conventional drugs has necessitated the need for materials that can transport drugs to target site without difficulty or problem during and after delivery. Normally, drugs are delivered repeatedly on prescription to the body in measures that will bring about remediation and quick recovery to the patient during the treatment period. In this wise, drug concentration levels will increase and when above the body’s tolerance level, the problems associated with over therapeutic concentrations could occur that could result into toxic side [1]. It is also possible that the drug release rate is so fast that therapeutic actions are no longer effective owing to low drug concentrations at the delivery site, which may occur through drug metabolism, degradation, and transport out of the target [1]. Consequently, this phenomenon would result in drug wastage and transport medium loss with high risk offside effects on surrounding body cells, tissues, and organs. The solution to these problems is to have drug carriers that can provide controlled release rate to the target and would allow for complete therapeutic rehabilitation before degradation and transport of excess concentration of drug and carrier medium [2]. The drug and its carrier in form of capsules are orally administered and may be formulated for parenteral administration [3]. The drug release rate of the capsule can be controlled via the use of cellulose coatings exhibiting slow dissolution, incorporation of drug-complexing elements or compounds which hinder fast dissolution of drug, use of compressed tablets, and the inclusion of emulsion and suspensions. Materials that can permit drug release without changing or decaying over time with longer therapeutic windows (days to years) are required. These carries are such that they can be injected and/or implanted directly to target diseased tissues/cells for enhancing delivery efficiency [4]. To achieve target drug delivery, the use of affinity ligands deposited on biomaterial surfaces to allow for a set retention and usage by infirm tissues and cells have been employed [5]. The design of biomaterials for drug carriers aside permitting surface modification using ligands should also shield drugs from speedy break down and/or degeneracy within the target site.
Thus, the design parameters include: (i) the encapsulation of the sufficient drug of the biomaterial for lengthened release pattern to achieve efficient healing, (ii) sustaining drug stability for effective therapeutics through body transport and at the target site while preserving biological activity, (iii) predictable release rate in the therapeutic period from days to years, (iv) biomaterials and its degradation products must be biocompatible and nontoxic within the body, and (v) the cost of biomaterial synthesis and/or fabrication.
Lupron Depot, a poly (lactic-co-glycolic) acid (PLGA) microsphere encapsulating the hormone leuprolide, for the treatment of advanced prostate cancer, and endometriosis [6], PLGA, poly (lactic acid) (PLA), and polyglycolic acid (PGA) materials have FDA approval as micro-particle depot systems as they versatile in controlling material biodegradation time, are biocompatible with nontoxic natural degradation products (lactic acid and glycolic acid). Clinical nanoparticles with FDA approval for cancer nanomedicine treatment of Kaposi’s sarcoma (approved 1995) and for recurrent ovarian cancer (approved 1998) is Doxil [7], a poly (ethylene glycol) (PEG) coated (i.e., PEGylated) liposomal encapsulating the chemotherapeutic doxorubicin [8]. This enhances circulation half-life and tumor uptake of the drug, and also reduces its toxicological activity in patients in comparison to the use of free drug [9]. Other approved nanoparticle drug carriers include Marqibo, a liposomal encapsulating vincristine for rare leukemia treatment [10] and Abraxane an albumin-bound paclitaxel nanoparticle for the treatment of breast cancer [11]; Duragesic-transdermal drug delivery system patch containing the opioid fentanyl embedded within an acrylate polymer matrix, in the treatment of chronic pain [12]; and OROS, an osmotically controlled oral drug delivery technology, incorporated into several oral delivery products including Concerta [13]. Implantable biomaterials used include the Gliadel wafer, which consists of dime-sized wafers comprised of the chemotherapeutic agent carmustine and a polymer matrix made of poly (carboxyphenoxy-propane/sebacic acid), which are surgically inserted into the brain post-tumor resection [14, 15, 16] use as an adjunct to surgery in patients with recurrent glioblastoma multiforme.
An ideal therapeutic drug is expected to treat or cure a disease without resulting to any side effects [17, 18, 19]. However, this goal has not been achieved. Many chemotherapeutics are found to destroy both cancerous and healthy cells within the vicinity of the target site [20]. An efficient chemotherapeutics would administer drug, directly to diseased cell populations. Polymers have been found to permit the creation of “responsive” materials within the host environment and can be formulated with drugs to control release [21]. This polymer attribute is due to tuning propensity of the molecular weight of polymers that can be controlled via monomer stoichiometry using controlled polymerization strategies like ATRP [22], RAFT [23], NMO [24], and ROMP [25]. A bioresponsive material is one that can respond to a specific “trigger” inside or outside of the human body. Because the body have unique pathological parameters as pH gradients, temperatures, enzymes, small molecules, etc., the creation of materials that will respond to physiological alterations in both space and time are required.
Triggers include chemical, biological, and physical stimuli [26, 27], the chemical and biological ones are intrinsic to the body, while the physical stimuli are extrinsic to the body can thus be used to quicken sole drug delivery.
Bioresponsive materials are initiated by redox potential difference tissue environment and its surrounding [28]. There are materials that can respond to both oxidation and reduction triggers, which are incorporated into responsive polymers, e.g., diselenides with chemical structure like those of disulfides [29]. Diselenides allows for alternative triggers within nano-biotechnology applications [30].
The constituents of the human body such as tissues, fluids, and organelles have varied pH values. Areas like stomach, vagina, and lysosomes display acidic pHs (<7); ocular surface (7.1), the blood (≈7.4), and bile (7.8) [21]. Owing to these varied pHs of systems and organs in the body improvement in the efficacy and precision of therapeutic molecules will necessitate the design of polymeric drug delivery systems that are pH specific. pH-responsive materials have been useful in nucleic acid delivery, doxorubicin delivery, and taste masking [31, 32]. The target treatment of tumors has been enhanced using the pH-responsive materials. Such known target delivery includes multifunctional acid sensitive nanocomposites for anticancer drugs and acid-responsive poly(ethylene glycol) derivatives [33] for the controlled release of therapeutics in tumor target treatment (Figure 1).
Schematic illustration of drug loading and controlled release of poly (ethylene glycol) [34]. DOX, doxorubicin; PAE, poly (β-amino esters); PEG, poly (ethylene glycol).
Hydrolysis prone materials can be degraded by body fluid via nucleophilic addition of water into an electrophilic functional group on a polymer. The electrophilic functional groups often used on polymers include esters and anhydrides [35]. The Gliadel wafer consisting of chemotherapeutic Carmustine impregnated within a polyanhydride material has been demonstrated as hydrolysis-sensitive materials for drug delivery [36] in the treatment of brain tumors. Enzyme-responsive polymers such as matrix metallo-proteins, hyaluronidases, phospholipases, and prostate-specific antigen [21] have been incorporated into polymers for target drug delivery in areas like tumor imaging, doxorubicin delivery, and minimization of inflammation in the colon [37].
Another drug delivery vehicle is the temperature-sensitive polymers that can operate at both human body temperature of 37°C and at ambient temperature such as 25°C [38]. These polymers include poloxamers, poly(N-alkyl acryl amides), poly(N vinyl caprolactams), cellulose, xyloglucan, and chitosan. These thermo-responsive polymers can be modified via [39] varying the ratio of monomers, end-group modifications, and post-polymerization modifications to make them suitable for varying applications [40].
Magnetic-responsive polymers are therapeutic drug-loaded polymers that work under the influence of magnetic resonance imaging (MRI) to delivery its drug to the target [41]. These include the following: systematic release of dopamine from alginates impregnated with magnetic beads; targeted plasmid delivery to the lung via chitosan nanoparticles; and insulin delivery [42].
Light-responsive polymers are used as external drug delivery systems that use noninvasive and painless techniques [26, 43, 44, 45, 46, 47, 48] as drugs are delivered by light UV- and visible-wavelength irradiation stimulation. In this technique, a remote-activated approach without direct patient contact is used [49]; this includes the release of drugs from a light-responsive azobenzene modified amphiphilic block copolymer to target melanoma cells [50].
There are polymers that can swell or shrink in response to external stimuli [51]. This phenomenon can have stemmed from changes in porosity occasioned as ionic cross-linking molecules are leached, resulting in alteration of the diffusion pathways for sensing molecules. Alginate is a commonly employed polymer that is isolated from seaweed, is relatively biocompatible, and has been used for sustained delivery of vascular endothelial growth factor (VEGF) to a target within the body.
While a limited number of affinity-based delivery systems have been developed for the delivery of neurotrophic factors, we also examine the broad spectrum of reservoir-based delivery systems, including microspheres, electrospun nanofibers, hydrogels, and combinations of these systems.
Drug delivery systems transport biological active agents, such as growth factors and genetic material, into the desired location to promote beneficial effects for the treatment of diseases and disorders [52], osmotic pumps for the delivery of neurotrophic factors [53] to target site, affinity-based delivery systems (ABDS) in which drug loading and controlled release are achieved through the interactions of therapeutic drug and the delivery system, and reservoir-based delivery systems, where a polymer structure encapsulates the drug while its release is controlled via the material properties.
ABDS operate through the noncovalent interactions between device material and target drug [54] in a similar pattern to the interactions that occur in the extracellular matrix where the delivery of proteins and other biomolecules are controlled [55]. ABDS include molecular imprinting, cyclodextrin-based delivery, and heparin-based delivery [56]. Molecular imprinting uses polymer networks synthesized via a precursor molecule that is removed to reveal an imprint that acts as an affinity binding zone. In cyclodextrin-based delivery systems, small hydrophobic drugs are attracted to the hydrophobic center of an oligosaccharide cyclodextrin torus, which permits the complexes formation with enhanced solubility when compared to the drug itself. ABDS is observed to be superior to traditional reservoir-based systems as the release characteristics are dependent on the activities occurring between the drug and the matrix in a way not affected by the matrix properties [57].
Reservoir-based delivery systems (RBDS) are porous with drug release rate controlled by diffusion [58]. In RBDS, the drug is immersed or dissolved in a polymer solvent/reservoir. The drug penetrates via the biodegradable polymer structure to control the initial release followed by another release as surface and bulk erosion occurs in polymer reservoir. RBDS include nanogels, nanoparticles, micelles, hydrogels, microspheres, and electrospun nanofibers.
Microspheres are usually used as controlled drug release systems for stereotactic injections to isolated disease or injury sites in medicine and pharmacology [59]. Drugs like neurotransmitters, hormones, and neurotrophic factors have been encapsulated using microspheres obtained from biodegradable polymers [60]. These polymers include poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(ε-caprolactone) (PCL). Microsphere-based drug delivery uses localized surgical injection to circumvent the blood-brain barrier; this is better in performance to orthodox methods like intravenous injection and oral drug delivery. The parameters of the microsphere such as the particle size, polymer degradation rate, and method of erosion (bulk versus surface degradation) can be utilized to control the rate of drug delivery rates [61]. PCL has been found useful as a microsphere for the carrier of sustained long period drug delivery as it demonstrates the slowest degradation rate [62]. The double emulsion method is often used in synthesizing of microspheres. The method involves dissolving the desired polymer in a nonpolar solvent to form an oil emulsion. The hydrophilic compound that is to be encapsulated is dissolved in an aqueous solution and then emulsified with the dissolved polymer-solvent solution to give a water-in-oil emulsion. After this the solvent evaporates, the polymer solidifies as it forms microspheres that encapsulated the inner aqueous solution [63].
Electrospinning process involves the application of an electric potential to draw out thin nanometer to micrometer diameter polymer fibers (natural or synthetic). A viscous solution of the polymer is prepared (at room or elevated temperature), then pumped via a spinneret nozzle (positive terminal) into an electric field such that the applied force due to the high voltage counters the surface tension leading to the formation of fiber droplets onto a collector plate that serves as negative terminal. The nanofibers produced are often used as drug based-reservoir delivery systems as the pores in the matrix serves as receptive sites for bioactive agents [64]. This fiber production process advantages include surface flexibility with respect to function or application, reduced initial burst release, and the possibility of producing different fiber configuration depending on usage [65]. Drugs are embedded in the pores of electrospun nanofibers by emulsion electrospinning; the target drug is dissolved in a desired polymer solution [64] such as in diclofenac sodium (DS) and human serum albumin (HSA) [66]. Electrospun nanofibers show some draw backs that include formation of drug aggregates during encapsulation along nonsmooth fibers, maintaining uniform fiber size distribution, the use of toxic solvents to form polymer-drug emulsion in drug delivery and its attendant health concerns. Despite these drawbacks, advances in the development of less toxic electrospun fibers, which contain extracellular matrix components such as keratin and collagen, have been developed for wound healing application. The biocompatibility potential of PVA with the bioactive nature of keratin, CoQ10, and antimicrobial mupirocin has been evaluated for wound care due to its ability to support the growth of keratinocytes and hasten skin regeneration [67].
Hydrogel is a hydrophilic network of cross-linked polymer chains with swelling capability but does not dissolve in aqueous solution in the presence of water to create a three-dimensional gel-like structure. The synthesis of hydrogels is through polymerization [68], its properties, and drug release mechanism that depend on the polymer type used. The mechanisms involved in the drug delivery of hydrogel may be diffusion controlled, chemical controlled, swelling controlled, and modulated release systems. The use of acetyl-(Arg-Ala-Asp-Ala)4-CONH2 self-assembling peptide hydrogel to carry model factors such as lysozyme, trypsin inhibitor, BSA, and IgG [69] reveals the potential of these hydrogels carriers of therapeutic agents with the preservation of protein activity. An agarose hydrogel has been found capable of delivering sustained bioactive lysozyme release [70] and was used for the local delivery of BDNF in adult rat models.
The biomaterial surface chemistry and topography impact protein adsorption, cell interaction, and host site response. Monocyte adhesion in vitro [71] have been shown to be altered by its surface chemistry, while in vivo surface chemistry does not significantly influence the foreign body reaction. Polymeric, ceramic, or metallic-based biomaterials exhibit variability in surface properties such as hydrophilic to hydrophobic; hard to soft in vivo [72].
Cell adhesion to adsorbed proteins is achieved via integrin and other receptors in the cell membrane and the occurrence of this triggered intracellular signaling events. Thus, the control of protein adsorption on biomaterials surfaces is crucial to controlling and directing cell responses. Oligopeptides with specific binding sites have been incorporated to control cell adsorption to the protein surface and these include short oligopeptide, e.g., adhesive oligopeptide is an arginine-glycine-aspartic acid (or RGD) [73] that is found in a number of different extracellular matrix proteins, such as fibronectin [74], laminin [75], collagen [76], and vitronectin [77]. Short oligopeptides are less expensive, easy to synthesize, and has greater flexibility for surface modification compared to bulky and labile intact proteins. To a surface modified using nonfouling PEG (99%) and RGD (1%), the protein adsorption was minimal (2 ng/cm2) leaving the sufficient RGD sites for fibroblast cell adhesion [78]. Structure and conformation of oligopeptides influence modulating cell adhesion as demonstrated with the use of immobilized cyclic RGD peptide which increased human bone marrow stromal cell adhesion to that of linear RGD peptides [79] (Table 1).
S/No. | Drug delivery systems | Biomaterial | API | Significance of the study | Reference |
---|---|---|---|---|---|
ORAL DRUG DELIVERY SYSTEMS | |||||
Silk Nanoparticles | Silk and fibrin | Celecoxib and curcumin | Silk fibroin nanoparticles were seen to promote anti-inflammatory properties of celecoxib or curcumin and could be exploited for oral osteoarthritis management since a controlled drug release was achieved by varying the drug loading | [80] | |
Electrospun fibers | Polylactic acid | Metronidazole | PLA nanofibers associated with metronidazole (MNZ) were used to control microbiological proliferation during periodontitis treatment, inhibiting bacteria growth during the treatment | [81] | |
OCULAR DRUG DELIVERY SYSTEMS | |||||
Nanocomposite hydrogel | Hyaluronic acid | Latanoprost | The hyaluronic acid nanocomposite hydrogels, with controlled degradation properties and sustained release, could serve as potential drug delivery systems for many ocular diseases as they controlled the release of latanoprost in vitro | [82] | |
Hydrogel contact lens | Silicone | Ofloxacin and Chloramphenicol | The drug release from the lenses was directly proportional to the amount of drug loaded and the lenses at the different loading concentrations showed transmittance of 95–97%. The silicone hydrogel contact lenses can be used to control drug delivery to the eye and is an alternative ocular delivery technique in the treatment or prevention of corneal infections | [83] | |
PULMONARY DRUG DELIVERY SYSTEMS | |||||
Porous particles | Poly(lactide-co-glycolide) (PLGA) | Celecoxib | Large porous celecoxib-PLGA microparticles prepared using supercritical fluid technology exhibited sustained drug delivery and antitumor efficacy, without causing any significant toxicity | [84] | |
Nanoparticles | Nanopolymeric particles consisting of hydroxyl propyl methylcellulose (HPMC), poly-vinylpyrrolidone (PVP) | Fluticasone | The in vitro antibacterial studies showed that HPMC-PVP-FLU nanoparticles displayed superior effect against Gram-positive bacteria compared to the unprocessed FLU and positive control | [85] | |
IV | IMPLANT DRUG DELIVERY SYSTEMS | ||||
Silk disc implants | Silk fibrin | IgG antibody or human immunodeficiency virus (HIV) inhibitor 5P12-RANTES | SF was formulated into insertable discs that can encapsulate either IgG antibody or human immunodeficiency virus (HIV) inhibitor 5P12-RANTES. The water vapor annealing showed a sustained release for 31 days and this released protein could inhibit HIV infection in both blood and human colorectal tissue | [86] | |
Bone biomaterials implant | Hydroxyapatite | Doxorubicin-loaded cyclodextrin | Hydroxyapatite-cyclodextrin-doxorubicin chemotherapeutic strategy enhanced the drug-targeting effect on tumor cells while protecting the more sensitive healthy cells after implantation. A successful integration of such a drug delivery system might allow healthy cells to initially survive during the doxorubicin exposure period | [87] | |
V | SYSTEMIC DRUG DELIVERY | ||||
Polylactide scaffold hydrogel injections | Cholesterol-modified poly(ethylene glycol)–polylactide | Chondrocytes | The formulation shows lower critical gelation temperature, higher mechanical strength, larger pore size, better chondrocyte adhesion, and slower degradation compared to plain polylactide scaffold gels. The hydrogel serves as a promising chondrocyte carrier for cartilage tissue engineering and gives an alternative solution to surgical cartilage repair | [88] | |
ANG-(1–7) functionalized plant chloroplast | Lyophilized lettuce cells (ACE2/ANG-(1–7)) | Lyophilized lettuce cells (ACE2/ANG-(1–7)) | Toxicology studies showed that both male and female rats tolerated ~10-fold ACE2/ANG-(1–7) higher than efficacy dose. The efficient attenuation of pulmonary arterial hypertension with no toxicity augurs well for the clinical advancement of the first oral protein therapy to prevent/treat underlying pathology for this disease. | [89] | |
VI | VAGINAL DRUG DELIVERY SYSTEMS | ||||
Organogel | Palm oil and hyaluronic acid | Maraviroc | There was a 2.5-fold increase in the percentage of maraviroc release in the presence of hyaluronidase, hence the effectiveness of hyaluronidase enzyme acting as a trigger. This shows the potential use of palm oil/hyaluronic acid-based organogel for the vaginal delivery of anti-HIV microbicide for HIV prevention | [90] | |
Vaginal rings | Silicone matrix polymer | Dapivirine | A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence | [91] | |
VII | TOPICAL DRUG DELIVERY SYSTEMS | ||||
Electrospun fibers | Polylactic acid and collagen | Collagen and silver sulfadiazine | The electrospun fibers were nontoxic to the cells and provided favorable substrates for the neonatal epidermal keratinocytes cells to undergo cell attachment and proliferation, hence its potential for use in chronic wound management | [92] | |
Hydrogel | Polyvinyl alcohol and carbopol | Diclofenac diethylamine | In vitro skin permeation for 10 h showed that the enhancement ratios of the flux of diclofenac was higher compared to the marketed formulations. The study highlighted the advantage of the experimental transdermal hydrogel over the hydrogel with microsized drug particles | [93] |
Drug delivery systems showing the significance of the biomaterials utilized in delivering active pharmaceutical ingredients at their biological target site.
Poly (ethylene glycol) (PEG), or poly(ethylene oxide) (PEO) having nonfouling surfaces demonstrates protein and cell resistance capabilities. PEG have been attached to materials in such a manner to render them nonfouling through processes like covalent immobilization, adsorption, or interpenetration. PEG has been covalently attached to mussel adhesive protein to form a nonfouling and a sticky segment copolymer [94] with gold and titanium surfaces attached to the sticky segment, while the PEG chains occur at the new interface. It should be noted that the nonfouling ability/attribute of PEG is dependent on the surface chain density that is prone to oxidants damaged. However, the use of plasma deposition of tetra ethylene glycol dimethyl ether (tetraglyme) on PEG will reduce protein surface adsorption [95]. Other materials with nonfouling surfaces include phospholipid surfaces [96] and saccharide surfaces [97], and these biomaterials ensure increased compatibility issues between the drug carrier systems and biological systems to which they are introduced to elicit a pharmacological activity.
Materials which respond to environmental changes are attractive particularly in vivo as these can be utilized to control drug release, cell adhesiveness, mechanical properties, or permeability. These environmental changes can be brought about by stimulants like pH [98], temperature [99], and light [100]. The body employs changes in pH to facilitate a range of different processes. For example, along the gastrointestinal track, food is broken down into nutritive substances in the stomach under acidic pH ∼ 2 and subsequently absorbed in the small intestine (pH ∼ 7). Patient often prefers the oral drug delivery requiring routine, periodic delivery of drugs and for effectiveness, the drug must resist the stomach acidic pH. The pH-sensitive materials that are mindful of gastrointestinal tract pH variation have been developed to transport drugs successfully through the stomach to the small intestine. Such successful materials include pH responsive hydrogels prepared from poly(methacrylic acid) grafted with poly(ethylene glycol) (PMAA-g-PEG) that swells in response to pH. For instance, the gel shrinks by trapping the drug cargo pH ∼ 2 as interpolymer complexes are formed, but at physiological pH ∼ 7, the gel can swell 3–25 times based on its composition as it releases its cargo in the target site [101]. Insulin-loaded PMAA-g-PEG gels have been orally delivered to diabetic mice with a significant decrease in glucose levels as protein function is protected in acidic and digestive enzymes environments [102].
Self-organization or self-assembly is based on the formation of weak noncovalent bonds, like hydrogen, ionic, or Van der Waals bonds or hydrophobic interactions [103]. In amphiphilic molecules, there are hydrophobic and hydrophilic segments that self-assemble to form nanometer 3D structures like micelles, vesicles, and tubules, which depend on the molecule’s length and composition [104, 105, 106, 107]. When any of these are dispersed in aqueous solvent, the hydrophobic segments agglomerate and water is expelled to produce a well-ordered structure useful in biomedical applications. Phospholipid a naturally occurring amphiphilic molecule that is largely compose of cell membrane is one such amphiphilic molecules while an oligomer, a polymer of amino acids, can be synthesized to have hydrophobic, hydrophilic, charged, etc., regions that can self-assemble into a macroscopic hydrogel [108]. The self-assembled biomaterials can be engineered for use in nanotechnology, tissue engineering for drug and cell carriers.
Polymers are large molecules formed from simple monomers and may be synthetic or biopolymers that are the constituents of living organisms like proteins, nucleic acids, and sugars. Biopolymers are active in controlling and regulating many biochemical and biophysical functions of living cells, and thus can participate in cooperative interactions, resulting in nonlinear response to external stimuli. The cooperative interaction mechanism of biopolymers is utilized in producing synthetic polymers that are similar in behavior to biopolymers, which are used as biomaterials with ability to interface with biological systems for a variety of living cells functions.
Polymeric, biodegradable materials are often useful in biomedical applications, as the polymers degrade into normal metabolites of the body or eliminated from the body with or without further metabolic transformation [109, 110]. Developed polymeric biomaterials have physical and chemical properties that are maintained and are not tampered with during synthesis. The use of synthetic polymeric biomaterials includes artificial corneal substitute, blood contacting devices, hip joint replacements, and formation of intraocular lenses [111, 112]. Biodegradable polymers are either natural or synthetic. Natural polymers are derived from natural resources and have potential to be considered for biomedical and pharmaceutical applications owing to biocompatibility, biomimicking environments, unique mechanical properties, and biodegradability. Natural polymers are prone to viral infection, antigenicity, and unstable material supply, which limit biomedical application. On the other hand, synthetic polymers are flexible in synthesis procedure technique with excellent reproducibility which made them useful for surgical and short-term medical application, orthopedic applications that may slowly transfer the load as it degrades [113].
The drug administration into the body is either via an oral or intravenous route with repeated administration done to increase concentration and performance. But this may reach an extreme level before it declines rapidly especially when the elimination rate from the body is high. A too low or too high drug concentration in the body will not benefit the patient because of the side effects. This phenomenon then becomes a concern requiring the use of controlled drug release mechanism which can only be offered by biomaterials [114]. For controlled drug release, the therapeutic and bioactive agents are enveloped or encapsulated in an insoluble biodegradable subnano, nano, micropolymer matrix cavity where the therapeutic agents are released in a controlled fashion.
Widely used drug delivery systems include a liposomal drug delivery system [115, 116] that consists of phospholipids, i.e., fatty acid esters and fat alcohol ethers of glycerol phosphatides; they are negatively charged at physiological pH due to their phosphate groups. Cationic liposomes are prepared using lipid molecules having a quaternary ammonium head group. Because cellular membranes carry negative charges, cationic liposomes interact with these cellular membranes [117]. The stability of liposomes in biological environment is improved with steric stability that can extend its blood circulation time after being administered [118]. Biodegradable polymers are usually used to enhance the steric stability of the liposomes. Natural biodegradable polymers that are suitable for drug delivery systems include proteins (collagen, gelatin, albumin, etc.) and polysaccharides (starch, dextran, chitosan, etc.) [119].
Polysaccharides are many monosaccharide repeating units with high molecular weight. It is biodegradable, biocompatible, and water soluble which make suitable for drug delivery. There are several different types of polysaccharides having different functional groups, which are as follows:
Alginic acid is a linear hetero polysaccharide, nonbranched, high-molecular-weight binary copolymer of (1–4) glycosidic linkage with β-D-mannuronic acid and α-L guluronic acid monomers [120, 121]. Natural alginic acid can be obtained from the cell walls of brown algae. Its acidic nature helps in its spontaneous formation of salts and later gels in the presence of divalent cations like calcium ions. This occurs by the interaction of divalent cations with guluronic acid blocks present on other polysaccharide chains. The gel property paves way for the encapsulation of molecules that can act as drugs within alginate gels with negligible side effects. The drug delivery mechanism of alginates is hinged on the drug polymer interaction and chemical immobilization of the drug on the polymer backbone via reactive carboxylate groups [122, 123, 124].
Starch, which is a carbohydrate source can be isolated from corn, wheat, potato, tapioca, rice, etc., and consists of two glucosidic macromolecules: 20–30% of linear molecule—amylase and 70–80% of branched molecule—amylopectin. The products of starch processing include thin films, fibers, and porous matrices. It is an important polymer for thermoplastic biodegradable materials due to its low cost, availability, biocompatibility, biodegradability, and having renewable resources [125]. The products of starch degradation include fructose and maltose that are low molecular weight sugar [126]. Microspheres from starch have bioadhesive drug delivery system potential for nasal delivery of proteins [127].
Dextran is a natural polysaccharide of large glucose molecules with long and branched chains of varying lengths from 3 to 2000 Kd at 1,6- and partly at 1,3-glucosidic linkages. It is synthesized from sucrose via lactic-acid bacteria like Leuconostoc mesenteroides, Streptococcus mutans, and lactic acid bacterium Lactobacillus brevis. It is colloidal and hydrophilic in nature; it is inert to the in vivo environment with no effect on cell viability [128]. Dextran is used as an antithrombotic (antiplatelet), to reduce blood viscosity, and as a volume expander in anemia [129]. Dextran can be degraded by enzyme dextranase in the colon and thus can serve as a colonic drug delivery system.
Pullulan occurs naturally as linear homopolysaccharide polymer with maltotriose units of 3-glucose or D-glucopyranose units which are linked by α-(1 → 4) glycosidic linkages. It is edible, bland, and tasteless and thus is added to food and beverages. It serves as a coating agent in pharmaceutics, breath fresheners, or oral hygiene products [130]. Consecutive maltotriose units are linked to one another via α-(1 → 6) glycosidic bond. The pullulan backbone structure is similar to dextran, as both are plasma expanders. Pullulan is commercially synthesized via fermentation process involving the growth of fungus Aureobasidium pullulans on a carbohydrate substrate, which is then harvested. This process is followed by the rupture of cell using either an enzyme or a physical force, and pullulan is then extracted via simple water extraction method [130]. This method does not constitute any threat to the environment and therefore it is ecofriendly. This then makes pullulan suitable as a drug delivery vehicle. Pullulan hydrogel micro and nanoparticles are employed in oral administration of gastro-sensitive drugs.
Hyaluronic acid also a natural occurring negatively charged linear polysaccharide made of repeating disaccharide units of D-glucuronic acid and 2-acetamido-2-deoxy-D-glucose monosaccharide units. It exists majorly in articular cartilage, connective tissues, synovial fluids of mammals and the mesenchyme of developing embryos. It is water soluble and forms highly viscous solutions and therefore suitable for use as wound dresser as it can act as scavenger for free radicals in wound sites to modulate inflammation [131]. Its use in tissue repair application include to protect delicate tissue in the eye in removal of cataract, corneal transplantation, and glaucoma surgery, as vitreous substitute in retina re-attachment surgery, to relieve pain and improve joint mobility in osteoarthritis (knee) patients suffering and accelerate bone fracture healing [132].
Chitin a natural occurring polysaccharide of 1 → 4 β-linked glycan containing 2-acetamido-2-deoxy-D-glucose is a component of shells of crustaceans, cell walls of fungi, etc. When chitin is deacetylated chitosan a semi-crystalline linear copolymer polysaccharide is produced with (1 → 4) β-linked D-glucosamine and some N-acetyl glucosamine groups. The degree of deacetylation (DD) of chitosan may be from 70% and 90% and the MW is in between 10 and 1000 k [133]. While chitin is insoluble in regular solvents, chitosan is fully soluble in aqueous solutions with pH <5.0 [134]. Chitosan degrades in vivo enzymatically via lysozyme to nontoxic products [134]. Chitosan is easy to process and applied, oxygen permeability, water absorptivity, hemostatic property, and ability to induce interleukin-8 from fibroblasts. It uses include wound and burn dressing material, drug delivery and controlled drug release.
Polyurethane is a polymer with a chain of organic units linked by carbamate (urethane), which is formed from two or several bi- or higher-functional monomers, one having two or more isocyanate functional groups (–N=C=O) and the other with two or more hydroxyl groups (–OH) [135]. It is a material with similar elasticity to rubber, possess toughness and durability comparable to metal, and is chemically inert. Polyurethane micelles are suitable drug delivery systems.
Advances in medical research have led to the exploration of various materials as drug carriers for suitable delivery. Biomaterials are currently well explored in recent years as a result of their ubiquitous nature, ease of accessibility, biodegradability, and biocompatibility with living tissues. They have been singly used or blended with other materials as composites. This chapter has thus discussed the different biomaterials with their functionalities in the area of drug release. More biomaterials can be explored by processing and characterizations from natural origin to ensure effective performance and limit health complications associated with drug release.
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