Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas: Volume 2

Cover
TRANSPLANTATION,
BIOENGINEERING,
AND
REGENERATION OF
THE ENDOCRINE
PANCREAS,
VOLUME 2
Copyright
Contributors
Part A: Islet auto-transplantation
Section I: Chronic pancreatitis
1
Etiopathogenesis and pathophysiology of chronic pancreatitis
	Etiopathogenesis
	Alcohol-induced chronic pancreatitis
	Autoimmune pancreatitis
	Genetic pancreatitis
		Enzymatic- and ion-related mutations in PRSS1, SPINK1, CTRC, and CaSR
		CFTR mutation
		Metabolic disorders
		Hyperparathyroidism
	Hereditary pancreatitis
	Recurrent acute pancreatitis
	Ductal obstruction
	Pancreas divisum
	Sphincter of Oddi dysfunction
	Pancreatic trauma
	Tropical chronic pancreatitis
	Drug toxicity-induced pancreatitis
	Idiopathic
	Gallbladder dysfunction
	Smoking and pancreatitis
	Pathophysiology
	Exocrine insufficiency
	Endocrine insufficiency and diabetes mellitus
	Pathophysiology of pain
	Calcification
	Fatty infiltration
	Fibrosis
	Pseudocysts
	Atrophy
	Pancreatic cancer
	Molecular mechanisms in the development of pancreatitis
	Conclusion
	References
2
Nonreplacement treatment of chronic pancreatitis: Conservative, endoscopic, and surgical (resection and drainage procedures ...
	Introduction
	Clinical evaluation
		Abdominal pain
		Pancreatic insufficiency
		Diagnosis of chronic pancreatitis
	Medical and conservative management
		Lifestyle modifications
		Exocrine pancreatic insufficiency and malnutrition
		Pain management
	Endoscopic and surgical management of chronic pancreatitis
		Endoscopic management of chronic pancreatitis
			Management of pancreatic duct stricture
			Management of pancreatic duct stones
		Management of benign biliary strictures
		Surgical management of chronic pancreatitis
		Large duct disease
		Roux-en-Y lateral pancreaticojejunostomy (Puestow procedure)
		Dominant head mass
		Pancreaticoduodenectomy
		Beger procedure and Berne modification
		Frey procedure
		Results of clinical trials
	Conclusion
	References
Section II: Islet auto-transplantation for chronic pancreatitis
3
Requirements for clinical islet laboratories
	Introduction
	Allogeneic vs autologous islet
	Registration with the FDA
	Registration with other regulatory agencies
	General requirements for a clinical auto islet lab
		Establishment and maintenance of a quality program
	Facilities and environmental control
		The vulnerability of islet cells to contamination
		Use of a clean room to manufacture islet cells
		Clean room entry and exit
		Training
		Clean room cost
		Environment control
	Equipment
		Specific equipment needs for an auto islet lab
		Telemedicine (communications between the operating room and the clinical islet lab)
	Personnel
	Procedures
		Supplies and reagents
		Storage
		Recovery
		Process and process controls
		Labeling
		Product tracking
		Records
		Reporting
		Deviation in processing
	Inspections
		Corrective actions and process improvement
		Outcome analysis
	References
4
Islet isolation for autotransplantation, following total or near total pancreatectomy
	Introduction
	Islet isolation
		Organ procurement and transport
		Laboratory preparation and setup
		Islet isolation
		Pancreas cleaning, trimming, and cannulation
		Pancreas perfusion
		Collagenase: Selection and dose
		Phase 1: Digestion
		Phase 2: Dilution and tissue collection
		Islet cell purification
		Preparation for administration
	Conclusions
	References
	Further reading
5
Strategies to improve islet yield from chronic pancreatitis pancreases intended for islet autotransplantation
	Introduction
	Islet cell isolation
	Pancreatectomy and pancreas transport
	Trimming and cannulation of the pancreas
	Enzyme selection and perfusion
	Tissue digestion
	Tissue recombination
	Purification process
	Transplant preparation
	Conclusion
	Conflict of interest
	Acknowledgments
	References
6
Surgical techniques for total pancreatectomy and islet autotransplantation
	Introduction
	Indications and contraindications
		Patient selection
			Candidates
		Contraindications
		Preoperative testing and assessment
	Operative technique
		Total pancreatectomy
			Principles
			Preoperative preparation
			Operative procedure
		Islet isolation
		Islet infusion/transplantation
		Minimally invasive surgery
			Robotic TP and islet autotransplant
			Laparoscopic TP and islet autotransplant
			Robotic and laparoscopic TP outcomes
	Percutaneous infusion/transplantation of islets
	Postoperative care
	Complications
		Portal vein thrombosis
		Islet contamination
		Delayed gastric emptying
		Biliary anastomotic leak
		Rare complications
	Outcomes
	Salvage pancreatectomy
	Pediatric population
	Remote processing
	QOL after TPIAT
	Future
	Conclusions
	Acknowledgments
	References
7
Total pancreatectomy with islet autotransplantation in children
	Introduction
	Pancreatitis in children
	Determining when TPIAT is indicated for the management of children with pancreatitis
	Surgical procedure and islet isolation and transplant in children
	Postoperative management of the child after TPIAT
		Diabetes management after TPIAT
		Pain management after TPIAT
		GI management after TPIAT
		Asplenia management after TPIAT
	Short-term and long-term outcomes after TPIAT in children
		Surgical outcomes
		Pain relief and quality of life after TPIAT
		Diabetes after TPIAT
	Conclusions
	References
8
Islet autotransplantation: Indication beyond chronic pancreatitis
	Introduction
	Incidence of pancreatogenic diabetes after pancreatic resection
	Autologous islet transplantation to prevent or minimize pancreatogenic diabetes in patients requiring total pancreatectomy ...
	Expanding indications for IAT: Nonneoplastic diseases beyond chronic pancreatitis
	Expanding indications for IAT: Neoplastic benign diseases
	Expanding indications for IAT: Neoplastic malignant diseases
	Expanding indications for IAT: Milan protocol
	Conclusion
	References
Section III: Outcomes
9
Postoperative care and prevention and treatment of complications following total pancreatectomy with islet cell autotranspl ...
	Introduction
	Patient selection and preoperative preparation
	Postoperative management and complications
		Islet yield and glycemic management
		Pain control
		Nutrition
		Islet cell infusion and its complications
			Mesenteric thrombosis
			Hemorrhage
			Hepatic changes on imaging
		Infection
		Risk of cancer
		Surgical complications
	Conclusion
	References
10
Metabolic outcomes after total pancreatectomy followed by islet autotransplantation (TPIAT): Mixed blessings☆
	History and rationale for TPIAT: Points of view
	Favorable metabolic outcomes: Normal levels of glycemia, HbA1c, and β -cell function
	Unfavorable metabolic outcomes: Hypoglycemia following meals and exercise and deficient α -cell counter-regulatory respons ...
	The need to consider nonhepatic transplantation sites
	References
11
Long-term results of TPIAT
	Introduction
	Surgical outcomes
		Cholangitis
		Bowel obstruction
		Internal hernia
	Gastrointestinal function outcomes
		Dysmotility, delayed gastric emptying, and slow transit
		Exocrine dysfunction
		Nutritional deficiency
	Pain and quality of life outcomes
		What is known about long-term pain/QOL outcomes?
		Development of new abdominal pain syndrome
	Metabolic outcomes
		Long-term islet graft function
		Hypoglycemia
		Long-term complications of diabetes
	Survival and cost of care
	Conclusions
	References
Part B: Bioengineering and regeneration of the endocrine pancreas
Section I: Pancreas development and regeneration
12
Embryonic development of the endocrine pancreas
	Introduction to pancreas development
	Pancreas development
		Foregut endoderm compartmentalization
		Pancreatic buds and branching morphogenesis
		Exocrine versus endocrine development during secondary transition
			Exocrine cell fate allocation
			Endocrine cell fate allocation
				Endocrine cell subtype specification: α - and β -cells
				Endocrine cell subtype specification: δ, PP, and ε cells
		Endocrine development during late gestation
	Postnatal islet development and function
		Maturation of postnatal islets
		Communication between endocrine cells in postnatal islets
			α - and β -cell interactions
			Interactions with other hormone-expressing cells
	Conclusions
	Acknowledgments
	References
13
Human pancreatic progenitors
	Introduction
	Induction and patterning of pancreatic endoderm
		Conservation of endoderm formation across vertebrates
		Nodal signaling initiates endoderm development
		Endodermal patterning
		Foregut-derived organogenesis and generation of the pancreatic buds
		Patterning of the dorsal and ventral pancreas
			Dorsal pancreas induction
			Ventral pancreas induction
	Lineage specification, proliferation, and compartmentalization of pancreatic progenitors
		Common pancreatic progenitors arising from the pancreatic bud
		Size control
		Pancreatic tubulogenesis and the ductal plexus
		Endocrine and exocrine specification: The secondary transition
		Endocrine differentiation
		Exocrine differentiation
			Ductal differentiation
			Acinar differentiation
	Adult pancreatic progenitors
		Ductal progenitors
		Intraislet progenitors
		Exocrine progenitors
	Transdifferentiation in the pancreas
		Exocrine to endocrine transdifferentiation
		Endocrine to endocrine transdifferentiation
	Extrapancreatic sources of pancreatic precursors
		Biliary tree stem/progenitor cells and biliopancreatic stem/progenitor cells
	Mesenchymal stem cells as potential sources for pancreatic endocrine cells
		Pancreatic islet-derived MSC
		Exocrine pancreas-derived MSCs
	Therapeutic modulation of pancreatic regeneration and β -cell mass
	Concluding remarks
	Acknowledgments
	References
14
Strategies to promote beta-cell replication and regeneration
	Introduction
	Beta-cell replication is the major contributor to the postnatal beta-cell growth
		Neonatal period
		Partial pancreatectomy
		Pregnancy
		Insulin resistance
	Cell-cell communications regulate beta-cell proliferation
		Cross-talk between endothelial cells and beta cells
		Cross-talk between macrophages and beta cells
		Cross-talk between stromal cells and beta cells
	Molecular signaling pathways that control beta-cell proliferation
		FoxM1
		TGF-beta/SMAD
	Concluding remarks
	References
15
Diet as a therapeutic approach to diabetes management and pancreas regeneration
	Introduction
	Proper nutrition is key to the maintenance of β -cell homeostasis and function
	Dietary intervention for T1D: Feasibility, outcome, and recent progress
	Diet in T2D: The two sides of diet and eating habits as causing factor and potential treatment for T2D
	Dietary recommendations for women with gestational diabetes
	Clinical relevance of fasting or fasting-like regimens as a nutritional therapeutic approach in diabetes
	Molecular mechanisms supporting the potential of fasting and FMD to promote pancreas functional restoration
	Conclusion
	References
16
The benefits of metabolic/bariatric surgery on diabetes mellitus
	Introduction
	History of metabolic/bariatric surgery
	Metabolic/bariatric surgery for diabetes
	Nonbariatric metabolic surgery for diabetes
	Metabolic/bariatric surgery mechanisms
		Metabolic/bariatric surgery and diabetes mechanisms
	The present
	The future
	Conflict of interest
	References
Section II: Scaffolds for endocrine pancreas bioengineering
17
ECM-based scaffolds for pancreas bioengineering
	Introduction
	Extracellular matrix
	Extracellular matrix in pancreatic islets
		Collagen
		Laminin
		Fibronectin
		Glycosaminoglycans
		Fibrin
	Tissue engineered islet scaffold incorporating ECM
	Whole organ engineering of pancreas
		Whole organ decellularization
		Biophysical properties of decellularized organs
			Microarchitecture
			Mechanical properties
			Growth factor retention
		Whole organ recellularization
			Parenchymal reconstruction
			Reendothelialization of the acellular scaffold
	Hybrid organs using repurposed biological scaffolds: Liver and kidney to pancreas
	Conclusion
	References
18
Plasma scaffolds for islet transplantation
	Introduction
	Islet microenvironment
	Integrins and mechanotransduction
	Concept of anoïkis
	Organoid organization protects islet from anoïkis
	Strategies to counteract anoïkis
		Molecular approach
		Integrin activation
		3D culture systems: Scaffolds for islets
			Overview
			Mechanotransduction
			Decellularized gels
			Hydrogels
		Challenges in reproducing the natural islet environment
	Using plasma as a scaffold
		Ubiquitous tunable scaffold
		Biodegradable scaffold
		GFs of interest for islets
		Fibronectin
	Plasma scaffolds for islets: Drawbacks
		Plasma scaffold for islet culture
		Plasma scaffold composition
		Oxygen diffusion in plasma scaffold
	Uses of plasma for other applications
	Conclusion
	Acknowledgements
	Conflict of interest statement
	References
19
A biologic resorbable scaffold for tissue engineering of the endocrine pancreas: Clinical experience of islet transplantati ...
	Introduction: The intrahepatic site for islet transplantation
	Extrahepatic sites for islet transplantation
	The greater omentum: A novel site for islet transplantation
		Preclinical experience
		Clinical experience
	Conclusions
	References
20
Endothelialized collagen modules for islet tissue engineering
	Introduction
	Transplantation into the omental pouch of immune competent rats
	Subcutaneous transplantation into immune-compromised SCID/bg mice
	Future directions
	References
Section III: Islet encapsulation
21
Conformal coating
	Introduction
	Conformal coating technology
		Composition of coating hydrogel
		The physical phenomena permitting conformal coating—Flow focusing and the Plateau-Rayleigh instability
		The conformal coating device, system, and process
		In vitro performance of conformally coated islets
		In vivo performance of conformally coated islets
			Transplantation in syngeneic mouse models
			Transplantation in allogeneic mouse models
	Conclusion and future directions
	Disclosure
	References
22
Co-encapsulation of ECM proteins to enhance pancreatic islet cell function
	Introduction
	Overview of the islet extracellular matrix
	Effects of ECM co-encapsulation on β -cell survival
	Effects of ECM co-encapsulation on β -cell function
	Effects of ECM co-encapsulation on β -cell proliferation
	Future directions
	References
23
Co-encapsulation of mesenchymal stromal cells to enhance islet function
	Type 1 diabetes and islet transplantation
	Current issues with encapsulated islet transplantation
	Mesenchymal stromal cells
	MSC and islet transplantation
	Islets and MSC co-encapsulation
	Conclusion
	References
24
Silk-based encapsulation materials to enhance pancreatic cell functions
	Introduction
	Silk as a biomaterial
		Structure of silk
			Silkworm silk
				Silkworm silk fibroin
				Silkworm silk sericin
			Spider silk
		Biocompatibility of silk matrices
		Biodegradability and bioresorbability of silk matrices
	Silk matrices used for islet culture and encapsulation
		Hydrogels
		Scaffolds
			Silkworm silk scaffolds
			Spider silk foams
	Conclusions and future perspectives
	Acknowledgments
	References
25
Cell pouch devices
	Introduction
	Cell encapsulation technology
	Macroencapsulation devices
		β Air
		ViaCyte
		Sernova cell pouch
		MailPan
	Concluding remarks
	References
Section IV: Stem cells to generate insulin producing cells
26
Pancreas progenitors
	Introduction
	Regeneration of pancreatic islets
		The role of residing islets
		The role of pancreatic duct epithelial cells
		The role of pancreatic acinar cells
	Biliary tree stem/progenitor cells and the network of hepatic, biliary, and pancreatic stem/progenitor cell niches ( Fig. 1 ...
	Pancreatic progenitor cells ( Fig. 1)
	Pancreatic duct gland as the niche of pancreatic progenitors ( Fig. 1)
	Conclusions
	References
27
Human embryonic stem cells (hESC) as a source of insulin-producing cells
	Introduction
	Current therapeutic approaches and challenges
		Pancreatic and islet transplantation: Scarcity, graft loss, and immunosuppression
		Diabetes targets of future IPC therapies
	Pancreas development
	Stem cell-derived β cells
		Cell sources, characterization, and requirements for use in β cell differentiation
		Dead ends: Pathways to polyhormonal cells which never mature
		In vitro vs in vivo: Paracrine signals, cell-cell contact, understanding the signals
	Hurdles still preventing a final functional product
		Maturation
		Evaluating other signals: Endoplasmic reticulum stress and mitochondrial function
		Cross talk: Matrix, blood vessels, cell-cell interactions, and paracrine signals
		Genome editing for therapeutic advantage
	Immunogenicity
		Autologous PSCs
		HLA-typed haplobanks
		Genetic modification to prevent immune rejection
		Immune tolerance
		Humanized mice
	Current clinical trials of stem cells for diabetes
	Interspecies organogenesis and stem cells
	Conclusion
	References
28
Human-induced pluripotent stem cells (iPSC) as a source of insulin-producing cells
	Pluripotent stem cells: Embryonic stem cells and somatic cell nuclear transfer
		Embryonic stem cells
		Somatic cell nuclear transfer (SCNT)
	Every cell can be pluripotent: The discovery of induced pluripotent stem cells
	iPSC are in the clinic: active protocols in humans
	iPSC for β -cell replacement: In vitro differentiation into β -cells
	Immunogenicity of iPSC-derived cells
	Graft protection
		Immunosuppression
		Haplobank
		Micro/macro-encapsulation
		Gene editing: The invisible cell
	Safety of iPSC-derived cells
		Generation of safer iPSC lines
		Removal of pluripotent cells from differentiated cell product
	Conclusions
	References
29
Ductal cell reprograming to insulin-producing cells as a potential beta cell replacement source for islet auto-transplant r ...
	Introduction
	Ductal cells as a potential source for beta cell regeneration
	In vitro reprogramming of pancreatic ductal cells
	In vivo studies on the pancreatic ductal progenitor cells
	Controversies regarding endocrine differentiation from ductal lineages
	Conclusions and future perspectives
	Conflict of interest
	Acknowledgments
	References
30
Synthetic biology technologies for beta cell generation
	Introduction
		Synthetic biology
		Type I diabetes
		Stem cell-based therapy for type I diabetes
		Human pancreatic development
		Gene-regulatory networks involved in human pancreatic development
	Synthetic biology approaches for generating beta cells
		Lineage-control networks
		Clustered regularly interspaced short palindromic repeats-Cas9
		Synthetic messenger RNAs
		Synthetic receptors
		Synthetic biomaterials
	Artificial designer cells
	Synthetic biology—Moving toward clinical applications
		Roadblocks in generating functionally mature beta cells from PSCs
		Roadblocks in engineering artificial beta-mimetic cells
	References
Section V: Animal-based platforms for pancreas bioengineering
31
Xenotransplantation of the endocrine pancreas
	Introduction
		A novel approach to discrepancies in supply and demand
		Defining success
	A brief history of xenotransplantation
		Earliest attempts in xenotransplantation and xenotransfusion
		Origins of endocrine transplantation
		Advancing to the modern era of xenotransplantation
	Optimizing the pig-to-NHP model
		The pig-to-NHP as the preferred preclinical model
	Laying the foundation: preclinical studies in islet xenotransplantation
		Hurdles to free and encapsulated islet xenotransplantation
		Encapsulation
		Overcoming immediate host responses: pharmacotherapies to prevent the instant blood-mediated inflammatory reaction
		Ideal placement of free islets in xenotransplantation
		Composite islet-kidney grafts
		Cotransplantation of islet xenografts and “regulatory” cells
		Genetic modifications to combat IBMIR
		Control of the T cell response
		Will sensitization to human leukocyte antigens be detrimental to islet xenotransplantation?
		Will sensitization to pig antigens preclude subsequent islet allotransplantation?
		The induction of immune tolerance: The “Holy Grail” of transplantation
		Improving function of porcine islets
	Justification for translation to clinical trials
		Lessons from early clinical trials
		Establishing safety
		Determining efficacy
		Patient selection
	Future directions
		Research priorities
		Conclusions
		Acknowledgment
	Conflict of interest
	References
32
Interspecies blastocyst complementation
	Introduction
	Basic principles of IBC
	Generation of pancreas with IBC
	Transplantability of IBC pancreas
	Advantages of IBC
	Pretransplant immunogenicity
	Posttransplant immunogenicity
	Potential for IBC vasculature
	Autograft tolerance
	Allograft considerations
	Efficiency of IBC
	Breeding schemes
	Gene editing with IBC
	Suitability of large animal hosts
	Ethical concerns
	Outlook
	References
Section VI: Tissue engineering technologies applied to ß-cell replacement
33
Bioengineering, biomaterials, and β -cell replacement therapy
	Introduction
	Immunoprotective barrier strategy
	Revascularization strategy
	Biomaterials
		Hydrogels
		Natural hydrogels
			Agarose
			Alginate
			Chitosan
			Collagen
			Fibrin
			Hyaluronic acid
			Gelatin
		Decellularized ECM-based biomaterials
		Synthetic hydrogels
			Pluronic
			Poly(ethylene glycol)
			Methacrylated compounds
		Solid biomaterials
		Nondegradable biomaterials
			Pdms
			PEOT-PBT block copolymers
		Degradable biomaterials
			PGA, PLA, and PLG
			Ethisorb
			Pva
	Islet delivery device fabrication techniques
		Scaffold fabrication techniques with random islet distribution
			Particulate leaching
			Phase separation
			Electrospinning
			Microencapsulation by droplet generators
		Microfabrication techniques (controlled islet distribution)
			Pillared wafer
			Microthermoforming
			Microfluidics
			Nanoencapsulation by layer-by-layer techniques
	3D Printing in regenerative medicine
		3D printing for β -cell replacement therapy
	Future outlook
	References
	Further reading
34
Subcutaneous islet transplantation using tissue-engineered sheets
	Introduction
	Subcutaneous islet transplantation
	Cell sheet engineering in cell transplantation
		Cornea
		Heart
		Esophagus
		Liver
		Others
	Subcutaneous islet transplantation using cell sheet engineering
	Our concept of subcutaneous islet transplantation using cell sheet engineering
	Cell sources
	Cytokines
	Previous study
	Conclusions
	Conflict of interest
	References
Section VII: Regulation and funding
35
Regulation for regenerative medicine-based therapies
	Regulatory approach to regenerative medicine in the EU
		General considerations
		A brief historical perspective of the use of cells
		Advent of cell and gene therapies
	Differences between United States and European Union regulatory framework
		Classification procedure
	Therapeutic use of pancreatic cells
		Pancreas transplant
		Pancreatic islet transplant—Encapsulated cells
		RM—In vitro creation of pancreatic cells
	Conclusion
	References
36
Catalyzing beta-cell replacement research to achieve insulin independence in type 1 diabetes: Goals and priorities
	JDRF mission
	Beta-cell replacement
		Islet transplantation
		BCR strategies
		Clinical trials in beta-cell replacement
		Beta-cell replacement: Key considerations
		Bridging the gap: Priorities and opportunities
	Additional considerations
	Conclusion
	Acknowledgments
	References
	Further reading
37
Regenerative medicine technologies applied to beta cell replacement: The industry perspective
	Can a “replenishable” (stem cell-derived) beta cell therapy mimic islet transplant therapy?
	Immune suppression
	Beta cells within devices
		Device size
		Access to blood supply
		Stimulation of fibroses
	Can the therapy be removed and replaced?
	Can the therapy be mass-produced?
	Regulatory approval
	Cost and reimbursement
	Patient acceptance
	Conclusion
	References
	Further reading
38
Pancreas whole organ engineering
	Introduction
	Fundamental concepts of tissue development
		Whole organ engineering
	Three-dimensional bioscaffolds for whole organ pancreas engineering
		Whole organ decellularization
		Pancreatic whole organ decellularization
		Effects of pancreatic organ decellularization on ECM composition, structure, and mechanics
			Bioreactors vs in vivo pancreatic organ engineering
			Bioprinting of pancreas
			Pancreatic tissue engineering
	Challenges to current approaches
	References
Index
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