The problem of the missing organ1. Irreversible injury (acute and chronic) destroys organ function.Various Medical ProblemsIrreversible organ injuryPoor organ function leads to unpleasant choices --- scarred heart muscle: poor pumping action; congestive heart failure; dru2. Five therapies for the missing organ.Five Approaches to the Problem of the Missing OrganA. Transplantation (e.g., kidney transplant, heart transplant)B. Autografting (e.g., heart bypass, skin grafting) 6-yr-old burn victim – total skin loss on upper and lower abdomenC. Passive Implant (e.g., hip prosthesis, pacemaker) C. Passive Implant (cont.)D. In vitro synthesisE. In vivo synthesis (regeneration)Design strategy Identify nonregenerative tissuesMembers of the tissue triadThe tissue triad in skin and nervesThe tissue triad in the organismThe central question is…Skin: In vitro or in vivo synthesis? Peripheral nerves: In vitro or in vivo synthesis?ArthritisThe problem of the missing organ1. Irreversible injury (acute and chronic) destroys organ function.2. Five basic therapies for the missing organ.3. Examples of widespread clinical problemsthat have not been solved adequately. Additional reading: [TORA] Tissue and Organ Regeneration in Adults (TORA), by I.V.Yannas, New York, Springer, 2001. Chap. 1.1. Irreversible injury (acute and chronic) destroys organ function.Various Medical Problems• The aggressive bacterium (virus)• The missing enzyme• The defective gene• The missing organIrreversible organ injury• The mammalian fetus regenerates lost organs spontaneously.• Adultmammals do not regenerate damaged or diseased organs.• The adult response to trauma or chronic disease includes wound closure by contraction and formation of scar (repair).Amphibian (newt) limbs regenerate spontaneously4 1. The Irreversibility of InjuryFigure 1.1. Montage of individual newt limbs amputated across the lower or upper arms, photographed at indicated times and regenerating spontaneously. (From Goss, 1992.)Figure removed due to copyright restrictions. See Figure 1.1 in [TORA].Liver: compensatoryhypertrophy,not “real”regeneration of two lobesAll Organs Can Be Irreversibly InjuredFIGURE 1.2. Liver does not regenerate at the anatomical site of injury. When the median and left lateral lobes of a rat liver are removed (broken line shows shape of intact organ), only the caudate and right lateral lobes remain, representing about one-third of the intact organ. After three weeks, these lobes enlarge to a mass equivalent to the initial size of the liver. The shape of the intact liver is not restored. (From Goss, 1992.)Figure removed due to copyright restrictions. See Figure 1.2 in [TORA].Example of adult healing response.Severe burncauses skin loss. Woundcloses by contractionand scar synthesisPhoto removed due to copyright restrictions.Figure removed due to copyright restrictions. See Chapter 1 in [TORA] - examples of injury healing in various tissue types.Poor organ function leads to unpleasant choices--- scarred heart muscle: poor pumping action; congestive heart failure; drugs, heart transplant--- scarred kidney: poor filtration; use kidney dialysis machine--- scarred heart valve: inefficient pumping due to leaky valve; congestive heart failure--- scarred liver: cirrhosis; poor function; liver transplant--- scarred eye: loss of vision2. Five therapies for the missing organ.Five Approaches to the Problem of the Missing OrganApproachTransplantationAutograftingPassive implant(Stem cellsIn vitro synthesisIn vivo synthesisExampleKidneyCoronary bypassHip prosthesisNot available)EpidermisSkinA. Transplantation (e.g., kidney transplant, heart transplant)donor organdonor ⇒⇒⇒⇒host ⇒rejection? ⇒⇒ treatment impairs immune systemAlso, demand for organ transplants greatly outstrips supply807060504030201020001990ThousandsPatients on waiting listsNon-living donorsDemand for organs is growing, while the supply stays constant.Figure by MIT OCW.Data from United Network for Organ Sharing.B. Autografting (e.g., heart bypass, skin grafting)Donor = recipientExample: In heart bypass surgery, a length of leg vein is removed and used to shunt clotted coronary arterypart host organHost ⇒⇒⇒⇒⇒host ⇒ host trauma? sufficient recovery of function?Third-degree burn: complete skin lossFigure removed due to copyright restrictions.6-yr-old burn victim – total skin loss on upper and lower abdomenpatient of Dr. John BurkeFigure removed due to copyright restrictions.C. Passive Implant (e.g., hip prosthesis, pacemaker)metallics/polymers/ceramics ⇒ device fabrication ⇒ host ⇒ long-term function?materials used: stainless steel, Ti alloys, CoCralloys, polylactic acid, polyglycolic acid, nylon; dacron (PET) vascular graft; polyurethane heart chamberC. Passive Implant (cont.)Problem #1: host attacks implantmigration of hip prosthesisabrasion of polyethylene 'cup'tissue fluid attacks pacemaker electronicsProblem #2: implant attacks hosthip prosthesis causes bone loss (stress shielding)heart valve causes blood cell rupturevascular graft causes blood clottingSeveral slides on different implants removed due to copyright restrictions. Cementing artificial hip with PMMASilicone gel breast implantHeart pacemakerBalloon catheterLeft ventricular assist device: responds to changes in workload by adjusting its beats per minuteLiver assist machine: passes blood through culture of human cells, provides 20% normal liver functionArtificial lung device inserted into large vein in chest, enables body to absorb oxygenHearing aidD. In vitro synthesis1. Synthesize a construct resembling the desired organ (organoid) in vitro in the presence of cells of one or more types, solutions of cytokines and one or more scaffolds.2. Implant the organoid at the correct anatomical site. 3. If successfully synthesized, the organoidbecomes incorporated in the organism and functions physiologically.Problem: Physiological cytokine field unknown, cannot be replicated in vitro.Several slides removed due to copyright restrictions.Design strategyAnalyze problem of irreversible injured organ by identifying tissues in organs that regenerate spontaneously (regenerative) and those that do not (nonregenerative). Rather than planning a device that can synthesize the entire organ, the designer’s task is made simpler if the design focuses on synthesis of just those tissue(s) that do not regenerate by themselves. Which are they?Identify nonregenerative