Prolotherapy is the iatrogenic stimulation of the wound healing and tissue repair process

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  • Prolotherapy is the iatrogenic stimulation of the wound healing and tissue repair process

  • PROLOTHERAPY or REGENERATIVE INJECTION THERAPY RIT is an interventional technique for treatment of chronic pain due to connective tissue diathesis by induction of collagen chemo-modulation through inflammatory, proliferative and regenerative/reparative responses mediated by multiple growth factors.

  • REGENERATIVE INJECTION THERAPYMechanism1. Mechanical transection of cells and matrix induced by needle trauma stimulates an inflammatory cascade2. Compression of cells by the extra-cellular volume of injected solution stimulates intracellular growth factors


    3. Chemomodulation of collagen through inflammatory proliferative, regenerative/reparative responses induced by the chemical properties of the proliferants and mediated by cytokines and multiple growth factors

  • Dextrose exposure to human periodontal fibroblastsElevates polypeptide growth factors within minutes to hours after injection

    Causes cell multiplication and matrix formation

  • Human ligaments after injury Elevated levels of PDGF, TGF-beta, EGF, bFGF and IGF

  • In vitro exposure of human cells to extra-cellular glucose 0.5% (normal intracellular concentration 1.1%) results in activation of 15 different gene segments within minutes to hours of exposure = growth factor production

  • Hypertonic SolutionsExposure of human and animal cells to hypertonic solution has been found by several researchers to result in a rise of growth factors

    This rise is more limited than with dextrose elevation and in studies comparing equal osmolar concentrations of glucose and mannitol, glucose caused more GF elevation

  • Effect on Disrepair FactorsIn osteoarthritis a variety of interleukins and plasminogen activator are involved in damage to cartilaginous tissueDextrose exposed to human cells has been shown to decrease activity of interleukins 2, 6, and 10 and plasminogen activatorNot just growth factor production but limitation of destructive activity


    4. Chemoneuromodulation of peripheral nociceptors and antidromic, orhthodromic, sympathetic and axon reflex transmissions


    5. Modulation of local hemodynamics with changes in intra-osseous pressure leading to the reduction of pain (dextrose/lidocaine combination more prolonged action than lidocaine alone)


    6. A temporary repetitive stabilization of the painful hyper-mobile joints, induced by the inflammatory response to the proliferants, provides a better environment for regeneration and repair of affected ligaments and tendons.

  • Wound Healing

  • Prolotherapy is the iatrogenic stimulation of the wound healing and tissue repair process

  • Wound Healing has distinct phases that overlap in time.InflammationGranulationRemodeling

  • Wound Healing has distinct phases that overlap in time.

  • Inflammation PhaseCoagulation cascade initiatedFibrin clot results in the release cytokines and growth factors from platelets. Platelet derived growth factor (PDFG)Transforming growth factor- (TGF-)Platelet activating factor (PAF)

  • Inflammation PhaseLocal fibrin clot serves as scaffolding for invading cellsNeutrophilsMonocytesFibroblastsEndothelial cellsReceptors on the cells and clot ensure selectivity of response

  • Inflammation PhaseAttraction of cells to the wound by chemotaxis is followed by functional activation.Particularly important is the activation of the macrophages and lymphocytes.DebridementMatrix synthesisAngiogenesis

  • Inflammation PhaseSoft tissue injury releases many chemical mediators that sensitize the nociceptors = painHistamineProstaglandin E2Bradykinin

    These are also the major activators of the macrophages

  • Major mediators of theinflammatory Process

  • At the end of the inflammation phase the production of the cytokine mediators ceases and the granulation phase begins

  • Granulation PhaseDominated by the activity of the fibroblasts and endothelial cells beginning 100 hours after the injury

    Macrophages, fibroblasts and blood vessels move into the wound space as a unit.

  • Granulation PhaseFibroblasts construct new extra-cellular matrix (ECM) to support cellular growth.

    Neovascularity supplies the oxygen and nutrients.

  • Granulation PhaseFibroblasts differentiate to myofibroblasts which pull the wound together

  • Granulation PhaseAt the end of the granulation phase the fibroblasts begin to produce collagen.

    Net collagen synthesis is increased for 4-5 weeks during the remodeling phase.

  • Remodeling PhaseMain feature is deposition of collagen in the woundFibroblasts under tensile stress produce SM actin and as the stress increases they form adhesion complexes with the extracellular matrixThese cells predominate in connective tissue injuries

  • Remodeling Phase

  • Remodeling PhaseThis leads to connective tissue contracture that is incremental and a true anatomical shortening of the extra cellular matrix (ECM).As the ECM is remodeled, the myofibroblasts become surrounded by the new load-carrying matrix.As myofibroblasts are shielded from the stress they disappear by apotosis.

  • Remodeling PhaseThe final ECM is not distinguishable from the original by any analytical means.There is no scar tissue.This process gives animals the resources to repair minor injuries in such away that they will have lost no capability to survive.

  • Pre prolotherapyPost prolotherapy12 wks0 weeks

  • Remodeling PhaseTo complete healing of ligament and tendons, movement and loading of the tissue is critical to a good outcome.There is period of vulnerability when the curve of wound healing is plotted against pain and ligament strength.Period of vulnerability is proportional to original severity of injury and expected demand.

  • Remodeling Phase

  • Chronic InjuriesMay result from: Chronic postural dysfunctions Repetitive work Chronically contracted muscles responding to pain such as in old ligament or enthesis injuries

  • Chronic Injuries If present for years, it may take up to 1 or 2 years for the ligaments to heal and for the associated pain to finally settle down

  • The enthesisNormal tendons and ligaments (TL) share a common feature where they attach to bonethe enthesis.This site creates a firm union by splaying out the fibers to create a larger surface area.The enthesis has 2-3 times the cross sectional area as the mid substance TL.

  • The enthesis Two basic types differentiated by structure and locationFibrocartilaginousFibrous

  • Fibrocartilaginous

    Found at apophyses and epiphysis of long bones and in short bones in hands and feetFibrocartilage cells and matrix are present at the attachment site.

  • Fibrous Characteristic of tendons and ligaments that attach to the metaphases and diaphyses of long bones by dense fibrous connective tissue known as Sharpeys fibers.

  • The enthesisBone and enthesis interlock Allowing for stress dissipation at the attachment siteUn-calcified fibrocartilage dissipates bending forces during insertional angle changes

  • Chronic Enthesis Injuries

  • Chronic Enthesis InjuriesConsequence of chronic stress at enthesis is tissue micro trauma with altered or incomplete tissue repair.Orderly phased wound repair is absent or aborted in these areas of micro trauma because of hypoxia.This is enthesopathy or tendinosis.

  • Enthesopathy & TendinosisFailed adaptation of the tendon or ligament to physical load and use

    Designates these altered focal areas of degeneration.

  • ligament and tendon changes

  • Fissures and Cracks

  • Fatty & Hyaline Degeneration

  • Fibrous Degeneration

  • Enthesopathy & TendinosisEnthesis is the most richly innervated region of a ligament or tendon.1. Myelinated A afferent fibers2. Non myelinated C afferent fibers (Sensitive to chemical mediators)

  • Pain & Soft TissuesSoft tissue injury releases manychemical mediators that sensitizethe nociceptorsHistamineProstaglandin E2Bradykinin

  • Pain & Soft Tissues

  • Pain & Soft TissuesEffects of neural stimulation includeSpinal reflex contraction of flexor musclesFacilitation of the flexor reflex leading to reflex muscle spasmInhibition of antagonistic musclesSensitization of nociceptors

  • Pain & Soft TissuesThe spinothalamic tract carries pain to the thalamus

    Connections between thalamus and hypothalamus integrate the autonomic nervous system response

  • Pain effects on the brain

  • Hormones ReleasedGrowth Hormone - HypothalamusNeural Growth Factor Cortisol - Adrenal Cortex

    Pain effects on the brain

  • Chronic Enthesopathy Often painless in spite of degenerative changesMicro insults do not trigger release of growth factorsPain does not develop until damage reaches an area where vessels are present

  • Pain ModeratorsTreating the pain without interfering with wound healing

    Corticosteroids and NSAIDs effect wound healing and collagen repair

  • Pain ModeratorsEicosanoid biosynthesis begins afterTraumaInfection Inflammation

  • Trauma releases arachidonic acid from cell wallArachidonic acid is converted into eicosanoids mediated by two different pathwaysCyclo-oxygenase P


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