Prolotherapy: Basic Science, Clinical Studies, and …

1 prolotherapy (growth factor or growth factorstimulation injection) raises growth factor levels oreffectiveness to promote tissue repair or factors are complex proteins (polypep-tides), and their beneficial effects on human liga-ment, tendon, cartilage, and bone are under intenseinvestigation. prolotherapy may utilize inflamma-tory or noninflammatory TENDON AND LIGAMENTHEALINGTo understand prolotherapy , a knowledge of thepathology of sprain or strain and the normal healingprocess is necessary. Sprains (ligaments) and strains(tendons) become chronic when healing does notresult in sufficient tensile strength or ,50 This condition also is termed connective tissue in-sufficiency(CTI), in which the structure is either tooloose or has insufficient tensile in CTI stimulates pain et al.

2 Reported that as long as connectivetissue remains functionally insufficient, the painmechanoreceptors can continue to malfunction. 4 Recent studies show that in chronic pain of soft-tissue origin the pathologic lesion is degenerativerather than ,33 Therefore, tendinosisisa more appropriate description of this tissue statethan ,33 Abnormal ligaments and tendons relate directlyto myofascial pain because mechanoreceptors alsotrigger twitch contractions,4which may explain thetaut bands observed in myofascial pain. Individualfiber bundles correspond to tight portions of themuscle sprain or strain results in cell damage,which in turn triggers an inflammatory healingcascade and the appearance of monocytes withinhours, fibroblast proliferation and migration within48 hours, procollagen deposition within one week,and maturation of procollagen to collagen by the maturation phase water is lost, caus-ing constriction of the tendon and tightening and al-lowing for both thickening and tightening of weakor loose ligament, tendon, or joint capsules.

3 Afterinjury, growth factors are elevated enough to stimu-late growth only for a matter of days. Thereafter,healing is dependent on maturation of immaturerepair laxity or tensile strength deficit is not correctedsufficiently to stop pain mechanoreceptor stimula-tion, a chronic sprain or strain results. Without fur-ther stimulation by growth factors, sufficient repaircannot take place. In repetitive trauma, each indi-vidual trauma may be insufficient to provide a pro-liferation stimulus, so that even minor injury maybe enough to accumulate damage to the point of ini-tiating chronic pain.

4 prolotherapy raises the level ofgrowth factors to resume or initiate a repair se-quence that has prematurely aborted or neverstarted. Cells in the area of exposure, such as chon-drocytes or osteocytes in osteoarthritis (OA), alsocan be expected to respond if the growth factors arethose that proliferate such Role of Growth FactorsGrowth factors are powerful, hormone-like pro-teins produced by peripheral cells. Examples in-clude insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), epidermal growthfactor (EGF), fibroblast growth factor (FGF),transforming growth factor (TGF), bone morpho-genetic proteins (BMPs), nerve growth factor(NGF), and hepatocyte growth factor (HGF).

5 60 Normal cells require growth factors (mitogens) forproliferation; in their absence they withdraw fromthe cell cycle and stop order for a17220 prolotherapy : Basic Science, Clinical studies , and TechniqueK. Dean Reeves, : Basic SCIENCE, Clinical studies , AND TECHNIQUE173growth factor to work, it needs to be produced, ap-proach the target cell, avoid binding factors, andattach to its receptor. Disrepair factors such as inter-leukin 1 (IL-1) can interfere with these OF Basic SCIENCE ANDCLINICAL STUDIESC hronic sprain and strain pathology consists ofdecreased tensile strength and often laxity in liga-ments and tendons3,33(changes are primarily degen-erative rather than inflammatory).

6 Osteoarthritissimilarly involves primarily degenerative changes incartilage and cortical and subcortical bone. Poly-peptides are growth factors produced in peripheralcells that powerfully initiate growth and repair inconnective tissue (fibroblasts) and cartilage (chon-drocytes).60 Direct exposure of fibroblasts togrowth factors causes new cell growth and ,28,34,36,40,57 Inflammation creates sec-ondary growth factor elevation. studies of injectionof inflammatory proliferant solutions have demon-strated ligament thickening, enlargement of thetendinoosseous junction, and strengthening oftendon or ligament in animal ,35,44 Inhumans, inflammatory proliferant injection in twoprospective, randomized, double-blind studies ofchronic low back pain has resulted in clinically andstatistically significant improvement in pain and dis-ability ,43 Cartilage effects of polypeptidegrowth factors are considerable.

7 Healing of full-thickness cartilage defects in animals has been shownin several injection ,56,59,61 Simple dextrose or hyper- or hypoosmolarity ex-posure causes cells to proliferate and produce anumber of growth ,8,10,32,41,42,47,51,52,58A re-cently completed prospective, randomized, double-blind study by this author indicates the ability ofsimple dextrose injection interarticularly to tightenhuman ACL recently completedprospective, randomized, double-blind studies onosteoarthritis (knees and fingers) indicate sub-stantial and statistically significant Clinical benefitfrom dextrose injection as compared with ,50bEFFECTS OF prolotherapy ON LIGAMENTS AND TENDONSI njection of Growth FactorsStudies involving exposure of fibroblasts fromligaments and tendons have exposed cells to variousgrowth factors, primarily in vitro.

8 Responses togrowth factors differ between animal species9,28,57and between different tendons and ligaments withinthe same animal or ,57 Transforming growthfactor beta 1 (TGF- 1), erythrocyte growth factor(EGF), PDGF, and Basic fibroblast growth factor(bFGF) appear to be particularly important growthfactors for either new cell growth or collagengrowth in animals and ,34,36 Application ofthis information to growth factor injection studieshas only been reported in one animal study to date,in which direct injection of injured patellar liga-ment in rats was performed. The injected materialcontained a virus altered to produce a key growthfactor (PDGF)

9 , which resulted in a substantial in-crease in collagen deposition compared to nonin-jected Factor StimulatorsInflammatory SolutionsThe injection of inflammatory solution brieflystimulates the inflammatory cascade to simulatean injury without actually stretching or deform-ing an approach causes a complexcascade of chemical events, and measurement ofindividual growth factors and disrepair factors todetermine the exact mechanism is not > 10% concentration partially worksby this mechanism, as do phenol and sodiummorrhuate. Sclerotherapyis an older term for in-flammatory prolotherapy .

10 It is recommendedonly in varicose vein injection; sclerosis impliesscar induction for therapeutic effect. Biopsy stud-ies have not demonstrated scar formation withmechanical, inflammatory, or growth factor pro-lotherapy with the agents and concentrations cur-rently in research on inflammatory prolotherapyhas demonstrated an increase in tendon diameterand tendinoosseous junction in animals (Figs. 20-1and 20-2). Strengthening of knee medial collateralligament has been demonstrated in a double-blindstudy in rabbits,35and reduction of knee laxity hasbeen suggested by an initial study in humans usingan studies inwhiplash, chronic headache, chronic cervical andlow back pain, and temporomandibular joint syn-drome have indicated improvement in 70 85% ofcases using dextrose-glycerine-phenol, sodium mor-rhuate, or hypertonic dextrose ( ).