This is Part 2 of an article on Inflammation by Tom Bisio. Read Part 1 at the link below.
What is Inflammation?
In Inflammation Part 1: Inflammation, Joint Injuries & Anti-Inflammatory Drugs, the dangers of Non-Steroidal Anti-Inflammatory Drugs (NSIADs) was discussed in some detail. But what exactly is inflammation? To answer this question it is useful to dive into the stages of tissue repair and tissue remodeling after an injury to ligaments, tendons and muscles.
In general, tissue healing is a four-phased process that follows a fairly predictable course, although there is some variability according to tissue type and location. In injuries to ligaments, animal studies have indicated that different ligaments heal at different rates and that combined ligament injuries heal at a slower rate than isolated injures and produce tissue of lower quality.
The Phases of Tissue Repair
1. Hemorrhagic Phase
2. Acute Inflammatory Phase
3. Proliferation & Repair Phase
4. Remodeling & Maturation Phase
1. Hemorrhagic Phase
The Hemorrhagic Phase generally lasts only a few minutes and starts at the moment of injury, when torque, compression, impact, etc causes tissue damage, tearing, and blood vessels break. Injured cells die, causing bleeding of the surrounding tissues. This stage very quickly overlaps with the Acute Inflammatory Phase.
2. Acute Inflammatory Phase
The acute inflammatory phase begins within minutes of injury and continues over the next 48 to 72 hours. Inflammation is clinically recognized by the classical findings of:
1. dolor (pain)
2. calor (heat)
3. rubor (redness)
4. tumor (swelling)
5. functio-laesa (loss of function)
Tissue injury starts and inflammatory cascade beginning with the release of histamine, which stimulates capillary dilation, resulting in vascular stasis allowing the migration of phagocytes and plasma leakage – this leads to the classic redness (rubor), heat (calor), and swelling (tumor). The release of bradykinin increases pain sensitivity (dolor) in tissues containing nerve endings. and loss of function (functio-laesa) is regarded as a neurological reflex in response to pain.
During this phase, as blood collects at the site of injury it brings with it platelet cells interact with certain matrix components, initiating clot formation. The platelet-rich fibrin clot releases growth factors that are necessary for healing and provides a platform on which many cellular events occur:
Platelet-Derived Growth Factor and Transforming Growth Factor-B attract immune system cells to the area and stimulate them to proliferate; Vascular Endothelial Growth Factor aids in new blood vessel formation, which increases vascularity in injured areas; and Fibroblast Growth Factor promotes the growth of cells involved in collagen and cartilage formation. Additionally, when stimulated by growth factors, neutrophils, monocytes, and other immune cells migrate to the injured tissue where they ingest and remove debris and damaged cells produced during the inflammatory phase, thereby initiating matrix turnover.
Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage by macrophages. These actions are orchestrated by numerous cytokines. The response and communication between neutrophils and macrophages appears essential to proper regeneration. Macrophages mediate tissue repair and growth by the release of a number of growth-promoting factors and cytokines. In Inflammation Part 1: Inflammation, Joint Injuries & Anti-Inflammatory Drugs, a Canadian study on anti-inflammatories and back pain indicated that the action of neutrophils, a type of white blood cell, and macrophages play a key role in resolving pain and promoting tissue regeneration.
NSAIDs like COX-2 inhibitors have been show to reduce neutrophil and macrophage entry into the muscle, delay regeneration and healing, and result in increased TGF-β1 (a pleiotropic cytokine that exerts powerful anti-inflammatory function and that an important role in wound healing, angiogenesis – the formation of new blood vessels – and immune-regulation). Evidence is accumulating that NSAIDs may actually interfere with satellite cell proliferation, differentiation, and fusion and, therefore, may adversely affect muscle regeneration and repair. Similarly, inhibited tissue repair after NSAID administration has also been shown after injury in other soft tissues, including ligaments.
3. Proliferation/Repair Phase
This phase begins when immune cells release various growth factors, that signal fibroblasts to proliferate in order to rebuild the ligament-tissue matrix. Initially the new tissue appears as disorganized scar tissue, consisting of more blood vessels, fat cells, fibroblasts, and inflammatory cells than normal ligament tissue. Over the next several weeks, fibroblast cells deposit various types of collagen, proteoglycans, glycoproteins, and other proteins into the matrix. In ligaments, the collagen becomes aligned with the long axis of the ligament, however these newly-formed collagen fibers are still abnormal and smaller in diameter than normal ligament tissue. After several weeks this phase merges into the Remodeling Phase.
4. Remodeling & Maturation Phase
The Remodeling & Maturation Phase can last from months to even years after the initial injury. During this phase the collagen laid down in the previous phase matures and starts to resemble normal tissue. However, the injured tissues can be replaced with tissue that is similar to scar tissue. The remodeling phase of ligament repair can continue for many months to years: collagen and ligament matrices go through cycles of tissue synthesis and tissue degradation. These processes provide ongoing opportunities for the ligament to adapt, positively or negatively.
Summary of the Four Phases of Tissue Repair
In looking at these four phases of inflammation and ligament and tissue healing, and reading the current research, it is clear that intervention at each phase of the healing process must be carefully calibrated. It is also clear that many factors, for example the roles of Neutrophils and Macrophages in inflammation and healing, are not completely understood and that both Western Medicine and Eastern Medicine responses to tissue injury need to be closely examined. This comment by researchers Butterfield, Best, and Merrick is a good summation of the issues:
The inflammatory response of tissue to stress is a culmination of a series of multifaceted cellular events, leading to a recognizable physiologic response. Although clinicians have become cognizant of the many therapeutic interventions available for treating inflammation, the dogmatic approach commonly used has little scientific basis in the current literature. Most research regarding these clinical treatments has been very limited and has focused on clinical signs and symptoms in very small numbers of subjects. There remains a dearth of cellular evidence or significant clinical trials to support the traditional treatments used by athletic trainers to treat soft tissue injury and inflammation. This probably reflects the complicated and integrated cellular response to tissue trauma and stress and the concomitant ‘‘good’’ and ‘‘bad’’ aspects of the inflammatory response. Although it is becoming clear that neutrophils cause cell death and necrosis, their phagocytic actions are still required for proper macrophage function and tissue repair. What is not yet clear is the degree to which clinical attempts to minimize neutrophilic tissue damage may interfere with neutrophilic roles in tissue repair.
Current Mediation of Inflammation in Western Medicine
The dogmatic approach to treating injuries to tissue referred to above has traditionally been largely aimed at stopping or inhibiting inflammation and the inflammation response. Part of this approach involves stopping pain as soon as possible, something the Canadian study we saw in Part 1 of this article questions.
In practice, the Western Medicine approach consists of Rest, Ice, Compression and Elevation (R.I.C.E.), and the consumption of anti-inflammatories to kill pain and further mediate the inflammatory response. This approach has been called into question by current research into inflammation and tissue healing. Many of the problems with anti-inflammatories have already been discussed previously in this series of articles, but the almost universal use of R.I.C.E. has also been the subject of controversy. In fact, Dr. Gabe Mirkin, the man who coined the term R.I.C.E. in 1979, has subsequently changed his mind on the use of ice in treating injuries. He gives several reasons why:
1. Applying ice to reduce swelling delays healing by preventing the body from releasing Insulin-Like Growth Factor (IGF-1).
2. Applying ice to injured tissue causes blood vessels near the injury to constrict and shut off the blood flow that brings in the healing cells of inflammation The blood vessels do not open again for many hours after the ice was applied.
This observation is related to a study published in Knee Surgery Sports Traumatology Arthroscopy, which concluded that cryotherapy can create a deep state of vasoconstriction in the local area of treatment. In the absence of independent stimulation, the condition of reduced blood flow persists long after cooling is stopped and local temperatures have rewarmed towards the normal range, indicating that the maintenance of vasoconstriction is not directly dependent on the continuing existence of a cold state. The depressed blood flow may dispose tissue to an NFCI (Non-Freezing Cold Injury, which may be cause tissue necrosis and neuropathy.
3. Cooling may help to decrease pain, but it interferes with the athlete’s strength, speed, endurance and coordination Ice is often used as short-term treatment to help injured athletes get back into a game. However, as Dr. Mirkin points out, one review of 35 studies on the effects of cooling found that usually cooling was performed for more than 20 minute. Most Studies: after cooling, there was a decrease in strength, speed, power and agility-based running. 
A Japanese animal study on the influence of icing on muscle regeneration after crush injury is particularly interesting. After a crush injury to rat extensor digitorum longus, the rats was e randomly divided into non-icing and icing groups. In the latter, ice packs were applied for 20 min. The findings, summarized in the table below, suggest that icing applied soon after the injury not only considerably retarded muscle regeneration but also induced impairment of muscle regeneration along with excessive collagen deposition.
|Time After Injury||Pathological Effects of Icing Group
(Compared with Non-Icing Group)
|12 Hours||Fewer macrophages found within dead muscle fibers|
|Day 3||Reduction in regenerating muscle cells|
|Day 4||Regenerating muscle cells were smaller|
|Day 14||Maturation of regenerating tissues visibly reduced|
|Day 28||Regenerating muscle fibers were still significantly less and there were abnormal collagen formation where collagen fibers surround each muscle fiber.|
Icing is also often used by athletes to help recovery, and “reduce inflammation” after intensive exercise. This practice has been questioned in the last 20 years. In a Duke University Study (1992) researchers at Duke University tested whether applications of ice were helpful in physical recovery after strength training – of eccentric exercises that result in some muscle damage. The research team found that icing constricted the blood vessels, shutting off blood flow to the injured tissues off the blood flow, and after the ice was removed blood perfusion may returned, but the blood vessels often did not open for many hours after the ice application. The research team felt that this effect on circulation could cause the tissue to die due to a lack of blood flow. It can also lead to temporary or permanent nerve damage and disability in the athlete.
In another study eleven male subjects performed six sets of elbow extension at 85% maximum voluntary load and were randomly assigned to topical cooling or sham groups during recovery. Cold packs were applied to exercised muscle for 15 minutes at 0, 3, 24, 48, and 72 hours after exercise. The resulting data suggested that icing delayed rather than improved recovery. 
Other studies have simply concluded that there is insufficient evidence to suggest that cryotherapy (icing) improves clinical outcome in the management of soft tissue injuries.
Two other components of R.I.C.E., Compression and Rest, have also come under criticism in recent years. Compression if excessive also restricts blood flow, unless the compression is dynamic in nature and squeezes blood-flow through the muscle tissue. Therefore elastic bandages that compress the injured area may do more harm than good. Rest is of course necessary after an injury but a study done in 1960 showed that compressing or immobilizing an injured area interferes with the diffusion of nutritive fluid through the inter-cellular substance of the cartilage, and that this in turn can lead to necrosis of the cartilage.
Ice is for Dead People
When I was training in Xing Yi Quan (Form-Intention Boxing) in Taiwan in the early 80’s I met my teacher’s teacher, Master Xu Hong Ji. Master Ji showed me how to set a displaced ankle and mentioned the problems with icing injuries by saying “ice is for dead people.” This rather bald statement stuck with me, and further studies in Chinese medicine helped me to understand the concept of cold-induced damage to the body. I quoted Master Ji in the book A Tooth From the Tiger’s Mouth (2004, Simon & Shuster) in a chapter on injury, and subsequently others have used this same idea to express and further explore some of the problems associated with icing sports injuries.
For example, a lively discussion between Kelly Starrett (Crossfit) and trainer Gary Reni, entitled “Ice is for Corpses,” Reni explains in detail why icing makes no sense scientifically. To keep it simple, Reni says that when ice is applied to a soft tissue injury, the lymphatic vessels in the region increase their permeability, resulting in large amounts of fluid exiting the lymphatics into the injured area, thereby increasing the amount of local swelling. Ice effectively causes a back-flow in the interstitial fluid. Local muscle activation is necessary to aid lymph flow and help evacuation of deactivate blood (dead, stagnant blood in Chinese medicine terms) and cellular waste.
As Reni points out – how could icing, which shuts off the signals between muscles and nerves, possibly help to disperse built up fluid? It can’t. Similarly, NSAIDS will not decongest area either. He also quite rightly says that the pain one is experiencing is due to the congestion and the pressure of the swelling. Reduce the congestion and restore proper circulation, and the pain goes away.
Reni advocates the use of neuromuscular electrical stimulation (NMES) devices to stimulating muscle contraction through electricity. By involuntarily stimulating muscle contraction, NMES devices help pump excess fluid/waste out of the injured area through the passive lymphatic system, and dilate blood vessels to bring nutrients and other helpful white blood cells to enhance the healing process.
From a Chinese medical standpoint, massage methods that focus on moving lymph and the circulation of Qi, Blood and fluids will also facilitate this pumping action, particularly when combined with liniments that move stasis – as discussed in A Tooth from the Tiger’s Mouth – along with acupuncture and internal herbals formulas that move stasis
During the interview Reni quotes a top inflammation researcher: “There can be inflammation without healing, but here cannot be healing without inflammation.” If you skip the early inflammatory phase of healing you interfere with the later phases of Proliferation & Repair and Remodeling & Maturation.
What I like about Reni’s analysis vis a vis lymph circulation, is that it expresses common sense, which as we know is often not so common. It is also very similar to the idea expressed in Chinese Medicine as “Bu tong ze tong, tong ze bu tong.” Or “If there is no free flow, there is pain; if there is free flow, there is no pain.” When Qi moves blood and fluids also move and when free-flow is restored pain is ameliorated. In Chinese medicine, in addition to movement and exercise, we use acupuncture, sophisticated massage techniques and herbal formulas that normalize the flow of Qi and blood and help to break down and remove dead tissue, while simultaneously providing nutrition to aid tissue rebuilding.
Movement not RICE
Because rest, icing and compression are questionable, R.I.C.E. is currently used less and less by top trainers. Movement has largely replaced the idea of compression, elevation and rest. Immediate but gentle restoration of the active range of motion, with gradual introduction of functional activities are crucial. Inactivity shuts muscles down as blood flow is restricted and tissue atrophy follows. In contrast, activity improves blood flow, which brings oxygen and removes metabolic waste. In particular in the early stages of injury healing isometrics are recommended because they create contraction and movement while simultaneously encouraging joint stability.
Congestion and stasis are associated with death; movement and free-flow with life. Ice and NSAIDs don’t move the congestion and stasis. In a similar vein I remember treating my son’s ear infections with Chinese medicine against the advice of the pediatrician who suggested antibiotics. The sticking point for me was when she said he had no infection but needed antibiotics because he had fluid in his ears. I said, “but antibiotics don’t get the fluid out do they?” She immediately became defensive and I could see did not want to discuss treatment further. Antibiotics don’t treat the fluids, so typically the child gets another infection soon after a course of antibiotics. Creating movement with laser therapy, acupuncture, and using heat in the form of warm olive oil drops in the ears combined with herbs that move fluids, did get rid of the fluid, and then he had no more infections.
 “Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics.” Ross Hauser, E.E. Dolan et al. The Open Rehabilitation Journal: January 2013, 6. 1-20. DOI:10.2174/1874943701306010001
 “Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics.” Ross Hauser, E.E. Dolan et al.
 “The Dual Roles of Neutrophils and Macrophages in Inflammation: A Critical Balance Between Tissue Damage and Repair.” Timothy A Butterfield, Thomas M Best, and Mark A Merrick. Journal of Athletic Training: 2006 Oct-Dec; 41(4): 457–465.
“Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics.” Ross Hauser, E.E. Dolan et al.
 “The Dual Roles of Neutrophils and Macrophages in Inflammation: A Critical Balance Between Tissue Damage and Repair.” Timothy A Butterfield, Thomas M Best, and Mark A Merrick. Journal of Athletic Training: 2006 Oct-Dec; 41(4): 457–465
 “Why Ice Delays Recovery.” Dr, Gabe Mirkin. Dr.Mirkin.com: www.drmirkin.com/fitness/why-ice-delays-recovery.html – September 16, 2015
 “Cold-induced vasoconstriction may persist long after cooling ends: an evaluation of multiple cryotherapy units.” Sepideh Khoshnevis. Natalie K Craik, and Kenneth R Diller. Knee Surgery Sports Traumatology Arthroscopy: 2015 Sep;23(9):2475-83.
 Bleakley CM, Costello JT, Glasgow PD. “Should athletes return to sport after applying ice? A systematic review of the effect of local cooling on functional performance.” Sports Medicine. 2012 Jan 1;42(1):69-87. doi: 10.2165/11595970-000000000-00000. PMID: 22121908.
 “Influence of Icing on Muscle Regeneration After Crush Injury to Skeletal Muscles in Rats.” Ryo Takagi, Naoto Fujita, et Al. Journal of Applied Physiology. February, 1 2011 Vol. 110 no. 2) p. 382-388 http://jap.physiology.org/content/110/2/382
 Tseng CY, Lee JP, Tsai YS, Lee SD, Kao CL, Liu TC, Lai C, Harris MB, Kuo CH. “Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage.” J Strength Cond Res. 2013 May;27(5):1354-61. doi: 10.1519/JSC.0b013e318267a22c. PMID: 22820210.
 Collins NC, ”Is ice right? Does cryotherapy improve outcome for acute soft tissue injury?”Emergency Medicine Journal 2008;25:65-68.
 “The Effects of Continuous Compression on Living Articular Cartilage: An Experimental Investigation.” R. Salter and P. Field. Journal of Bone and Joint Surgery, American Volume. 1960.
 Ice is for Corpses, Recovery Tips with Dr. Kelly Starrett https://www.youtube.com/watch?v=0UmJVgEWZu4