Intrinsic Healing Research Articles

A composite scaffold of MSC affinity peptide-modified demineralized bone matrix particles and chitosan hydrogel for cartilage regeneration.

Articular cartilage injury is still a significant challenge because of the poor intrinsic healing potential of cartilage. Stem cell-based tissue engineering is a promising technique for cartilage repair. As cartilage defects are usually irregular in clinical settings, scaffolds with moldability that can fill any shape of cartilage defects and closely integrate with the host cartilage are desirable. In this study, we constructed a composite scaffold combining mesenchymal stem cells (MSCs) E7 affinity peptide-modified demineralized bone matrix (DBM) particles and chitosan (CS) hydrogel for cartilage engineering. This solid-supported composite scaffold exhibited appropriate porosity, which provided a 3D microenvironment that supports cell adhesion and proliferation. Cell proliferation and DNA content analysis indicated that the DBM-E7/CS scaffold promoted better rat bone marrow-derived MSCs (BMMSCs) survival than the CS or DBM/CS groups. Meanwhile, the DBM-E7/CS scaffold increased matrix production and improved chondrogenic differentiation ability of BMMSCs in vitro. Furthermore, after implantation in vivo for four weeks, compared to those in control groups, the regenerated issue in the DBM-E7/CS group exhibited translucent and superior cartilage-like structures, as indicated by gross observation, histological examination, and assessment of matrix staining. Overall, the functional composite scaffold of DBM-E7/CS is a promising option for repairing irregularly shaped cartilage defects.

Waiguan Stimulation May Kindle Anticorrelated Brain Networks: Functional Magnetic Resonance Imaging Data Revisited

Subtraction of functional magnetic resonance imaging activity data results in a loss of information regarding possible general patterns of brain activation under experimental conditions. We, hence, reanalyzed previous Waiguan acupuncture data to qualitatively elucidate patterns of cerebral correlations to acupuncture and placebo conditions. Healthy individuals (n=24) were randomly allocated to true and sham Waiguan acupuncture and to true and sham needling of a nonacupuncture point (nonacupoint), and functional magnetic resonance imaging scans were performed during stimulation. Statistical parametric mapping group comparisons revealed clearly different patterns of activation between Waiguan stimulation and the corresponding stimulation of a nonacupoint. The former condition produced less neocortical activation than the nonacupoint stimulation. Cerebellar activation was typically seen only during true Waiguan acupuncture. The reduced neocortical activity during both true and sham Waiguan acupuncture may indicate that this point activates anticorrelated networks, with possible intrinsic healing properties. Cerebellar activation during true Waiguan acupuncture implies the region's influence on healing networks.

Assessment of healed scratches in intrinsic healing coatings by AC/DC/AC accelerated electrochemical procedure

Abstract In the last years several intrinsic and extrinsic healing coatings have been presented in the literature. While extrinsic coatings have attracted more attention when dealing with electrochemical characterization techniques, protective intrinsic healing coatings have mainly been analyzed by traditional electrochemical impedance spectroscopy (EIS). In this article we introduce the potential use of the AC/DC/AC accelerated electrochemical protocol as a suitable tool for the fast evaluation of the goodness of the polymer-polymer interface (i.e. scar) in a healed scratch. For the purpose we employed a hybrid healable dual network coating containing disulfide linkages as the responsible reversible groups for the necessary local mobility and subsequent scratch interface sealing. The results obtained show the high discriminating power of AC/DC/AC of the level of interface sealing at the scratch in much faster times than traditional EIS.

Multiscale Biofabrication of Articular Cartilage: Bioinspired and Biomimetic Approaches.

Articular cartilage is the load-bearing tissue found inside all articulating joints of the body. It vastly reduces friction and allows for smooth gliding between contacting surfaces. The structure of articular cartilage matrix and cellular composition is zonal and is important for its mechanical properties. When cartilage becomes injured through trauma or disease, it has poor intrinsic healing capabilities. The spectrum of cartilage injury ranges from isolated areas of the joint to diffuse breakdown and the clinical appearance of osteoarthritis. Current clinical treatment options remain limited in their ability to restore cartilage to its normal functional state. This review focuses on the evolution of biomaterial scaffolds that have been used for functional cartilage tissue engineering. In particular, we highlight recent developments in multiscale biofabrication approaches attempting to recapitulate the complex 3D matrix of native articular cartilage tissue. Additionally, we focus on the application of these methods to engineering each zone of cartilage and engineering full-thickness osteochondral tissues for improved clinical implantation. These methods have shown the potential to control individual cell-to-scaffold interactions and drive progenitor cell differentiation into a chondrocyte lineage. The use of these bioinspired nanoengineered scaffolds hold promise for recreation of structure and function on the whole tissue level and may represent exciting new developments for future clinical applications for cartilage injury and restoration.

Cell-based chondral restoration.

As our patients become more physically active at all ages, the incidence of injuries to articular cartilage is increasing and is causing patients significant pain and disability at a younger age. The intrinsic healing response of articular cartilage is poor, because of its limited vascular supply and capacity for chondrocyte division. Nonsurgical management for the focal cartilage lesion is successful in the majority of patients. Those patients that fail conservative management may be candidates for a cartilage reparative or reconstructive procedure. The type of treatment available depends on a multitude of lesion-specific and patient-specific variables. First-line therapies for isolated cartilage lesions have demonstrated good clinical results in the correct patient but typically repair cartilage with fibrocartilage, which has inferior stiffness, inferior resilience, and poorer wear characteristics. Advances in cell-based cartilage restoration have provided the surgeon a means to address focal cartilage lesions utilizing mesenchymal stem cells, chondrocytes, and biomimetic scaffolds to restore hyaline cartilage.

Abrasion arthroplasty increases mesenchymal stem cell content of postoperative joint effusions.

BackgroundAbrasion arthroplasty (AAP) is a procedure by which intrinsic cartilage healing is believed to be stimulated. Although clinically accepted for degenerative and traumatic cartilage lesions scientific evidence at a molecular level that proves the effect of AAP is scarce.MethodMononuclear cells were extracted from postoperative joint effusions 21.5 h post AAP and simple debridement of cartilage lesions. Luminex, ELISA and FACS experiments were performed. Immunohistochemical stainings of cell cultures for cartilage markers were used to confirm the findings.ResultsPostoperative joint effusions after AAP showed increased contents of Mononuclear cells compared to Arthroscopic Chondroplasty (ACP). BMP-4 and IGF were increased in AAP as complared to ACP. Mononuclear cells isolated after AAP express the MSC markers CD 73, CD 105, CD 90, CD 44 and are CD34 negative. Chondrogenic differentiation was demonstrated by positive staining for Sox9, collagen II, proteoglycan, chondroitin-4-sulfate.ConclusionOur results support the clinical application of AAP as a procedure that enhances cartilage repair as an alternative to far more complex procedures that have gained popularity. Furthermore the data presented supports clinical investigations that recommend not to use suction drainage as by this procedure a considerable amount of the regeneratory potential of postoperative joint effusions might be extracted.

A Gathering of Native American Healers: Exploring the Interface of Indigenous Tradition and Professional Practice.

This article reports insights from a 4-day Gathering of Native American Healers at the University of Michigan in October of 2010. This event convened 18 traditional healers, clinically trained service providers, and cross-cultural mental health researchers for a structured group dialogue to advance professional knowledge about the integration of Indigenous healing practices and conventional mental health treatments in community-based mental health services for Native Americans. Our thematic analysis of transcripts from five Roundtable sessions afforded several key insights and understandings pertaining to the integration of Indigenous healing and conventional mental health services. First, with reference to traditional healing, the importance of a rampant relationality, various personal qualities, Indigenous spirituality, and maintenance of traditional life and culture were accentuated by Roundtable participants. Second, for traditional healers to practice effectively, Roundtable participants posited that these individuals must maintain personal wellness, cultivate profound knowledge of healing practices, recognize the intrinsic healing potential within all human beings, and work for the community rather than themselves. In speaking to the possibilities and challenges of collaboration between Indigenous and conventional biomedical therapeutic approaches, Roundtable participants recommended the implementation of cultural programming, the observance of mutuality and respect, the importance of clear and honest communication, and the need for awareness of cultural differences as unique challenges that must be collaboratively overcome.

DeNovo NT Particulated Juvenile Cartilage Implant.

Biological repair of focal chondral defects represents a significant clinical challenge as cartilage lacks intrinsic healing ability. Although it can be difficult to measure the objective success of cartilage repair techniques, the primary objective is symptom relief leading to less pain and improved function for the patient. Likely, the most important key to success is proper clinical indications. Second to this, the type of cartilage treatment utilized should be based on lesion location, size, depth, and other patient factors. One such treatment is DeNovo Natural Tissue. This method relies on the ability of juvenile chondrocytes to migrate from cartilage explants after being secured in a cartilage defect. Although approximately 8700 cases have been performed since 2007, long-term clinical outcomes are not yet available. However, basic science and early clinical data are promising.

The Effect of Smoking on Spinal Cord Healing Following Surgical Treatment of Cervical Myelopathy.

Retrospective cohort. The purpose of this study was to compare outcomes of surgical treatment of cervical myelopathy between smokers and nonsmokers as assessed by the Nurick score. The harmful effects of smoking on healing have been well established. However, the effect of smoking on postoperative outcomes for cervical myelopathy has not been specifically evaluated. The medical records of 212 patients who underwent surgery for cervical spondylotic myelopathy were reviewed. Inclusion criteria were the diagnosis of cervical spondylotic myelopathy with a Nurick score, surgical intervention, and at least 2 years of follow-up. The patients were categorized into 2 groups according to smoking status and stratified according to pack years and packs per day. Age at presentation, sex, preoperative and postoperative Nurick score, duration of symptoms preoperatively, duration of follow-up, procedure performed, surgical approach, number of levels fused, diabetes status, cocaine use, ethanol use, preoperative magnetic resonance imaging signal change, and whether the patient belonged to the Veterans Administration (VA) were recorded. Analysis was done using simple linear regression and multiple regression. Univariate analysis demonstrated a postoperative improvement in nonsmokers of 1.53 points on the Nurick scale compared with 0.6 points in smokers (P < 0.001). There is a progressive decrease in improvement as the number of pack years and packs per day increase (P < 0.001). There is a greater improvement in Nurick score with greater (worse) preoperative score but only in patients with fewer than 25 pack years. Smoking status is not associated with preoperative Nurick score. Smoking status is associated with poor improvement in Nurick score after surgical treatment of cervical myelopathy. Smoking may have a directly toxic effect on the intrinsic healing capability of the spinal cord, particularly beyond 25 pack years. 3.

AB177. Implications for differentiation of endogenous stem cells: therapeutic effect from icariside II on a rat model of postprostatectomy erectile dysfunction

ObjectiveSelf-renewal and differentiation of endogenous stem cells (SCs) are essential for adult tissue homoeostasis and intrinsic healing capacity. In this study, we hypothesize that penis contains a small population of endogenous SCs, which might help rejuvenation of damaged erectile function.MethodsIn this study, 60 newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous SCs. Twelve weeks later, 48 rats underwent bilateral cavernous nerves injury and were randomized into gavage feeding of solvent (vehicle group) or icariside II (0.5, 1.5, and 4.5 mg/kg/day, respectively). Twelve sham-operated rats received vehicle treatment and served as control. The treatments were continued for 4 weeks followed by a washout period of 72 h.ResultsResults showed that ICA II treatment significantly restored erectile function and effectively prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition compared with the vehicle group. The numbers of label-retaining cells (LRCs) co-expressing EdU and differentiated phenotypes (smooth muscle marker a-SMA or Schwann cell marker S100) were significantly higher in the three ICA II-treated groups than those in vehicle group in a dose-dependent manner. In addition, the changing trend of p38 mitogen-activated protein kinase (MAPK) activity in the penis between groups was same as that of the number of differentiated LRCs.ConclusionsTogether, these results suggest that the underlying mechanisms of ICA II in ameliorating erectile function and pathological changes appear to involve enhanced endogenous SCs differentiation, which might be regulated by p38 MAPK signaling pathway.

Riboflavin crosslinked high-density collagen gel for the repair of annular defects in intervertebral discs: An in vivo study

Open annular defects compromise the ability of the annulus fibrosus to contain nuclear tissue in the disc space, and therefore lead to disc herniation with subsequent degenerative changes to the entire intervertebral disc. This study reports the use of riboflavin crosslinked high-density collagen gel for the repair of annular defects in a needle-punctured rat-tail model. High-density collagen has increased stiffness and greater hydraulic permeability than conventional low-density gels; riboflavin crosslinking further increases these properties. This study found that treating annular defects with crosslinked high-density collagen inhibited the progression of disc degeneration over 18weeks compared to untreated control discs. Histological sections of FITC-labeled collagen gel revealed an early tight attachment to host annular tissue. The gel was subsequently infiltrated by host fibroblasts which remodeled it into a fibrous cap that bridged the outer disrupted annular fibers and partially repaired the defect. This repair tissue enhanced retention of nucleus pulposus tissue, maintained physiological disc hydration, and preserved hydraulic permeability, according to MRI, histological, and mechanical assessments. Degenerative changes were partially reversed in treated discs, as indicated by an increase in nucleus pulposus size and hydration between weeks 5 and 18. The collagen gel appeared to work as an instant sealant and by enhancing the intrinsic healing capabilities of the host tissue.

Optimization of intrinsic and extrinsic tendon healing through controllable water-soluble mitomycin-C release from electrospun fibers by mediating adhesion-related gene expression

To balance intrinsic and extrinsic healing during tendon repair is challenging in tendon surgery. We hypothesized that by mediating apoptotic gene and collagen synthesis of exogenous fibroblasts, the adhesion formation induced by extrinsic healing could be inhibited. With the maintenance of intrinsic healing, the tendon could be healed with proper function with no adhesion. In this study, we loaded hydrophilic mitomycin-C (MMC) into hyaluronan (HA) hydrosols, which were then encapsulated in poly(L-lactic acid) (PLLA) fibers by micro-sol electrospinning. This strategy successfully provided a controlled release of MMC to inhibit adhesion formations with no detrimental effect on intrinsic healing. We found that micro-sol electrospinning was an effective and facile approach to incorporate and control hydrophilic drug release from hydrophobic polyester fibers. MMC exhibited an initially rapid, and gradually steadier release during 40 days, and the release rates could be tuned by its concentration. In vitro studies revealed that low concentrations of MMC could inhibit fibroblast adhesion and proliferation. When lacerate tendons were healed using the MMC-HA loaded PLLA fibers in vivo, they exhibited comparable mechanical strength to the naturally healed tendons but with no significant presence of adhesion formation. We further identified the up-regulation of apoptotic protein Bax expression and down-regulation of proteins Bcl2, collage I, collagen III and α-SMA during the healing process associated with minimum adhesion formations. This approach presented here leverages new advances in drug delivery and nanotechnology and offers a promising strategy to balance intrinsic and extrinsic tendon healing through modulating genes associated with fibroblast apoptosis and collagen synthesis.

The influence of 2,4-toluene diisocyanate content on the intrinsic self-healing performance of polyurethane at room-temperature

A new kind of polyurethane was synthesized using 2,4-toluene diisocyanate (TDI) as the hard segment and polyether polyols as the soft segment. The influence of hard segment content on the self-healing ability of polyurethane was investigated by testing tensile strength and elongation healing rates after contact together for one week. Tensile test results indicate that the intrinsic healing capability of the polyurethane at room temperature decreased with an increasing hard segment content, and was lost when it reached fifty percent. Fracture morphologies of polyurethane were observed by confocal laser scanning microscopy, showing that roughness increased with an increasing hard segment content due to increased cross-link density and restraining of segment motion. The self-healing capability of this TDI polyurethane can be attributed to reversible H-bonds and to the mobility of the soft segment at room temperature. Segment mobility is a prerequisite of being able to self-heal.

Histological characteristics of ligament healing after bio-enhanced repair of the transected goat ACL.

BackgroundRecently, healing of a ruptured anterior cruciate ligament (ACL) is reconsidered. In a previous study, we have shown that the transected ACL can heal after treatment with the triple X locking suture alone or combined with small intestine submucosa (SIS). The first research question of this study was whether the healing ACLs in both groups show histological characteristics that are typical for ligament healing. Secondly, did the combined treatment with SIS lead to improved histological healing, in terms of the morphology of the fibrous synovial layer, the extracellular matrix (ECM), collagen fiber orientation, cellularity, ratio of myofibroblasts, and collagen type 3 staining. The hypothesis was that SIS enhances the healing by the scaffolding effect, endogenous growth factors, and chemoattractants.MethodsIn the Suture group, the left ACL was transected and sutured with the triple X locking suture repair technique. In the Suture-SIS group, the left ACL underwent the same procedure with the addition of SIS. The right ACL served as internal control. Standard histology and immunostaining of α-smooth muscle actin (SMA) and collagen type 3 were used.ResultsMicroscopy showed that the fibrous synovial layer around the ACL was reestablished in both groups. The collagen fibers in the Suture-SIS group stained denser, were more compactly arranged, and the ECM contained fewer voids and fat vacuoles. Neovasculature running between the collagen fibers was observed in both experimental groups. Collagen type 3 stained less in the Suture-SIS group. The cellularity in the Suture group, Suture-SIS group and Control was 1265 ± 1034 per mm2, 954 ± 378 per mm2, 254 ± 92, respectively; 49%, 26% and 20% of the cells stain positive for α-SMA, respectively.ConclusionThe healing ACL in both treated groups showed histological characteristics which are comparable to the spontaneously healing medial collateral ligament and showed that the ACL has a similar intrinsic healing response. Though, no definitive conclusions on the beneficial effects of the SIS scaffold on the healing process can be made.

Gene Therapy for Bone Engineering

Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures need to be taken by physicians. It is important to combine cells, scaffolds and growth factors, and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies.

Mesenchymal Stem Cells and Biomaterials Systems – Perspectives for Skeletal Muscle Tissue Repair and Regeneration

Skeletal muscle is essential in voluntary movement and other major vital functions. Muscle injuries are important in clinical practice and, despite skeletal muscle's good regenerative ability, severe tissue loss impairs complete myofibre regeneration, limiting structural and functional recovery of the affected muscle, eventually leading to the development of non-contractile fibrous scar. The intrinsic healing mechanisms rely in great extent on the residing progenitor population but significant drawbacks to their practical application in regenerative strategies boosted the search for alternative cell sources, such as extra-fetal mesenchymal stem cells (MSCs). MSCs have demonstrated to positively influence the regeneration of different disease models. When severe volumetric muscle tissue loss occurs, the body is seldom capable of replacing the lost portions with fully functional tissue. A rational strategy to aid the healing of such situations is the application of biomaterial implants that provide a structural matrix for the ingrowth of regenerating muscle fibres. Both synthetic and natural biomaterials have been hypothesized for this purpose and some have reached as far clinical cases applications. Obvious improvements are observed in most cases, but reaction to some biomaterials and functional recovery are still a challenge. The addition of MSCs to the biomaterials seems to improve the systems’ performance in the overall regenerative milieu. This strategies promote scaffold's vascularization and integration, as well as accelerated tissue ingrowth and reduces scar formation, resulting in improved recovery rates at both structural and functional levels.

Implications for differentiation of endogenous stem cells: therapeutic effect from icariside II on a rat model of postprostatectomy erectile dysfunction.

Self-renewal and differentiation of endogenous stem cells (SCs) are essential for adult tissue homoeostasis and intrinsic healing capacity. In this study, we hypothesize that penis contains a small population of endogenous SCs, which might help rejuvenation of damaged erectile function. In this study, 60 newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous SCs. Twelve weeks later, 48 rats underwent bilateral cavernous nerves injury and were randomized into gavage feeding of solvent (vehicle group) or icariside II (0.5, 1.5, and 4.5 mg/kg/day, respectively). Twelve sham-operated rats received vehicle treatment and served as control. The treatments were continued for 4 weeks followed by a washout period of 72 h. Results showed that ICA II treatment significantly restored erectile function and effectively prevented distortion of normal neural anatomy, smooth muscle atrophy, and collagen deposition compared with the vehicle group. The numbers of label-retaining cells (LRCs) coexpressing EdU and differentiated phenotypes (smooth muscle marker α-SMA or Schwann cell marker S100) were significantly higher in the three ICA II-treated groups than those in vehicle group in a dose-dependent manner. In addition, the changing trend of p38 mitogen-activated protein kinase (MAPK) activity in the penis between groups was same as that of the number of differentiated LRCs. Together, these results suggest that the underlying mechanisms of ICA II in ameliorating erectile function and pathological changes appear to involve enhanced endogenous SCs differentiation, which might be regulated by p38 MAPK signaling pathway.

Review of current strategies to induce self-healing behaviour in fibre reinforced polymer based composites

This paper addresses the various strategies to induce self-healing behaviour in fibre reinforced polymer based composites. A distinction is made between the extrinsic and intrinsic healing strategies. These strategies can be applied at the level of the fibre, the fibre/matrix interface or at the level of the matrix. It is shown that the degree of healing depends on the type of damage and the testing mode used and examples are given both for extrinsic and for intrinsic healing systems. The conclusion is drawn that self-healing in fibre reinforced composites is possible yet unlikely to become a commercial reality in the near future.

Flexor tendons repair: Effect of core sutures caliber with increased number of suture strands and peripheral sutures. A sheep model

BackgroundSurgeons have aimed to achieve strong repair so as to begin early active rehabilitation programs for flexor tendon injury. Multi-strand suture techniques were developed to gain improved gap resistance and ultimate force compared with the respective two-strand techniques. In vivo studies indicate that multiple strands may cause ischemia during the intrinsic healing process by decreasing the total cross-sectional area of the injured site, unless the total cross-sectional area of the sutures is not decreased. HypothesisThe hypothesis was to design an in vitro study to understand the biomechanical relationship between suture calibers of core sutures with increased number of suture strands and peripheral suture on final repair strength. Materials and methodsSixty fresh sheep forelimb flexor digitorum profundus tendons were randomly placed into three groups (A, B, and C), each containing 20 specimens, for tendon repair. Two-, four-, and eight-strand suture techniques were respectively used in Groups A, B, and C. A simple running peripheral suture technique was used in Subgroups A2, B2, and C2. For each repaired tendon, the 2-mm gap-formation force, 2-mm gap-formation strength, maximum breaking force and maximum breaking strength were determined. ResultsDifferences in 2-mm gap-formation force and 2-mm gap-formation strength were found between Subgroups A1 and A2, B1 and B2, and C1 and C2. Between Groups A and B, A and C, and B and C, there was no difference as well. ConclusionBoth the number of strands and the ratio between the total suture volume and tendon volume at the repair site are important for ideal repair. If the total cross-sectional area of the sutures is equal in 2-strand, 4-strand, and 8-strand procedure, there is no difference in the strength of the repair. A decrease in caliber size suture requires more passes to achieve the same strength. Instead, it is much better to use peripheral suture techniques to improve the strength of the repair with larger diameter 2-strand core sutures.

Bioengineered Skin Substitute Considerations in the Diabetic Foot Ulcer

Diabetes constitutes a global emergency with case numbers increasing exponentially every year. Diabetic foot ulcers are the leading cause of nontraumatic lower limb amputations. A complex background of pathophysiologic events has been identified with advances in molecular biology such that newer interventions are possible. Bioengineered skin substitutes currently play an important role in the diabetic foot ulcer, particularly in the "stalled" wounds that fail to show progress in their healing trajectory. However, newer designs and scaffold incorporation may herald a new generation of products with more focused targeting of these pathophysiologic events. The major background impairment is that of vasculogenesis brought about as a direct result of hyperglycemia, advanced glycation end product/methylglyoxal generation, and its direct effect on endothelial progenitor cell production and attraction to the wound site. At the same time, glycation end products affect immunity and inflammation, increasing the susceptibility to infection. Thus, reactive oxygen species scavengers, methylglyoxal scavengers, vascular endothelial growth factor stimulators as well as various lipids and neuropeptides are all potential agents that could be incorporated into such templates. The logical sequence of events and possible interventions is detailed. In this manner, intrinsic healing is encouraged in preference to our current attempts at adding unknown quantities of specialized cellular and growth factor components which seem to provide very temporary advantages.